WO1999060051A2

WO1999060051A2 - Low friction hydrophilic surfaces

Info

Publication number: WO1999060051A2
Application number: PCT/US1999/011085
Authority: WO
Inventors: Milos Sovak
Original assignee: Biophysica, Inc.
Priority date: 1998-05-19
Filing date: 1999-05-18
Publication date: 1999-11-25
Also published as: EP1003806A2; WO1999060051A3; AU4005199A; CA2306146A1

Abstract

Novel manufactures are provided having surfaces which upon contact with water promptly provide for high and permanent lubricity. The surfaces involve a carboxylic acid functionality which at least in part is present as an ester and/or amide and/or salt. Various polymers are used with a wide variety of solid polymeric carriers. The surfaces may be achieved by applying a solution onto the carrier and then heating, by coextrusion of the coating and the carrier or by contacting the carrier with the polymer.

Description

LOW FRICTION HYDROPHILIC SURFACES

INTRODUCTION

BACKGROUND

There is a large number of applications requiring a substantial lowering of friction between a device and an aqueous milieu. There are many potential uses for a mechanically resistant, slippery surface in medicinal, naval and other applications of hydrodynamics. In moving an object actively through water, a low drag is desirable for maximum speed, and best propelling economy. In medical use, for interventional and diagnostic use, tubes, catheters, or other devices must be directed atraumatically into precisely defined locations within the extra- and intra-vascular spaces. Such devices should interact with the host as little as possible, especially avoiding inducing rapid blood clotting in the vessels and/or irritation in other bodily ducts or cavities, by damaging their cellular lining. Also, the insertion and negotiation of multiple turns and bends with catheters in the tortuous vasculature is facilitated by a highly slippery surface.

In surgical suturing, it is desirable to inflict as little trauma as possible on the sewn tissues. Braided surgical sutures induce considerable friction and special care is required to prevent the thread from cutting through fragile tissues. Heretofore, no lubricious threads have been described and no threads have been modified to provide highly lubricious, hydrophilic surgical sutures. Medical tubes and catheters covered with different polymeric compositions inducing slipperiness in water milieu have been described. The previous compositions have had numerous drawbacks. In many cases they may require wetting before use and often are impermanent, unstable, or difficult to prepare. Low friction string guides for vascular catheters are in clinical use (Terumo Corp.), but the technology is not applicable to tubes for catheters; the guides consist of a metallic wire embedded in a polyurethane, containing 40% tungsten, and are coated with a hydrophilic polymer. While the polymer induces high slipperiness, it can be mechanically sheared off, which carries a risk of vascular embolization. (Prewitt, KC, et al., Catheterization and Cardiovascular Diagnosis, (1993) 27-9).

There is a clear need for compositions and methods to provide for mechanically stable lubricious surfaces which are amenable to use in a variety of environments. These compositions could find use in reducing the drag on surfaces, such as with vessels and devices, to maintain linear flow in tubes and pipes to give a high flow output, to enhance the mechanical and physiological properties of medical devices, such as urological and vascular tubes and catheters, various implantates and surgical sutures.

RELEVANT T TTEK ATT T E

Various lubricious coatings have been reported in U. S. Patent Nos. 5,001,009; 5,331,027; 5,531,715; 5,603,991; and 5,662,960, and references cited therein, and EPA 0 586 324. See also Mathis et al., American Society of Neuroradiology (1997) 18:1087-1091.

SUMMARY OF THE INVENTION Manufactures having high lubricity and compositions for providing such manufactures are provided by modifying the surface of a substrate by attaching a covalently bound layer or coextruding the substrates with appropriate polymeric hydrophilic laminating compositions comprising a carboxylic functionality containing monomer. The resulting surfaces are mechanically stable, abrasion resistant, have high lubricity, and find application in a wide variety of environments, both industrial and medical. Particularly, a copolymer of methyl vinyl ether and maleic anhydride, e.g. available under the trademark Gantrez® (available from Dajac, Inc. and GAF), are used in combination with hydroxyl or ammo-containing (amino including imino) carriers, under conditions of covalent bonding, where the functionalities are present as part of the carrier or introduced as a result of using a mixture of polymers; or a combination of hydroxyalkyl, methylcellulose and acrylate-butadiene-styrene ("ABS") polymer for extrusion coating; or apolyhydroxyamine salt of a carboxylic ionomer applied as a non-covalent laminate to any retaining carrier.

FSrttTPTTON OF THE SPECIFIC EMBODIMENTS In accordance with the subject invention, manufactures having highly lubricious surfaces are provided on a wide variety of substrates, particularly devices, where the resulting surface has good mechanical, biological, physiological, and chemical properties. The products are characterized by having two polymeric compositions cross-linked by virtue of a carboxylic acid ester or amide, fused together by coextrusion or having an amine salt of a carboxylic ionomeric copolymer applied to form a laminate, where the exposed surface is highly lubricious. Depending upon the particular laminating composition, carrier and device, the composition may be layered onto the substrate, with or without covalent bonding, or coextruded as a coating.

For covalent bonding or coextrusion, a wide variety of carrier materials may be employed, usually rigid or semi-rigid plastic materials, thermoplastic or thermosetting, which may be addition or condensation polymers, such as polyethylene, polypropylene, polyurethane, polyvinyl chloride, polyvinylidene chloride, polyamides, such as various nylons, e.g. 6,6; 6,4, etc. acrylics, polyethylene-vinyl alcohol, polyimides, etc. The surfaces may take the shape of films, formed objects, threads, including individual, braided and woven threads, tubes, pipes, sheets, etc. Thus, the device may be a suture, pipe, channel for the transport of liquids, stents, catheter balloons, implantables, nasogastric and endotracheal tubes, as well as other devices where a lubricious surface is required which is resistant to removal by wet abrasion, such as ship hulls, water propellers, torpedoes, etc.

The compositions which are employed use combinations of materials where the combination may be a reactive carrier or a mixture of two materials to be fused by coextrusion onto the carrier or the arnine salt of a carboxylic ionomer copolymer to be layered on a mechanically retaining surface. The compositions are characterized by being hydrophilic, by involving a macromolecule which comprises available carboxyl functionalities and a second macromolecule which comprises hydroxyl and/or amino functionalities which are available for reaction with the carboxylic group at an elevated temperature, or an amine for forming a salt. The first composition to be described employs a copolymer of methyl vinyl ether and maleic anhydride ("MEMA"). The copolymer may be a random or block, straight or branched chain copolymer, including the commercially available polymers under the Gantrez® trademark, where the maleic anhydride may be present in from about 30 to 80 mol. %, more usually from about 40 to 60 mol. %. The polymer will have a weight average molecular weight in the range of from about 5 to 1000 x 10⁴, more usually from about 5 to 200 x l0⁴.

The copolymer is reacted with carriers having available hydroxyl or amino groups, based on their preparation or as a result of mixture or reaction to provide the available functionalities. Compositions of particular interest include polyurethanes and its copolymers, especially with polyamides, such as nylon (Pebax®, Putnam Corp.), 10 -80 weight %, usually 40 -60 weight % of the total polymer, polyamides, e.g. nylons, and polyimides (Putnam Corp.). The carrier polymers which lack the necessary functionalities are selected to provide good bonding or fusion with a polymer having the active hydroxyl and/or amino functionalities

To react it with a plastic carrier, the MEMA may be dissolved in a suitable polar solvent, particularly an organic solvent substantially free of water, such as propylene glycol, ethanol, acetone, etc. e.g. oxygenated solvents. The concentration of the polymer in the solvent is relatively low, generally being under about 5 wt.%, and more than about 1 wt.%, desirably being in the range of about 2 to 3 wt.%. The solution may be applied to the surface by any convenient means, such as dipping, spraying, rolling, etc., followed by evaporation of the solvent and then heating at a temperature in the range of about 110°C to 150°C for sufficient time to produce a lubricious when contacted with an aqueous medium, tenaciously persisting surface, generally at least about 5 minutes, usually at least about 10 minutes, and generally not more than 1 hour, generally not more than about 30 minutes.

If desired, a carrier composition may be modified by being coated with a polymer having available hydroxy and/or amino groups or may be first coextruded with the polymer carrier to provide the available functionalities. Various polymers are available which provide the active functionalities and may be selected according to their extrusion properties and compatibility with the carrier composition. Illustrative polymers include ethylene-(vinyl alcohol) copolymer, the ethylene ranging from about 15 to 50 mol %, usually 20 to 30 mol % (e.g. EVOH by Eval Corp, F104 and 105). Depending on the nature of the polymer, it may be used anywhere in from about 1 to 25 wt. % of the carrier polymer or may be laminated onto the carrier polymer as a layer from about 0.1 to 10 mμ in thickness. The resulting product, particularly the outer laminate, may then be reacted with MEMA to provide the lubricious surface. Another method is to use a combination of macromolecular compositions and coextrude such composition onto the substrate. In a first composition, poly(methyl methacrylate)-butadiene-styrene ("MBS"), available as Paraloid EXL 3691 (Rohm and Haas) is employed with hydroxyalkyl cellulose or methyl cellulose, where the alkyl group is up from 1 to 4, usually 1 to 3 carbon atoms, there being at least 2 carbon atoms between oxy groups. Generally, the weight ratio of the polymer MBS to the hydroxy- or carboxyalkylated cellulose will be 1:1-5, more usually 1 :2-5. For coextrusion, the two components may be combined and melted, generally at a temperature in excess of 150°C, conveniently from about 170°C to 190°C. The composition may then be coextruded onto the carrier generally at a temperature in excess of about 150 °C and less than about 225 °C, desirably less than about 200°C. The coating thickness can be varied widely, generally not exceeding about mμ, more usually not exceeding about 10 mμ, and conveniently in the range of about 1 to 10 mμ.

Another composition which provides for a lubricious surface, applicable to mechanically retaining surfaces, such as braided sutures, is a salt of an ionomer { a copolymer of ethylene and methacrylic acid (e.g. Surlyn 1707, DuPont) containing at least 20 mol % methacrylic acid and not more than about 70 mol % methacrylic acid, usually available as a metal salt, such as sodium}, with an organic polyhydroxylamine, having from 3 to 9, usually 4 to 7 carbon atoms and at least 2 and not more than 7 hydroxyl groups, generally from 3 to 5 hydroxyl groups, such as N-methyl glucamine, tris, glucosamine, aminotetritols, etc. The weight average molecular weight will usually be about 35,000 and not greater than about 250,000, more usually in the range of about 50,000 to 150,000. The organic amine salt may be formed by combining the polymer in an appropriate solvent e.g. aqueous polyethylene glycol, aqueous propylene glycol, water, ethanol, higher alkanols and mixtures thereof. The mixture is maintained at an elevated temperature, generally greater than about 50°C and not more than about 150°C for sufficient time for a reaction to go to completion. The weight ratio of amine to polymer will generally be in the range of about 0.5 to 2 more usually 1 to 2, for example, with Surlyn and N-methyl glucamine, the weight ration is 1:1. The resulting amine salt may be precipitated with any convenient non-solvent, e.g. acetone, the precipitate dried and dissolved in an appropriate solvent as described above.

The effectiveness of the composition in providing for a useful coating is somewhat sensitive to the concentration, and should generally be at least about 15 wt. %, generally about 20 wt. % where significantly higher concentrations do not seem to improve the result. The subject composition finds particular application with braided materials e.g. braided surgical sutures, which may be prepared from polyamides, polyesters, catgut, polyglycolic acid, natural or artificial silks, etc. The device may be coated by any convenient means as described previously, mechanically treated to ensure sufficient penetration, and then dried at an elevated temperature, which will depend in part upon the nature of the solvent, generally being in excess of 50 °C, more usually in excess of 75°C, and generally below about 150°C, for sufficient time to substantially remove all of the solvent.

The subject hydrophilic laminates provide for a plurality of desirable properties. Compared to controls, with the subject compositions when exposed to water, reductions in friction against tissue simulating surfaces have been increased by at least 50%. These subject compositions provide for extremely tenaciously adhering, mechanically stable and slippery compositions, both as inner and outer coatings of tubing, pipes, and the like, as well as other carriers, such as films, sheets, fibers, molded objects, and the like. For many of the subject compositions, high mechanical resistance and low elution of components is provided. In addition, subject compositions have a decreased affinity to cyanoacrylate glues. In interventional procedures requiring injection of these rapidly hardening polymers into the vasculature, particularly in the case of tumors or vascular malformations, the catheter may become glued to the setting embolus, which prevents the atraumatic retrieval of the catheter. Furthermore, among the subject compositions described, coating of surgical braided sutures can be achieved, where the impregnated sutures remaining highly pliable, the coating remains flexible and adhering, being smooth and easily extended through tissue. When tested, the coatings provide for at least a 50% reduction of force with repeated passages through fresh pig skin. Also, the tests in vivo show that the modified sutures induce significantly less acute or chronic inflammatory changes, as contrasted to control sutures which initially induced an inflammatory response. Test and or control sutures (braided silk) were implanted into the muscles of rabbits and the test and/or control sutures were also used to close the incision. After 4 weeks, histological examination revealed that the modified sutures induced practically no acute inflammation compared to the control sutures, which were surrounded by disintegrating leucocytes.

The following examples are offered by way of illustration, and not by way of limitation.

EXAMPLE 1 A commercial copolymer of methyl vinyl ether/maleic anhydride (50/50), approximate mw 100,000 (Gantrez, Dajac Corp.) was dissolved in anhydrous ethanol at 25 °C to make a 2% solution. Test foils and a test tubing made of polyurethane (Texin 5265, Bayer), polyimide (Putnam Corp.)or a polyurethane/nylon polyether block copolymer (Pebax, Putnam Corp.) were suspended in the solution for 20 minutes. The solution was also flushed through the tube lumen. The tubing was air blow dried at 45 °C inside and out and placed in a 125 °C hot air oven for 20 minutes. EXAMPLE 2 Commercial ethylene- vinyl alcohol copolymer (EVOH F101, Eval Corp.) was melted at 160°C-180°C and axially coextruded with polyurethane (Texin 5265, Bayer) as a tube. A layer varying from 2-3 μ in thickness was achieved. Following cooling, the tubing was treated as in Example 1.

EXAMPLE 3 50 g methyl methacrylate-butadiene-styrene (MBS) (Kureha Corp., Japan) of approximately 100,000 mw was melted with 100 g hydroxypropyl methyl cellulose of similar molecular weight (Methocel, van Waters and Rogers) at 170°C-190°C and axially coextruded at 170°C with polyurethane (Texin 5265, Bayer) and/or Ellastolan® (BASF) and/or nylon, to produce a 2-5 μ thick surface.

EXAMPLE 4 100 g of N-methylglucamine was dissolved in 800 mL of PEG (polyethylene glycol 400) with 10% water and under stirring at 100°C, 80 g of copolymer of the ionomer ethylene/methacrylic acid (mw 70,000, 20% content of the methacrylic acid) was added. The salt was precipitated with acetone, dried and dissolved in aqueous polyethylene glycol to make a 20% solution at 24 °C and filled into a 25 cm long trough through which the surgical braided sutures were passed continuously at 1 m min., followed by passage through an aperture of a ring, to force the composition into the braiding and to remove the excess liquid. The thread was dried by continuous passage through an oven at 95 °C, at 1 m/min.

Each of the compositions was tested in a variety of ways.

The compositions of Examples 1 - 4 were tested by placing them between two wet sponges, side-by-side with controls (untreated tubings or foils) and the sponges were clamped together between two plates, the test and /or control materials were then pulled. The minimal force needed to pull the tubes or foils was measured with a dynanometer. As compared to controls, the subject devices had a reduction of friction against the tissue simulating surface of from 50% to 70%. Furthermore, it was found that unless the parameters set forth for combining the coating with the carrier were employed within the ranges given, with lower concentrations, both lubricity and duration were lowered, while with higher concentrations, mechanically unstable thick layer gels were obtained. When the temperature was lower, the reaction did not proceed, while when the temperature was higher, the surface did not become slippery.

In addition, the products of Examples 1 - 4 were tested for mechanical resistance and for elution of the components. The test materials were wetted and wound on a glass cylinder of 1 cm diameter. After drying for 24 h at 35 °C, they were examined under a microscope while scraped. No detachment was observed. The test materials were also suspended into stirred saline at 37°C pH 7-7.4, and samples were taken over 170 hours. No elution of the components was observed with the products, except that about 20%-40% of the cellulosic product of Example 3 was eluted under these test conditions, but sufficient lubricity was maintained.

The product of Example 4 was found to have a smooth surface, where the sutures remained highly pliable and the surface layer did not become brittle. Treatment of silk, polyester, nylon and/or polyglycolate confirmed increasing lubricity, which in addition to the above test was tested dynamometrically by repeated passages of 20 cm long filaments through pig skin, where a reduction in force of 50%- 60% was observed, except with silk where the reduction was on average 70%, and with catgut where the reduction was about 60%. Best impregnation resulted with a 20% salt solution, while higher concentrations did not increase the lubriciousness and substantially lower concentrations reduced the resistance force only by 10%-20%. When the novel sutures were tested in vivo, (by muscle, subcutaneous and cutaneous suturing in rabbits), no acute or chronic inflammatory changes were found, while control sutures induced, at least initially an inflammatory response.

It is evident from the above results, that the subject invention provides for novel manufactures which have high lubricity, mechanical stability, and can find application in a wide variety of environments. The subject compositions may be coated onto solid objects, such as films, fibers, and molded objects, and can also be used to impregnate woven or braided objects. These products find use in commercial applications and medical applications. The foregoing descriptions of specific embodiments of the present invention have been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching. The embodiments were chosen and described in order to best explain the principles of the invention and its practical application, to thereby enable others skilled in the art to best use the invention and various embodiments with various modifications as are suited to the particular use contemplated. It is intended that the scope of the invention be defined by the Claims appended hereto and their equivalents.

Claims

WHAT TS CLAIMED IS:

1. A manufacture, having a lubricious organic adhering surface when contacted with water, said adhering surface comprising carboxyl functionalities, comprising:

(a) a solid polymeric carrier comprising at least one of reactive amino or hydroxyl groups to which are covalently bonded a copolymer of methyl vinyl ether and maleic anhydride, as a result of heating said polymeric carrier with said copolymer; or

(b) a solid polymeric carrier on which is laminated a mixture formed by heating a methyl methacrylate-butadiene-styrene copolymer with an hydroxy- or carboxyalkyl cellulose, wherein said alkyl group is of from 1 to 4 carbon atoms; or

(c) a solid polymeric suture on which is coated a polyhdroxyamine salt of a copolymer of ethylene and methacrylic acid.

2. A manufacture according to Claim 1, wherein said manufacture is (a) and said polymeric solid carrier comprises polyurethane, polyimide, nylon or polyurethane/nylon polyether block copolymer.

3. A manufacture according to Claim 2, wherein said manufacture is made by the process comprising:

coating a dilute solution of said copolymer onto said solid polymeric carrier; and

heating said coated solid polymeric carrier at at least 100┬░C for sufficient time for said copolymer to bond to said solid polymeric carrier.

4. A manufacture according to Claim 2, wherein said solid polymeric carrier comprises a laminate of a polymer ethylene- vinyl alcohol copolymer.

5. A manufacture according to Claim 1 , wherein said manufacture is (b) and said solid polymeric carrier comprises polyurethane, polyurethane-nylon or nylon.

6. A manufacture according to Claim 5, wherein said 1 cellulose is hydroxypropyl methyl cellulose or carboxymethylcellulose.

7. A manufacture according to Claim 5, wherein the weight ratio of said methyl methacrylate-butadiene-styrene copolymer to said hydroxyakyl cellulose is 1:1-10.

8. A manufacture according to Claim 5, wherein said manufacture is produced by the method comprising:

coextruding the polymer of said solid polymeric carrier with said mixture to form a laminate of said mixture on said solid polymeric carrier.

9. A manufacture according to Claim 1 , wherein said manufacture is (c) and said solid polymeric carrier is braided and comprises polyamide, polyester, catgut, polyglycolic acid, natural or artificial silk.

10. A manufacture according to Claim 9, wherein said polymer salt is the N- methyl glucamine salt of ethylene-methacrylic acid copolymer.

11. A manufacture according to Claim 9 produced by the method comprising:

coating a solution of said amine salt of said ethylene-methacrylic acid copolymer onto said solid polymeric carrier; and

heating said coated solid polymer carrier to drive away solvent in said solution.

12. A composition comprising the reaction product of methyl vinyl ether copolymer with a macromolecule selected from the group consisting of polyurethane, polyimide or nylon polyether block copolymer, or mixtures thereof, by heating said methyl vinyl ether copolymer with said macromolecule at a temperature resulting in formation of covalent bonds between said methyl vinyl ether - maleic anhydride copolymer and said macromolecule.

13. A composition comprising the reaction product of methyl vinyl ether - maleic anhydride copolymer and ethylene vinyl alcohol copolymer fused onto a macromolecule, by heating said methyl vinyl ether - maleic anhydride copolymer with said ethylene vinyl alcohol copolymer fused onto said macromolecule at a temperature resulting in formation of covalent bonds between said methyl vinyl ether - maleic anhydride copolymer and said ethylene vinyl alcohol copolymer.

14. A composition comprising the reaction product of methyl methacrylate- butadiene-styrene and an hydroxyalkyl cellulose, wherein said alkyl group is of from 2-4 carbon atoms, said reaction product produced by heating at an elevated temperature sufficient to form covalent bonds between said methyl methacrylate- butadiene-styrene and said hydroxyalkyl cellulose.

15. A composition comprising the N-methyl glucamine salt of ethylene methacrylic acid copolymer.