CA1339091C - Blood compatible, lubricious article and composition and method therefor - Google Patents
Blood compatible, lubricious article and composition and method thereforInfo
- Publication number
- CA1339091C CA1339091C CA000594427A CA594427A CA1339091C CA 1339091 C CA1339091 C CA 1339091C CA 000594427 A CA000594427 A CA 000594427A CA 594427 A CA594427 A CA 594427A CA 1339091 C CA1339091 C CA 1339091C
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- CA
- Canada
- Prior art keywords
- composition
- heparin
- complex
- silicone
- carbon atoms
- Prior art date
- Legal status (The legal status 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 status listed.)
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
- C08L83/04—Polysiloxanes
-
- 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
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- 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
- A61L33/0017—Anticoagulant, e.g. heparin, platelet aggregation inhibitor, fibrinolytic agent, other than enzymes, attached to the substrate using a surface active agent
-
- 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
-
- 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
- A61L33/0047—Enzymes, e.g. urokinase, streptokinase
-
- 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
- A61L2400/00—Materials characterised by their function or physical properties
- A61L2400/10—Materials for lubricating medical devices
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G77/00—Macromolecular compounds obtained by reactions forming a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon in the main chain of the macromolecule
- C08G77/04—Polysiloxanes
Abstract
A leach resistant composition includes a quaternary ammonium complex of heparin and a silicone. A method for applying a coating of the composition to a surface of a medical article is within the purview of the present invention. Medical articles having surfaces which are both lubricious and antithrombogenic, are produced in accordance with the method hereof.
Description
A BLOOD COMPATIBLE, L~J~T~T~ lOu~ ARTICLE
AND C O~ll AND METHOD L~I~;K~ 'OR
K~T~nTlNn OF TTTT~ TNV!i~NTIt)N
1. Field of thl~ Tnvent; mn . This invention relates to medical articles, and more particularly relates to a lubricious and antithrombogenic composition and method for its application to a medical article.
AND C O~ll AND METHOD L~I~;K~ 'OR
K~T~nTlNn OF TTTT~ TNV!i~NTIt)N
1. Field of thl~ Tnvent; mn . This invention relates to medical articles, and more particularly relates to a lubricious and antithrombogenic composition and method for its application to a medical article.
2 . F~ kSTrol1n~ of thf~ Inv~nt ion . Extensive investigations have been undertaken over many years to find material that will be biologically and hemically stable toward body fluids. This area of research has become increasingly important with the 5 development of various objects and articles which may come into contact with blood, such as artificial organs, vascular grafts, probes, ~nnl1l~, catheters and the like.
Synthetic plastics have come to the fore as preferred 10 materials for such articles. ~owever, su~ch materials have the major drawback of being thL. ~,~..ic. Even such plastics as polytetrafluoroetheylene and the silicone rubbers, which are more compatible with blood than most plastics, still show thrombogenic characteristics.
O~ten, use of such articles, as for example, probes, c~nn~ , catheters and the like, include puncture and passage of the article through the skin. Friction between the patient ' 8 skin and the plastic - 2 - ~ 1339091 surface of the article may cause substantial discomfort to the patient. Further, catheters are often used in conjunction with an introducer device which typically ~ n~; nC a soft rubber one-way check valve through which the catheter must be 5 threaded. When one surface of an article must slide across another surface, frictlon may develop which can cause damage to the article. In particular, fragile catheter balloons may be damaged by friction during passage through the valve of the introducer. Thus, both antithrombogenicity and lubricity are 10 highly desirable properties for article surfaces tQ come into contact with blood.
Surfaces may be rendered lubricious by simple application of any common lubricant. Silicone ~oils are generally 15 recognized to be among the best lubricants available.
Application o~ a silicone lubricant to a surface is known to result in significant reduction in the surface drag upon catheter insertion, facilitate catheter placement, and reduce the force required for catheter retraction. However, a 20 silicone lubricant~ ~ coated over a heparïnized surface in accordance with the prior art masks the heparin and severely es its antithrombogenic activity.
Thrombogenicity has conv~nt;nn~lly been counteracted by 25 the use of anticoagulants such as heparin. A variety of hepar;n;7at;rn procedures have been reported For example, Solomon et al., in ~r.s. Patent No. 4,521,564, discloses a method to convalently bond heparin to a polyurethane substrate.
Eriksson et al., in U.S. Patent No. 4,118,485, coats a ~ ' ( 1339091 plastic surface with a comPlex of heparin and either an alkylamine salt or a quaternary amine salt and subsequently stabilizes the heparin by crosslinking with a dialdehyde.
Williams et al., in U.S. Patent No. 4,613,517, reveals a Process for ionically bonding heparin to a polymeric surface including the steps of plasma-treating the surface, absorbing a surface active agent onto the plasma-treated surface, reacting the surface active agent with heparin, and crosslinking the heparin with glutaraldehyde.
Substrates rendered blood compatible by coating with a layer of silicone have been disclosed. Durst et al. in Am. J. of Roent., Radium Ther. and Nuclear Med., 120, 904 (1974) reported that, in vitro, siliconized stainless steel guidewires, polytetrafluoroethylene coated guidewires and polyethylene catheters were hypothrombogenic compared to untreated substrates, but, in vivo in dogs, no antithrombogenic effect was observed except with heparin coated substrates.
McGary et al., in U.S. Patent No. 4,678,660, discloses dipPing a polyurethane substrate into a solution of a complex of heparin and tridodecylmethyl ammonium chloride (TDMAC) in polyurethane to form a layer of ~he complex in polyurethane on the substrate. A lower leach rate of heparin is claimed for the patented product having heparin distributed throughout the polyurethane layer as compared to heparin ionically bonded to TDMAC on the s~face of the polyurethane substrate.
~ ! 'fl339~91 U.S. Patent No. 4,529,614 to 8urns discloses coatings of an anticoagulant and a water soluble copolymeric silicone applied to plastic surfaces. The coatings render the surfaces hydrophobic and dissolve in the blood to impart anticoagulant properties to a sample to be analyzed.
Thus, while the prior art has recognized for many years the desirability of rendering substrate surfaces antithrombogenic or lubricious, there are no reports known to the authors of the simultaneous achievement of both effects. The present invention addresses this need.
SUMMARY OF THE INVENTION
One aspect of the invention is a leach resistant composition including an anticoagulant and a lubricant. The preferred anticoagulant is an ammonium complex of heparin. Preferred complexes are quaternary ammonium complexes having at least one long chain alkyl group on the nitroqen, and preferred lubricants are water insoluble silicones having a viscosity range of about 20 to 1,000,000 centistokes.
In particularly preferred compositions, the complex has three long chain alkyl groups on the nitrogen and the lubricant is a polydimethylsiloxane of viscosity about 1,000 to 60,000 centistokes.
Another aspect of the invention is a medical device adapted for contact with blood. The device includes a medical article, preferably a shaped medical article having a coating of the composltlon of 30 the invention on its surface. Preferred medical ~ 39091 articles are polymeric, most preferably polyolefin or polyurethane. The most preferred article of the invention is a catheter or catheter introducer having a coating of the composition on its surface.
In another aspect of the invention, a method is provided to coat the surface of the article with the composition so that the surface is both antithrom-bogenic and lubricious. In the preferred method, the article is coated by dipping into a solvent solution of the composition.
Thus, the invention solves two problems simultaneously which the prior art has addressed only individually. For example, general int~ravascular catheters coated with the composition of the invention may be inserted easily into the body consequént to the lubricating silicone and, once inserted, exhibit enhanced hemocompatibility consequent to the heparin.
If used as a coating on balloon intravascular catheters, the composition, in addition to the above advantages, provides easier insertion of the balloon segment of the catheter thereby decreasing the potential for damage to the balloon during insertion.
Further, large gauge and/or multilumen catheters coated with the composition of the invention may be inserted through a rubber introducer valve with minimal damage to the balloon and reduced abrasive removal of a heparin coating.
A particular advantage to coating a medical article with the composition of the invention is that the admixture of heparin and sllicone~Provides lubricity due to the silicone with no compromise of 13~9091 the antithrombogenic activity of the heparin. The water insolubility of the silicone renders the composition resistant to leaching by blood so that antithrombogenicity is retained for periods of up to 5 seven days, and even longer, during medical procedures such as long term catheterization.
DETAILED DESCRIPTION OF THE INVENTION
While this invention is satisfied by embodiments in many different forms, there will herein be 10 described in detail preferred embodiments of the invention, with the understanding that the present disclosure is to be considered as eYemplary of the principles of the invention and is not intended to limit the invention to the embodiments described. The 15 scope of the invention will be measurëd by the appended claims and their equivalents.
In one aspect of the present invention, there is provided a medical device having a surface which is both antithrombogenic and lubricious. The device 20 includes a shaped medical article and a leach-resistant composition on the surface thereof, and, lnanother aspect of the invention, there is provided an antithrombogenic and lubricious composition. In still another aspect of the invention, a method for 25 rendering a substrate surface both antithrombogenic and lubricious is provided.
The invention will be described in terms of a tubing, such as a catheter; however, it will be apparent to one ordlnarlly skllled in the art ~hat the 30 substrate may equally be any of a variety of other shaped medical articles. Exemplary, but not limitative, of suitable articles are peripheral and central catheters of all types, including large gauge ~nd multilumen types, introducers and check valves therefor, sheaths, guide wires and stylets. The invention also contemplates applying the composition to either or both of an exterior or interior surface of an article.
The lubricated, antithrombogenic tubing of the invention is preferably made of a polymeric material, though it is appreciated by one skilled in the art that other materials, such as glass, metal or ceramic may be used. Suitable polymers are, for example, polyolefins, such as polyethylene or poly'propylene, polyvinyl resins such as polyvinylchloride, polyvinylacetate, polyvinylidene fluoride and copolymers thereof, f luorinated polymers such as polytetrafluoroethylene (PTPE), fluorinated ethylene-propylene polymer (FEP) and polytrifluorochloro-ethyler.e, polyurethanes, polyamides, silicone elastomers, polystyrenes, styrene-butadiene copolymers, polysiloxane modified polystyrenes and polystyrene-polyolefin copolymers, and thermoplastic interpenetrating network polymers. In addition, the tubing may have an additional coating, such as a hydrogel, on its surface, and the composition of the invention may be applied over the hydrogel coating.
The composition of the invention includes an antithromoogenic agent and a lubricant. ~;xemplary of suitable antithrombogenic agents are prostaglandins, urokinase, streptoklnase, tissue plasminogen~ctivator and heparinoids such as heparin sulfate, dextran ( 1339~91 sulfate and other sulfonated polysaccharides. The preferred antithrombogenic agent is heparin. Although heparin in any form may be admixed with the lubricant, it is preferred to form the composition of the 5 invention from a complex of heparin with an alkylammonium salt of general structure I:
R
Rl --~ -- R4 X
I
wherein Rl may be selected from the group consisting of an alkyl group of about 7 to 18 carbon atoms and R2,R3 and R4 may independently be selected from the group consisting of hydrogen, an alkyl group of 1 to 18 carbon atoms and an aralkyl group of 7 to 18 carbon atoms and X may be a halide ion, such as chloride or bromide.
The Preferred salt to be complexed with heparin is a quaternary ammonium salt of formula I in which Rl,R2,R3 and R4 may independently be an alkyl group, straight chain or branched, of from 1 to 18 carbon atoms, or an aralkyl group of about 7 to 18 carbon atoms and X may be a negative monovalent ion, such as a halide ion. For example, the commercially available quaternary salt benzalkonium chloride wherein Rl is C8H17 ' R2 is C6H5CH2 and R3 and R4 are methyl may be used. In particularly preferred quaternary salts for complexation with heparin, Rl,R2 and R3 may independently be straight chain alkyl groups of from 8 to ~8 ca-rbon 30 atoms and R4 ~ay be lower alkyl group of from 1-4 _ g _ carbon atoms. In the most preferred salt, R1,R2 and R3 are dodecyl groups, R4 is methyl and X
is chloride. This guaternary salt is commonly referred to as TDM~C. Thus, the most Preferred 5 complex has the formula I wherein X is an anion of heparin. Such complexes of heparin are well-known in the art, and are described in McGary et al. and Eriksson et al., supra.
The com~lex as previously described and silicone 10 are mixed to form the composition of the invention.
If the complex has suff icient solubility in the silicone, the mixing may be done merely by dissolving the complex in the silicone at the desired concentration. Preferably, the complex and silicone 15 may be mixed merely by dissolving in an appropriate solvent or solvent system. Use of a solvent is particularly advantageous when a silicone oil of high viscosity is included in the comPOsitiOn. Exemplary of suitable solvents are toluene, petroleum ether, 20 methylene chloride or any one of the fluorinated hydrocarbons conventionally termed Freon . In some cases, it may be desirable to use a more polar solvent such as ethanol or isopropanol in the solvent system to aid in dissolution of the complex. The 25 concentration of the complex in the solvent system is not critical, and may advantageously be from about 0.1 to 5~ by weight. Higher concentration may be used but generally do not provide any advantage. The preferred concentration is f rom about 1-296 . Determination of a 30 suitable solvent and concentration for the complex is well within the purview of one ordinarily skilled in the art.
1339~gl A lubricating oil is added to the solvent solution of the complex. Any water insoluble lubricating oil may be used, as, for example, refined white oil. Preferred lubricants are stable, noncurïng S high purity medical grade silicones such as the polydialkylsiloxanes of formula II:
C~ H3 ~Rl ~ CH3 CH3 -- Si ~ ~ t si - ~ t si CH3 CH3 ~R2 ~ n CH3 II
10 In formula II ' Rl and R2 may be independently an alkyl grouP of from 1 to 20 carbon atoms or taken together may form a ring of frrom 4 to 8 carbon atoms. The number of repeating units, n, is sufficient to provide a viscosity of from about 20 to 1,000,000 centistokes. In particularly preferred Polydialkylsiloxanes of formula II, Rl is methyl and the viscosity is from about 1,000 to 60,000 centistokes. The most Preferred silicones are polydi-methylsidoxanes having a viscosity of from about S,000 to 20,000 as exemplified by the commercially available product DC-360TM available from Dow Corning, Midland, MI.
The quantity of silicone to be added to the solvent solution of the complex may be varied over a wide range. It has been found that a compositlon having as little as 2~ by weight of the silicone, based on the complex, yields a significant improvement in lubricity when applied to the substrate, as described below. On the other hand, as much~s 75~ by 30 welght of sillcone may be advantageous for certain ( i339091 compositions and substrates. A preferred concentration range of silicone may be from about 20-SO~ by weight of the complex.
Application of the composition of complex and S silicone to the substrate may be carried out by any conventional technique. For example, the composition, preferably in the solvent, may be brushed or sprayed onto the substrate. The preferred method of application is merely to immerse the substrate into 10 the solvent containing the composition. If the substrate is a tubing, such as a catheter, and it is desired to ensure that the composition coats the lumen wall, it may be advantageous to draw the composition into the lumen by the application of reduced pressure.
ImmersiOn of the substrate in thé solvent solution of the composition may be carried out at any suitable temperature up to the boiling point of the solvent and may be maintained for any convenient length of time. The time and temperature of contact are not critical, but preferably are about 1 second to 1 hour and ambient temperature.
A~ter withdrawing the substrate from the solution, the solvent may be removed by evaporation.
If desired, the rate of evaporation may be accelerated by application of reduced pressure or mild heat. The coating of the composition applied to the substrate may be of any convenient thickness, and in practice, the thickness will be determined by such factors as the viscosity of the sllicone, the temperature of the aPplication and the rate of withdrawal. rOr most substrates, the film preferably is applled as thinly _ as practical, since no significant advantage is gained by thicker films.
In another embodiment of the invention, the substrate may 5 be treated with a plasma prior to application of the composition. This ~mbodiment of the invention is particularly advantageous for substrates of very low surface energy, such as the fluorinated polymers as exemplified by PTFE and FEP.
Suitable conditions for plasma treatment of fluorinated 10 surfaces are described in copending ~AnA~l;An application of common assignee, serial number 571, 669 filed July 11, 1988 .
When a substrate is coated with the composition of the invention, the surface of the substrate is rendered both 15 antithrombogenic and lubricious, as tested by conventional methods described in the examples . A 1/16 inch (1. 6 mm) thick natural rubber membrane may be used as a close approximation of human skin for studies simulating the friction or drag which develops when a catheter, introducer, stylet or guide wire is 20 inserted or withdrawn through the skin of a patient.
Antithrombogenicity for the substrates coated with the composition of the invention may be determined by mea~uring clotting times by the standard partial (PTT) and activated~5 partial thromboplastin time (APTT) tests (B.A. Brown, ~to1ogy Pr~ne;~1e~ An8 Proc~ re8, Third Edition, I-ea and Febiger Co., 1980). These tests are qualitative procedures for det~rm-n;n~ the efficacy of TDMAC-heparin, as a raw ~ 339091 material or as a coating. As a measure of the total anti-clotting activity, the APTT can detect the presence of anticoagulants by giving prolonged clotting times. Non-coated control substrates 5 generally give clotting times of between 25 to 40 seconds. The heparinized tubings of the invention give clotting times greater than 1800 seconds.
The stability of the coatings on the substrates may be determined by performing leach rate studies 10 using normal saline as leachant, as described in Example V.
In vivo thrombus_formation on catheters coated with the composition of the inventiori may be determined by the method of solomon et al., J. of Biomedical Materials P~esearch, 21,43 (i987), as described in Example VI.
This invention will be further described by the following examples, which are illustrative only and not to be considered as limitative. In the examples, 20 the percentages of the complex are given as weight percentages based on the solvent, and the percentages of silicone are weight percentages based on the weight of the complex.
EXAMPLE I
To a 1.25% solution of the heparin-TDMAC complex ~Mct:ary et al. supra) in 90:10 ~reonTM TF/petroleum ether (v/v), various percentages by weight of 12,500 centistoke sllicone oil were added. The ~solutions were drawn by application of a sllght vacuu~ lnto the lumens of thermoplastic polyurethane (TP~) catheters of .017 and 0.35 in (.4 and .8 mml inside diameter and 0.92 in (2.3 mm) outside diameter. The solutions were removed and the lumens were dried at 60~C for 24 5 hours. Stylet wires were inserted into the lumens of the catheters and then withdrawn at a constant rate of 50mm/min. The forces required for withdrawal were measured using the Instron~ Universal Testing InstrUment. The results of this experiment are 10 tabulated below in Table I. ~ Trademark TABLE I
WITHDRAWAL FORCEa FOR STYLET WIRE
con~ol ~llicone ~ cone co=ple~ col~ple~ ~nd co~pler ~nd co=pler ~nd only only only 2~ ilicone 10~ ~licone 30~ ~llicone l 5 ~o dny ~q~ng < 85 0.31 0.3s s.20 11.60 0.30 o.2c 5 25 0 ~ C.31 s.30 11 50 1 50 0.12 6.30 0.36 0.39 7 00 11 00 0.7s 0.15 8.30 0.32 0.37 7.90 7 50 1 10 0.13 4 9C 0.39 9.10 7.s0 0 90 9.32 6.7C 0.3s 8.5C 7.7s 1.00 0.33 0.36 0.13 0 3~
6.0s C 32 C.36 7.17 9.51 C 92 C 21 a) all values are in newtons (1 newton = 102g) b ) mean It i8 ~3een that a coating of ~;1; C~n~' only greatly reduces the wi~ rA~-l force (column 2) and that this ef3fect remains sub~3t~nt;~11y unchanged a3cter lB
.. , . . . .. , .. . . ~ . . . . . . .. .... . .. .
. . ~ , q3390gl -- ls --90 days lcolumn 3). Withdrawal forces are somewhat greater when the catheter is coated with the complex only (column 4), and still greater with 2% silicone (column 5). Columns 6 and 7, however, show that very 5 effectiVe lubrication is achieved when higher concentrations of silicone are used, establishing that the complex does not interfere with lubrication by silicone .
EX-MPLE II
Solutions were prepared containing 12.5 g of the TDMAC-heparin complex and DC 360TM silicone oil of 12,500 centistokes viscosity in 1 liter rof 90:10 FreonTM TF/petroleum ether ( v/v ) . Fif teen cm 15 sections of TPU catheters were coated with the composition of the invention by briefly dipping into the solution, quickly withdrawing in less than one second, and drying at 60~C for 24 hours. The catheter sections were pulled at a constant speed of 50 mm/min 20 through the rubber check valve of a catheter introducer and the drag forces measured on an Instron universal Testing Instrument. The results of this experiment are shown in Table II.
TAi~L E I I
2 s cl~rB~r~R COATIN~ ~
COn~rOI COnt~OI CO~PIeK COnPIeK CO-PI~K compl~K CO~PI~ CO~PIeY
}P~K ~IIICOn~ ~nd 2.9B~ nnd 7.50- ~nd l<.B~ ~nd 2~.76~ ~nd ~.6~ ~nd 7S.C~
OnIY b OnlY C ~ On~ ~llCOn~ ~LIiCOn~ ~il;COn~ ~ili~One ~ COne 561 332 2BO 277 22~ 2~3 127 I~B
30 600 168 . 316 2~B 2C9 le9 122 ,,_ ill ~OB 15~ ~03 306 311 178 139 1~2 ~8~ 257 2Be 301 21~ IB7 111 97 --- ISB ~17 306 286 --- 112 10 513 21~ 3~1 2BB 2~9 199 133 120 133g~9~
a) all drag force values are given in grams b) coated from a 1.25% solution of the complex in 1 liter of 90:10 FreonT TF-petroleum ether c) coated from a 2~6 solution of silicone in Freon TF
d ) mean It is seen from Table II that as little as 2.9896 of silicone oil in the composition reduces the drag force from an average of 513 grams to 341 grams, and that when the silicone percentage is raised to 75~ by weight of the complex, the drag force is reduced to 120 grams, or about 2096 of the control. As observed in ~xample I, the presence of the complex does not interfere with the lubricating propertyf of the sillcone.
EXAMPLE I I I
Pieces of TPU catheter tubing 15 cm long were coated with TDMAC-heparin complex and benzalkonium-heparin complex by the procedure of Example II using the solvents and silicones indicated in Table III. The coefficients of friction of these tubings were determined by a Friction Drag Test ~ccessory to the Instron Universal Testing InstrUment. The results of this experiment are tabulated in Table III.
-- ( 1335~91 TABLE III
TUBING FRICTION
~--t Control T17!1AC-hep.rin ~en~-lk -hep~r~n ~Dh~C-hep~rin ~ cone ~2 NO. ~I b C l,oood 12,500d 1.7~ 2.~2 2 1.57 2.42 1.~2 I.5s 1.~ 2.06 0.96 0.6s 1.~6 ~ 73 1.~6 1.96 0.18 0.56 5I.~s 1.89 1.79 1.8~ 0.69 0.70 lo ~ ,.0O 1.6a 1 ~3 1.86 0.86 o.5s 71 31 1.69 1.53 2.07 o.7s 0.63 a) toluene-petroleum ether b) FreonTM TF-petroleum ether ~' c) isopropanol , 15 d j viscosity in centistokes It is seen from Table III that a coating of heparin complex increases friction over conteol value, but that a co2ting of the compositions having the complex admixed with silicone reduces friction EXAMPLE IV
Pieces of TP~ catheter tubing 15 cm long were coated with the TDMAC-heparin complex ( 30 ug/cm2 ~
admixed with silicone of 12,500 centistoke viscosity by dipping into FreonTM Ti~ solutions and drying for 24 hours at 60~C. A 78 gram weight was aPplied to a natural rubber membrane, and the membrane was dragged across the catheters. Coefficients of fri<3t~0n were determined with the Instron Universal Testing ( 1339091 Instrument .
Clotting times for these coated catheter sections were determined by the standard APTT. The results of this experiment are shown in Table IV.
TABLE IV
silicone coefficient of APTT
f riction ( sec ) 0 1.35 1800 2 0.63 1800 0 . 25 1800 0.28 1800 0 . 16 1800,' 0 . 19 1800 0 . 13 1800 100 0.077 33 Table IV shows that the coefflcient of friction decreases with increasing percentage of silicone, but no decrease is seen in clotting time up to 50~
silicone percentage, showing that the anticoagulant 25 effect of the heparin is not compromised by the silicone .
~XAMPLE V
LEACH RATE STUDY
Sectlons of TPU catheters 15 cm long were coated 30 with the TDMAc-heparin complex containing ~itiated heparin, with and without admLxed sillcone oil, by 1~339091 dipping into 2.0 or 1.25 weight percent solutions of the TDMAC complex in the solvents indicated in Tables V and VI. The sections were dried for 24 hours at 60~C, and the quantity of heparin on the catheter 5 surfaces was determined (by liquid scintillation counting and comparison with a standard curve) and expressed as ug heparin/cm2. The coated sections were dynamically leached in 1 1 of normal saline using an incubator shaker at 37~C and 150 rpm for up to 10 seven days. Saline was changed daily, and samples were removed every 24 hours and tested for heparin remaining. PTT ~ind APTT times were also determined.
The results of this experiment are given in Tables V ~APTT times) and Table VI ~ leach rate 15 study). All PTT times for all catheter sections were greater than 1800 sec. APTT times are tabulated in Table V and heparin remaining is shown in Table VI.
TABLE V
APTT TIMES ~in seconds)f 20 D~y~ ~ ~o~pl~ S~ ~o~ple~ 5~ ~:o~pl~ 7;25~ill ,p~,~b jo75 jlorpi~b iOiS I)I p~,~b 0 I~C0 1~00 l~on(6~ oO 1~00 1-00 1~00 1~00 Ii~00~ l-C0 50.5~1 S~.l 160.
~oo(~ 00 1~00~6) i~00 1~00 ,.0~ -D.0 ~00 1~00 1~00 _ 1~00 00~ 00~) 1-0015) 1~00~
1~0~ 0.~1) 7~0.0(1) 7~0.0(1) S60.0 37 I~OO (i') 75.Dil) ~.7 I DD~i~
a) in toluene - petroleum ether . .. . ..... _ _ .... _ _ . _ _ _ .. ..... _ _ _ _ _ 1~390gl b) in FreonTM - ~etroleum ether ~ Numbers in parenthesis indicate the number of test samples to obtain results. Unmarked results are from a sample size of three. Where more than one S sample was used, the clotting time given in the chart is the mean.
TABLE VI
LEACE.7 RATE STUDY
77eparin Remaining ( ug/cm2 ) 10 D~r- 2~ COllpl~l- 1.25~ co~pl~l~ 1.2~ pl~lb li25~ co~pl~ 1 25~ eo ~1 Ib ~ 25~io pl,lb 0 ".~ ,.. .... ~ s~ .7 ,. ~.ss ~-.~s , o. ~.C7 ,Ø . 2~ .. 72 ,2.. 7 2Q . 22 s -2 7 ,~ 7.-0 15 , s so . 2. sØ - s -s 5.~ 1 77 , 77 ~ s~ 1.72 ~,5~
7 ~ ~s 2 .s ~ os 2 ~7 2 ~. . "
a) in toluence - petroleum ether b) in FreonT - Petroleum ether The results of Example V show that even when the heparin remaining on the catheter sections has been reduced to as low as 2-3 ug~cm2 by a seven day saline leach, the PTT and APTT times are still more than 1800 seconds. ~
.
~ ' ~339091 p-1253 EXAMPLE VI
TPU catheters (16 gauge) were coated with the heparin-silicone composition of the invention and studied by the in vivo method for evaluation of 5 catheter thrombogenicity of Solomon et al. (supra).
Uncoated TPU catheters and polyvinyl chloride catheters (PVC, 16 gauge) served as controls in this experiment. Counts were plotted against time and the curve slopes were determined.
TABLE VII
Catheter Material Slope PVC 0 . 118 + 0 . 077 TPU 0.077 + 0.042 heparinized TPU 0.012 + 0.010 15 The signif icant decreases in the number of counts (deposited platelets) with time is readily apparent from the lower slope of the curve with the heparinized TPU of the invention.
Thus, in accordance with the invention, the 20 surfaces of medical articles adapted for contact with blood and f riction-generating movement across another surface or a patient's skin may be coated with a composition of anticoagulant, preferably heparin, and silicone. The heparin provides blood compatibllity 25 and the silicone provides lubricity without i~~any way compromising the antlcoagulant activity of the ~ 1~39091 _ 22 --heparin. secause the silicone is water insoluble, the composition is resistant to leaching by the blood and remains on the surface of the device for prolonged periods. This is a particular advantage for medical S procedures, such as long term catheterizations, and provides both safety and comfort to the patient.
f ,,
Synthetic plastics have come to the fore as preferred 10 materials for such articles. ~owever, su~ch materials have the major drawback of being thL. ~,~..ic. Even such plastics as polytetrafluoroetheylene and the silicone rubbers, which are more compatible with blood than most plastics, still show thrombogenic characteristics.
O~ten, use of such articles, as for example, probes, c~nn~ , catheters and the like, include puncture and passage of the article through the skin. Friction between the patient ' 8 skin and the plastic - 2 - ~ 1339091 surface of the article may cause substantial discomfort to the patient. Further, catheters are often used in conjunction with an introducer device which typically ~ n~; nC a soft rubber one-way check valve through which the catheter must be 5 threaded. When one surface of an article must slide across another surface, frictlon may develop which can cause damage to the article. In particular, fragile catheter balloons may be damaged by friction during passage through the valve of the introducer. Thus, both antithrombogenicity and lubricity are 10 highly desirable properties for article surfaces tQ come into contact with blood.
Surfaces may be rendered lubricious by simple application of any common lubricant. Silicone ~oils are generally 15 recognized to be among the best lubricants available.
Application o~ a silicone lubricant to a surface is known to result in significant reduction in the surface drag upon catheter insertion, facilitate catheter placement, and reduce the force required for catheter retraction. However, a 20 silicone lubricant~ ~ coated over a heparïnized surface in accordance with the prior art masks the heparin and severely es its antithrombogenic activity.
Thrombogenicity has conv~nt;nn~lly been counteracted by 25 the use of anticoagulants such as heparin. A variety of hepar;n;7at;rn procedures have been reported For example, Solomon et al., in ~r.s. Patent No. 4,521,564, discloses a method to convalently bond heparin to a polyurethane substrate.
Eriksson et al., in U.S. Patent No. 4,118,485, coats a ~ ' ( 1339091 plastic surface with a comPlex of heparin and either an alkylamine salt or a quaternary amine salt and subsequently stabilizes the heparin by crosslinking with a dialdehyde.
Williams et al., in U.S. Patent No. 4,613,517, reveals a Process for ionically bonding heparin to a polymeric surface including the steps of plasma-treating the surface, absorbing a surface active agent onto the plasma-treated surface, reacting the surface active agent with heparin, and crosslinking the heparin with glutaraldehyde.
Substrates rendered blood compatible by coating with a layer of silicone have been disclosed. Durst et al. in Am. J. of Roent., Radium Ther. and Nuclear Med., 120, 904 (1974) reported that, in vitro, siliconized stainless steel guidewires, polytetrafluoroethylene coated guidewires and polyethylene catheters were hypothrombogenic compared to untreated substrates, but, in vivo in dogs, no antithrombogenic effect was observed except with heparin coated substrates.
McGary et al., in U.S. Patent No. 4,678,660, discloses dipPing a polyurethane substrate into a solution of a complex of heparin and tridodecylmethyl ammonium chloride (TDMAC) in polyurethane to form a layer of ~he complex in polyurethane on the substrate. A lower leach rate of heparin is claimed for the patented product having heparin distributed throughout the polyurethane layer as compared to heparin ionically bonded to TDMAC on the s~face of the polyurethane substrate.
~ ! 'fl339~91 U.S. Patent No. 4,529,614 to 8urns discloses coatings of an anticoagulant and a water soluble copolymeric silicone applied to plastic surfaces. The coatings render the surfaces hydrophobic and dissolve in the blood to impart anticoagulant properties to a sample to be analyzed.
Thus, while the prior art has recognized for many years the desirability of rendering substrate surfaces antithrombogenic or lubricious, there are no reports known to the authors of the simultaneous achievement of both effects. The present invention addresses this need.
SUMMARY OF THE INVENTION
One aspect of the invention is a leach resistant composition including an anticoagulant and a lubricant. The preferred anticoagulant is an ammonium complex of heparin. Preferred complexes are quaternary ammonium complexes having at least one long chain alkyl group on the nitroqen, and preferred lubricants are water insoluble silicones having a viscosity range of about 20 to 1,000,000 centistokes.
In particularly preferred compositions, the complex has three long chain alkyl groups on the nitrogen and the lubricant is a polydimethylsiloxane of viscosity about 1,000 to 60,000 centistokes.
Another aspect of the invention is a medical device adapted for contact with blood. The device includes a medical article, preferably a shaped medical article having a coating of the composltlon of 30 the invention on its surface. Preferred medical ~ 39091 articles are polymeric, most preferably polyolefin or polyurethane. The most preferred article of the invention is a catheter or catheter introducer having a coating of the composition on its surface.
In another aspect of the invention, a method is provided to coat the surface of the article with the composition so that the surface is both antithrom-bogenic and lubricious. In the preferred method, the article is coated by dipping into a solvent solution of the composition.
Thus, the invention solves two problems simultaneously which the prior art has addressed only individually. For example, general int~ravascular catheters coated with the composition of the invention may be inserted easily into the body consequént to the lubricating silicone and, once inserted, exhibit enhanced hemocompatibility consequent to the heparin.
If used as a coating on balloon intravascular catheters, the composition, in addition to the above advantages, provides easier insertion of the balloon segment of the catheter thereby decreasing the potential for damage to the balloon during insertion.
Further, large gauge and/or multilumen catheters coated with the composition of the invention may be inserted through a rubber introducer valve with minimal damage to the balloon and reduced abrasive removal of a heparin coating.
A particular advantage to coating a medical article with the composition of the invention is that the admixture of heparin and sllicone~Provides lubricity due to the silicone with no compromise of 13~9091 the antithrombogenic activity of the heparin. The water insolubility of the silicone renders the composition resistant to leaching by blood so that antithrombogenicity is retained for periods of up to 5 seven days, and even longer, during medical procedures such as long term catheterization.
DETAILED DESCRIPTION OF THE INVENTION
While this invention is satisfied by embodiments in many different forms, there will herein be 10 described in detail preferred embodiments of the invention, with the understanding that the present disclosure is to be considered as eYemplary of the principles of the invention and is not intended to limit the invention to the embodiments described. The 15 scope of the invention will be measurëd by the appended claims and their equivalents.
In one aspect of the present invention, there is provided a medical device having a surface which is both antithrombogenic and lubricious. The device 20 includes a shaped medical article and a leach-resistant composition on the surface thereof, and, lnanother aspect of the invention, there is provided an antithrombogenic and lubricious composition. In still another aspect of the invention, a method for 25 rendering a substrate surface both antithrombogenic and lubricious is provided.
The invention will be described in terms of a tubing, such as a catheter; however, it will be apparent to one ordlnarlly skllled in the art ~hat the 30 substrate may equally be any of a variety of other shaped medical articles. Exemplary, but not limitative, of suitable articles are peripheral and central catheters of all types, including large gauge ~nd multilumen types, introducers and check valves therefor, sheaths, guide wires and stylets. The invention also contemplates applying the composition to either or both of an exterior or interior surface of an article.
The lubricated, antithrombogenic tubing of the invention is preferably made of a polymeric material, though it is appreciated by one skilled in the art that other materials, such as glass, metal or ceramic may be used. Suitable polymers are, for example, polyolefins, such as polyethylene or poly'propylene, polyvinyl resins such as polyvinylchloride, polyvinylacetate, polyvinylidene fluoride and copolymers thereof, f luorinated polymers such as polytetrafluoroethylene (PTPE), fluorinated ethylene-propylene polymer (FEP) and polytrifluorochloro-ethyler.e, polyurethanes, polyamides, silicone elastomers, polystyrenes, styrene-butadiene copolymers, polysiloxane modified polystyrenes and polystyrene-polyolefin copolymers, and thermoplastic interpenetrating network polymers. In addition, the tubing may have an additional coating, such as a hydrogel, on its surface, and the composition of the invention may be applied over the hydrogel coating.
The composition of the invention includes an antithromoogenic agent and a lubricant. ~;xemplary of suitable antithrombogenic agents are prostaglandins, urokinase, streptoklnase, tissue plasminogen~ctivator and heparinoids such as heparin sulfate, dextran ( 1339~91 sulfate and other sulfonated polysaccharides. The preferred antithrombogenic agent is heparin. Although heparin in any form may be admixed with the lubricant, it is preferred to form the composition of the 5 invention from a complex of heparin with an alkylammonium salt of general structure I:
R
Rl --~ -- R4 X
I
wherein Rl may be selected from the group consisting of an alkyl group of about 7 to 18 carbon atoms and R2,R3 and R4 may independently be selected from the group consisting of hydrogen, an alkyl group of 1 to 18 carbon atoms and an aralkyl group of 7 to 18 carbon atoms and X may be a halide ion, such as chloride or bromide.
The Preferred salt to be complexed with heparin is a quaternary ammonium salt of formula I in which Rl,R2,R3 and R4 may independently be an alkyl group, straight chain or branched, of from 1 to 18 carbon atoms, or an aralkyl group of about 7 to 18 carbon atoms and X may be a negative monovalent ion, such as a halide ion. For example, the commercially available quaternary salt benzalkonium chloride wherein Rl is C8H17 ' R2 is C6H5CH2 and R3 and R4 are methyl may be used. In particularly preferred quaternary salts for complexation with heparin, Rl,R2 and R3 may independently be straight chain alkyl groups of from 8 to ~8 ca-rbon 30 atoms and R4 ~ay be lower alkyl group of from 1-4 _ g _ carbon atoms. In the most preferred salt, R1,R2 and R3 are dodecyl groups, R4 is methyl and X
is chloride. This guaternary salt is commonly referred to as TDM~C. Thus, the most Preferred 5 complex has the formula I wherein X is an anion of heparin. Such complexes of heparin are well-known in the art, and are described in McGary et al. and Eriksson et al., supra.
The com~lex as previously described and silicone 10 are mixed to form the composition of the invention.
If the complex has suff icient solubility in the silicone, the mixing may be done merely by dissolving the complex in the silicone at the desired concentration. Preferably, the complex and silicone 15 may be mixed merely by dissolving in an appropriate solvent or solvent system. Use of a solvent is particularly advantageous when a silicone oil of high viscosity is included in the comPOsitiOn. Exemplary of suitable solvents are toluene, petroleum ether, 20 methylene chloride or any one of the fluorinated hydrocarbons conventionally termed Freon . In some cases, it may be desirable to use a more polar solvent such as ethanol or isopropanol in the solvent system to aid in dissolution of the complex. The 25 concentration of the complex in the solvent system is not critical, and may advantageously be from about 0.1 to 5~ by weight. Higher concentration may be used but generally do not provide any advantage. The preferred concentration is f rom about 1-296 . Determination of a 30 suitable solvent and concentration for the complex is well within the purview of one ordinarily skilled in the art.
1339~gl A lubricating oil is added to the solvent solution of the complex. Any water insoluble lubricating oil may be used, as, for example, refined white oil. Preferred lubricants are stable, noncurïng S high purity medical grade silicones such as the polydialkylsiloxanes of formula II:
C~ H3 ~Rl ~ CH3 CH3 -- Si ~ ~ t si - ~ t si CH3 CH3 ~R2 ~ n CH3 II
10 In formula II ' Rl and R2 may be independently an alkyl grouP of from 1 to 20 carbon atoms or taken together may form a ring of frrom 4 to 8 carbon atoms. The number of repeating units, n, is sufficient to provide a viscosity of from about 20 to 1,000,000 centistokes. In particularly preferred Polydialkylsiloxanes of formula II, Rl is methyl and the viscosity is from about 1,000 to 60,000 centistokes. The most Preferred silicones are polydi-methylsidoxanes having a viscosity of from about S,000 to 20,000 as exemplified by the commercially available product DC-360TM available from Dow Corning, Midland, MI.
The quantity of silicone to be added to the solvent solution of the complex may be varied over a wide range. It has been found that a compositlon having as little as 2~ by weight of the silicone, based on the complex, yields a significant improvement in lubricity when applied to the substrate, as described below. On the other hand, as much~s 75~ by 30 welght of sillcone may be advantageous for certain ( i339091 compositions and substrates. A preferred concentration range of silicone may be from about 20-SO~ by weight of the complex.
Application of the composition of complex and S silicone to the substrate may be carried out by any conventional technique. For example, the composition, preferably in the solvent, may be brushed or sprayed onto the substrate. The preferred method of application is merely to immerse the substrate into 10 the solvent containing the composition. If the substrate is a tubing, such as a catheter, and it is desired to ensure that the composition coats the lumen wall, it may be advantageous to draw the composition into the lumen by the application of reduced pressure.
ImmersiOn of the substrate in thé solvent solution of the composition may be carried out at any suitable temperature up to the boiling point of the solvent and may be maintained for any convenient length of time. The time and temperature of contact are not critical, but preferably are about 1 second to 1 hour and ambient temperature.
A~ter withdrawing the substrate from the solution, the solvent may be removed by evaporation.
If desired, the rate of evaporation may be accelerated by application of reduced pressure or mild heat. The coating of the composition applied to the substrate may be of any convenient thickness, and in practice, the thickness will be determined by such factors as the viscosity of the sllicone, the temperature of the aPplication and the rate of withdrawal. rOr most substrates, the film preferably is applled as thinly _ as practical, since no significant advantage is gained by thicker films.
In another embodiment of the invention, the substrate may 5 be treated with a plasma prior to application of the composition. This ~mbodiment of the invention is particularly advantageous for substrates of very low surface energy, such as the fluorinated polymers as exemplified by PTFE and FEP.
Suitable conditions for plasma treatment of fluorinated 10 surfaces are described in copending ~AnA~l;An application of common assignee, serial number 571, 669 filed July 11, 1988 .
When a substrate is coated with the composition of the invention, the surface of the substrate is rendered both 15 antithrombogenic and lubricious, as tested by conventional methods described in the examples . A 1/16 inch (1. 6 mm) thick natural rubber membrane may be used as a close approximation of human skin for studies simulating the friction or drag which develops when a catheter, introducer, stylet or guide wire is 20 inserted or withdrawn through the skin of a patient.
Antithrombogenicity for the substrates coated with the composition of the invention may be determined by mea~uring clotting times by the standard partial (PTT) and activated~5 partial thromboplastin time (APTT) tests (B.A. Brown, ~to1ogy Pr~ne;~1e~ An8 Proc~ re8, Third Edition, I-ea and Febiger Co., 1980). These tests are qualitative procedures for det~rm-n;n~ the efficacy of TDMAC-heparin, as a raw ~ 339091 material or as a coating. As a measure of the total anti-clotting activity, the APTT can detect the presence of anticoagulants by giving prolonged clotting times. Non-coated control substrates 5 generally give clotting times of between 25 to 40 seconds. The heparinized tubings of the invention give clotting times greater than 1800 seconds.
The stability of the coatings on the substrates may be determined by performing leach rate studies 10 using normal saline as leachant, as described in Example V.
In vivo thrombus_formation on catheters coated with the composition of the inventiori may be determined by the method of solomon et al., J. of Biomedical Materials P~esearch, 21,43 (i987), as described in Example VI.
This invention will be further described by the following examples, which are illustrative only and not to be considered as limitative. In the examples, 20 the percentages of the complex are given as weight percentages based on the solvent, and the percentages of silicone are weight percentages based on the weight of the complex.
EXAMPLE I
To a 1.25% solution of the heparin-TDMAC complex ~Mct:ary et al. supra) in 90:10 ~reonTM TF/petroleum ether (v/v), various percentages by weight of 12,500 centistoke sllicone oil were added. The ~solutions were drawn by application of a sllght vacuu~ lnto the lumens of thermoplastic polyurethane (TP~) catheters of .017 and 0.35 in (.4 and .8 mml inside diameter and 0.92 in (2.3 mm) outside diameter. The solutions were removed and the lumens were dried at 60~C for 24 5 hours. Stylet wires were inserted into the lumens of the catheters and then withdrawn at a constant rate of 50mm/min. The forces required for withdrawal were measured using the Instron~ Universal Testing InstrUment. The results of this experiment are 10 tabulated below in Table I. ~ Trademark TABLE I
WITHDRAWAL FORCEa FOR STYLET WIRE
con~ol ~llicone ~ cone co=ple~ col~ple~ ~nd co~pler ~nd co=pler ~nd only only only 2~ ilicone 10~ ~licone 30~ ~llicone l 5 ~o dny ~q~ng < 85 0.31 0.3s s.20 11.60 0.30 o.2c 5 25 0 ~ C.31 s.30 11 50 1 50 0.12 6.30 0.36 0.39 7 00 11 00 0.7s 0.15 8.30 0.32 0.37 7.90 7 50 1 10 0.13 4 9C 0.39 9.10 7.s0 0 90 9.32 6.7C 0.3s 8.5C 7.7s 1.00 0.33 0.36 0.13 0 3~
6.0s C 32 C.36 7.17 9.51 C 92 C 21 a) all values are in newtons (1 newton = 102g) b ) mean It i8 ~3een that a coating of ~;1; C~n~' only greatly reduces the wi~ rA~-l force (column 2) and that this ef3fect remains sub~3t~nt;~11y unchanged a3cter lB
.. , . . . .. , .. . . ~ . . . . . . .. .... . .. .
. . ~ , q3390gl -- ls --90 days lcolumn 3). Withdrawal forces are somewhat greater when the catheter is coated with the complex only (column 4), and still greater with 2% silicone (column 5). Columns 6 and 7, however, show that very 5 effectiVe lubrication is achieved when higher concentrations of silicone are used, establishing that the complex does not interfere with lubrication by silicone .
EX-MPLE II
Solutions were prepared containing 12.5 g of the TDMAC-heparin complex and DC 360TM silicone oil of 12,500 centistokes viscosity in 1 liter rof 90:10 FreonTM TF/petroleum ether ( v/v ) . Fif teen cm 15 sections of TPU catheters were coated with the composition of the invention by briefly dipping into the solution, quickly withdrawing in less than one second, and drying at 60~C for 24 hours. The catheter sections were pulled at a constant speed of 50 mm/min 20 through the rubber check valve of a catheter introducer and the drag forces measured on an Instron universal Testing Instrument. The results of this experiment are shown in Table II.
TAi~L E I I
2 s cl~rB~r~R COATIN~ ~
COn~rOI COnt~OI CO~PIeK COnPIeK CO-PI~K compl~K CO~PI~ CO~PIeY
}P~K ~IIICOn~ ~nd 2.9B~ nnd 7.50- ~nd l<.B~ ~nd 2~.76~ ~nd ~.6~ ~nd 7S.C~
OnIY b OnlY C ~ On~ ~llCOn~ ~LIiCOn~ ~il;COn~ ~ili~One ~ COne 561 332 2BO 277 22~ 2~3 127 I~B
30 600 168 . 316 2~B 2C9 le9 122 ,,_ ill ~OB 15~ ~03 306 311 178 139 1~2 ~8~ 257 2Be 301 21~ IB7 111 97 --- ISB ~17 306 286 --- 112 10 513 21~ 3~1 2BB 2~9 199 133 120 133g~9~
a) all drag force values are given in grams b) coated from a 1.25% solution of the complex in 1 liter of 90:10 FreonT TF-petroleum ether c) coated from a 2~6 solution of silicone in Freon TF
d ) mean It is seen from Table II that as little as 2.9896 of silicone oil in the composition reduces the drag force from an average of 513 grams to 341 grams, and that when the silicone percentage is raised to 75~ by weight of the complex, the drag force is reduced to 120 grams, or about 2096 of the control. As observed in ~xample I, the presence of the complex does not interfere with the lubricating propertyf of the sillcone.
EXAMPLE I I I
Pieces of TPU catheter tubing 15 cm long were coated with TDMAC-heparin complex and benzalkonium-heparin complex by the procedure of Example II using the solvents and silicones indicated in Table III. The coefficients of friction of these tubings were determined by a Friction Drag Test ~ccessory to the Instron Universal Testing InstrUment. The results of this experiment are tabulated in Table III.
-- ( 1335~91 TABLE III
TUBING FRICTION
~--t Control T17!1AC-hep.rin ~en~-lk -hep~r~n ~Dh~C-hep~rin ~ cone ~2 NO. ~I b C l,oood 12,500d 1.7~ 2.~2 2 1.57 2.42 1.~2 I.5s 1.~ 2.06 0.96 0.6s 1.~6 ~ 73 1.~6 1.96 0.18 0.56 5I.~s 1.89 1.79 1.8~ 0.69 0.70 lo ~ ,.0O 1.6a 1 ~3 1.86 0.86 o.5s 71 31 1.69 1.53 2.07 o.7s 0.63 a) toluene-petroleum ether b) FreonTM TF-petroleum ether ~' c) isopropanol , 15 d j viscosity in centistokes It is seen from Table III that a coating of heparin complex increases friction over conteol value, but that a co2ting of the compositions having the complex admixed with silicone reduces friction EXAMPLE IV
Pieces of TP~ catheter tubing 15 cm long were coated with the TDMAC-heparin complex ( 30 ug/cm2 ~
admixed with silicone of 12,500 centistoke viscosity by dipping into FreonTM Ti~ solutions and drying for 24 hours at 60~C. A 78 gram weight was aPplied to a natural rubber membrane, and the membrane was dragged across the catheters. Coefficients of fri<3t~0n were determined with the Instron Universal Testing ( 1339091 Instrument .
Clotting times for these coated catheter sections were determined by the standard APTT. The results of this experiment are shown in Table IV.
TABLE IV
silicone coefficient of APTT
f riction ( sec ) 0 1.35 1800 2 0.63 1800 0 . 25 1800 0.28 1800 0 . 16 1800,' 0 . 19 1800 0 . 13 1800 100 0.077 33 Table IV shows that the coefflcient of friction decreases with increasing percentage of silicone, but no decrease is seen in clotting time up to 50~
silicone percentage, showing that the anticoagulant 25 effect of the heparin is not compromised by the silicone .
~XAMPLE V
LEACH RATE STUDY
Sectlons of TPU catheters 15 cm long were coated 30 with the TDMAc-heparin complex containing ~itiated heparin, with and without admLxed sillcone oil, by 1~339091 dipping into 2.0 or 1.25 weight percent solutions of the TDMAC complex in the solvents indicated in Tables V and VI. The sections were dried for 24 hours at 60~C, and the quantity of heparin on the catheter 5 surfaces was determined (by liquid scintillation counting and comparison with a standard curve) and expressed as ug heparin/cm2. The coated sections were dynamically leached in 1 1 of normal saline using an incubator shaker at 37~C and 150 rpm for up to 10 seven days. Saline was changed daily, and samples were removed every 24 hours and tested for heparin remaining. PTT ~ind APTT times were also determined.
The results of this experiment are given in Tables V ~APTT times) and Table VI ~ leach rate 15 study). All PTT times for all catheter sections were greater than 1800 sec. APTT times are tabulated in Table V and heparin remaining is shown in Table VI.
TABLE V
APTT TIMES ~in seconds)f 20 D~y~ ~ ~o~pl~ S~ ~o~ple~ 5~ ~:o~pl~ 7;25~ill ,p~,~b jo75 jlorpi~b iOiS I)I p~,~b 0 I~C0 1~00 l~on(6~ oO 1~00 1-00 1~00 1~00 Ii~00~ l-C0 50.5~1 S~.l 160.
~oo(~ 00 1~00~6) i~00 1~00 ,.0~ -D.0 ~00 1~00 1~00 _ 1~00 00~ 00~) 1-0015) 1~00~
1~0~ 0.~1) 7~0.0(1) 7~0.0(1) S60.0 37 I~OO (i') 75.Dil) ~.7 I DD~i~
a) in toluene - petroleum ether . .. . ..... _ _ .... _ _ . _ _ _ .. ..... _ _ _ _ _ 1~390gl b) in FreonTM - ~etroleum ether ~ Numbers in parenthesis indicate the number of test samples to obtain results. Unmarked results are from a sample size of three. Where more than one S sample was used, the clotting time given in the chart is the mean.
TABLE VI
LEACE.7 RATE STUDY
77eparin Remaining ( ug/cm2 ) 10 D~r- 2~ COllpl~l- 1.25~ co~pl~l~ 1.2~ pl~lb li25~ co~pl~ 1 25~ eo ~1 Ib ~ 25~io pl,lb 0 ".~ ,.. .... ~ s~ .7 ,. ~.ss ~-.~s , o. ~.C7 ,Ø . 2~ .. 72 ,2.. 7 2Q . 22 s -2 7 ,~ 7.-0 15 , s so . 2. sØ - s -s 5.~ 1 77 , 77 ~ s~ 1.72 ~,5~
7 ~ ~s 2 .s ~ os 2 ~7 2 ~. . "
a) in toluence - petroleum ether b) in FreonT - Petroleum ether The results of Example V show that even when the heparin remaining on the catheter sections has been reduced to as low as 2-3 ug~cm2 by a seven day saline leach, the PTT and APTT times are still more than 1800 seconds. ~
.
~ ' ~339091 p-1253 EXAMPLE VI
TPU catheters (16 gauge) were coated with the heparin-silicone composition of the invention and studied by the in vivo method for evaluation of 5 catheter thrombogenicity of Solomon et al. (supra).
Uncoated TPU catheters and polyvinyl chloride catheters (PVC, 16 gauge) served as controls in this experiment. Counts were plotted against time and the curve slopes were determined.
TABLE VII
Catheter Material Slope PVC 0 . 118 + 0 . 077 TPU 0.077 + 0.042 heparinized TPU 0.012 + 0.010 15 The signif icant decreases in the number of counts (deposited platelets) with time is readily apparent from the lower slope of the curve with the heparinized TPU of the invention.
Thus, in accordance with the invention, the 20 surfaces of medical articles adapted for contact with blood and f riction-generating movement across another surface or a patient's skin may be coated with a composition of anticoagulant, preferably heparin, and silicone. The heparin provides blood compatibllity 25 and the silicone provides lubricity without i~~any way compromising the antlcoagulant activity of the ~ 1~39091 _ 22 --heparin. secause the silicone is water insoluble, the composition is resistant to leaching by the blood and remains on the surface of the device for prolonged periods. This is a particular advantage for medical S procedures, such as long term catheterizations, and provides both safety and comfort to the patient.
f ,,
Claims (10)
1. A composition for coating a polymeric surface comprising a mixture of a quaternary ammonium complex of heparin and about 2 to 75% by weight of a noncuring lubricating silicone, said complex having the formula wherein R1, R2, R3 and R4 are independently selected from the group consisting of an alkyl group of 1 to about 18 carbon atoms and an aralkyl group of about 7 to 18 carbon atoms and H- is a negative ion of heparin, said silicone having a viscosity of about 20 to 1,000,000 centistokes.
2. The composition of claim 1 wherein said silicone is a polydialkyl siloxane.
3. The composition of claim 2 wherein said siloxane has a viscosity of about 1,000 to 60,000 centistokes.
4. The composition of claim 2 wherein said siloxane is a polydimethylsiloxane.
5. The composition of claim 4 wherein said polydimethysiloxane has a viscosity of about 5,000 to 20,000 centistokes.
6. The composition of claim 1 wherein R1, R2 and R3 are independently alkyl groups selected from the group having from 8 to 18 carbon atoms.
7. The composition of claim 1 wherein R1, R2 and R3 are dodecyl and R4 is methyl.
8. A composition for coating a polymeric surface comprising a mixture of noncuring lubricating oil and an ammonium complex of heparin, said complex having the formula wherein R1 is selected from the group consisting of an alkyl group of about 7 to 18 carbon atoms and R2, R3 and R4 are independently selected from the group consisting of hydrogen, an alkyl group of 1 to 18 carbon atoms and an aralkyl group of 7 to 18 carbon atoms, and H- is a negative ion of heparin.
9. A composition for coating a polymeric surface comprising a mixture of a quaternary ammonium complex of heparin and about 20 to 50% by weight of a noncuring lubricating polydimethylsiloxane, said complex having the formula wherein R1, R2 and R3 are independently selected from the group consisting of a straight chain alkyl group of 8 to 18 carbon atoms, R4 is selected from the group consisting of a lower alkyl group of 1 to 4 carbon atoms, and H- is a negative ion of heparin, said polydimethysiloxane having a viscosity of about 1,000 to 60,000 centistokes.
10. The composition of claim 9 wherein R1, R2 and R3 are dodecyl, R4 is methyl and said polydimethylsiloxane has a viscosity of about 10,000 to 20,000 centistokes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US182,694 | 1988-04-18 | ||
| US07/182,694 US5013717A (en) | 1988-04-18 | 1988-04-18 | Blood compatible, lubricious article and composition and method therefor |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1339091C true CA1339091C (en) | 1997-07-29 |
Family
ID=22669608
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000594427A Expired - Fee Related CA1339091C (en) | 1988-04-18 | 1989-03-22 | Blood compatible, lubricious article and composition and method therefor |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US5013717A (en) |
| EP (1) | EP0338418B1 (en) |
| JP (1) | JPH02147694A (en) |
| AT (1) | ATE110285T1 (en) |
| CA (1) | CA1339091C (en) |
| DE (1) | DE68917631T2 (en) |
| ES (1) | ES2056999T3 (en) |
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-
1988
- 1988-04-18 US US07/182,694 patent/US5013717A/en not_active Expired - Lifetime
-
1989
- 1989-03-22 CA CA000594427A patent/CA1339091C/en not_active Expired - Fee Related
- 1989-04-13 DE DE68917631T patent/DE68917631T2/en not_active Expired - Fee Related
- 1989-04-13 AT AT89106582T patent/ATE110285T1/en not_active IP Right Cessation
- 1989-04-13 EP EP89106582A patent/EP0338418B1/en not_active Expired - Lifetime
- 1989-04-13 ES ES89106582T patent/ES2056999T3/en not_active Expired - Lifetime
- 1989-04-18 JP JP1098656A patent/JPH02147694A/en active Granted
Also Published As
| Publication number | Publication date |
|---|---|
| ES2056999T3 (en) | 1994-10-16 |
| DE68917631T2 (en) | 1995-02-09 |
| JPH0587120B2 (en) | 1993-12-15 |
| EP0338418B1 (en) | 1994-08-24 |
| JPH02147694A (en) | 1990-06-06 |
| US5013717A (en) | 1991-05-07 |
| EP0338418A1 (en) | 1989-10-25 |
| ATE110285T1 (en) | 1994-09-15 |
| DE68917631D1 (en) | 1994-09-29 |
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