CA1255235A

CA1255235A - Thermoplastic polyurethane anticoagulant alloy coating

Info

Publication number: CA1255235A
Application number: CA000496315A
Authority: CA
Inventors: Charles W. Mcgary; Donald D. Solomon
Original assignee: Deseret Medical Inc
Current assignee: Deseret Medical Inc
Priority date: 1984-12-07
Filing date: 1985-11-27
Publication date: 1989-06-06
Also published as: AU576132B2; HK48091A; EP0184465A2; AU5051185A; EP0184465B1; DE3576279D1; EP0184465A3; US4678660A

Abstract

ABSTRACT OF THE DISCLOSURE
An antithrombogenic thermoplastic polyurethane product and process for preparing the same which com-prises a substrate and at least one layer of a poly-urethane alloy complex comprising a thermoplastic polyurethane and completely dispersed therein a pre-formed complex of an antithrombogenic material ionically bonded with a quaternary ammonium compound.

Description

The present invention relate~ to a novel thermo-pla~tic polyurethane product and proces~ for making the ~ame. More particularly the invention relate~ to a polyurethane pro~uct having an an~i~hrombogenic and/or antibiotic alloy complex material bound thereto ~o that the material is permanently af~xed to the polyurethane ~ub~trate and remain~ leachable over prolonged periods ~when the product~ are in u~e.
Extensive investigation~ have been undertaken over many year.q to find materials that will be biologically and chemically -qtable toward~ body fluids~ Thi~ area of research ha~ become increa.~ingly important with the deveIopment of variou~ objects and arti~les which can be in contac~ with blood, such a~ artificial organ~t va~cular graft~, probe~, cannula~, catheters, hyperalimentation catheter~ and other long indwelling vascular catheter3, and the like.
Artificial material~ are being increa~ingly u~ed a3 blood cantact devices and may be subject to poten-tial generation of thrombus and bacterial infection.
When blood contact~ foreign material~ a complex serie~
of events occur. The~e involve protein deposition, cellular adhesion and aqgregation, and activation of blood coagulation scheme~. Con3iderable re.qearch effort has been focused on this blood-material-interaction in the la~t twenty year~ ag well a~
bacterial infection associated with such device~0 The overall objective of the3e investigation~ ha~ been to minimize the potential for thrombus formation and reduce potential bacterial infection found on the foreign materials, such a~ the device when introduced into the body upon contact with blood~
Variou~ method3 have been devised for producing such a material, mo~t of which involve chemically . ~ 9~

5S~ 5 bonding a quaternary ammonium salt to the polymer and then hepariniZin~ the 3ame. Separately, antibiotic~
have been coupled to these devices using similar technique~. U~ually, thi3 i9 done by incorporating an amine in the polymer, quaternizing the amine, and then - heparinizin~ or bonding an antiobiotic to the q uaternized mate~ial~
In one method taught by R. Io Leininger and G. A.
Grode, U.S. Patent 3,457,098, a quaternary amine i9 incorporated into an epoxy resin. Subsequent exposure to ~odium heparinate then resulta in ionically bound heparin. The polymer 3y3tem~ are ea~entially epoxy re~in~ which are rigid polymer3 which are not suitable for forming medical davice3 ~uch as catheters or other devices requiring extru~ion. These polymers also are not appropriate where flexibility in the device i9 required.
R. I. Leininger and R. D. Falb, di~close in U.S0 Patent 3,617,344 another proces~ ~or binding heparin.
This ~y~tem differs ~rom the previou~ ~ystem, in that, low molecular weight chloromethyl group~ are ad~orbed to the surface of a polymer substrate. Sub~equent amination by a tertiary amin0 and quarternization resulted in a po~itively charged aur~ace for binding with heparin. The concept, in general, embodies the use of low molecular weight quaternized group3 to ionically bind heparin.
UuS. Patsnt 3,846,353 to Grotta involve3 use of long chain alkyl quaternary amines on the surface of a polymer wherein the positively charged 3urface is expo~ed to a 301ution of ~odium heparinate. ThiJ
re~ulted in ionically bound heparin. Example ~II of this patent diacus~e3 the preparation of a complex of tridodecylmethyl ammonium chloride (TDMAC) and sodium - heparinate. The latter is commonly known as the one-3~ep TDMAC-Heparin proces3. An article by G. A. Grove (J. Biomed. Mat. Res. Symp. No. 3, PP. 7784, 1972) ~J ;`
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describ~s thi~ ~ethod in more d~t~il. The resultant coating from the Grotta method i~ a waxy leachable anticoagulant ~urface. The primary de~iciency of the Grotta method iq that the coating has relatively qhort-lived anticoagulant efficacy.
s-P.so Yen and A. Rembau~ prepared a neutral poly-urethane ela~tomer which is sub~equently quaternized and ionically bonded to heparin, U.S. Patent 3,853,804.
The main di~advantage of this sy~tem i9 that it i3 a chemical complex and toxic ~olvent~ are u~ed to achieve ~olubility when coating (~ee Example 8) The coating technique, however, i~ dif~icult to perform due to the solvent (DMF) requirement. The patent of N. ~arumiya et al. U.S. Patent No. 3,844,989 describe~ a polymer compo~ition of ~ater-in~oluble cationic copolymer~q having hydrophilic component3, quaternary amine group~
and hydrophobic moietie~. Heparin i9 bonded ionically to the quaternary ammonium group~ via ab~orption after the polymer component~ are contacted with a heparin qolution. Thi~ method involve~ a series of complex ~ynthe~is procedures and i~ not readily applicable to coating other polymeric or non-polymeric material~q.
In contrast, U.S. Patent 4,4~2,133 to Greco discloses a method of preparing a ~urgical va~cular graft wherein a length of graft material carries an ab~orbed coating of tridodecylmethylammonium chloride (TDMAC) ~qurfactant and an antibiotic bound thereto. A length of graft material such a~ polytetraflouroethylene or Dacron*i~
~oaked in a 5% by weight solution of TDMAC for 30 minutes at room temperature, air dried and then wa~hed in distilled water to remove exceq~ TDMAC. The graft carrying the ab~orbed TDMAC surfactant coating i~ then incubated in a solution of negatively charged antibiotic for one hour, wa~hed in ~teril~ water to remove unbound antibiotic and ~tored for u~e in the operating room.
Similar to the Greco US Patent, R. A. Harvey * trade ~ark ~, di~close~ in "~ntibiotic bond~ng to polytetra~luoroethylene with tri~odecylmethylammonium chlorlde", _u~ Vol. 92, p504-512 (1982) Polytetrafluoroethylene (PTFE) treated with tridodecylmethylammonium chloride (TDMAC) is shown to bind penicillin wherea~ untreated PTFE OR PTFE treated with anionic detergent3 Ahows little biodlng of antibiotic. TDMAC treated PTFE concomitantly bind~ penicillin and heparin, generating a ~urface that potentially can reqiqt both infection and thrombosis. The retention of these biologically active mole-cules is not due to uassive entrapment in the PTFE but reflect~an ionic interaction between the anionic ligands and surface-bound TDMAC.
It would be de~irable to provide a material which has excellent biological and chemical ~tability towards body fluids, namely blood and which retains its antithrombogenic agent and antibiotic effect for a long term while being slowly leachable when in contact with blood. It would also be desir-able to provide material~ which, while being biocompatible, - are also biofunctional, that is materlals which have biological activity in a variety of functions.
The present invention accompli~he~ all of these needs by use of an antithrombogenic antibiotic thermopla~tic poly-urethane alloy system. More particularly the invention involves a thermoplastic polyurethane product po~sessing long term antithrombogenic and antibiotic propertie~, comprising (a) a polyurethane alloy complex formed in a sol~ent solution;
(b3 the polyurethane allsy complex includlng (1) a thermoplastic rm/

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polyurethane (2) a material d.~s~ersed throughout the thermo-plastic polyurethane; (3) the disper3ed material being ~elected from the group con~isting of an antithrombogenic material, an antibiotic material, and mixtures thereof (4) the dispersed material lonically bonded to the thermoplastic polyurethane by a quaternary ammon~um compound (c) a ~olid polyurethane sub~trate separate from the thermopla~tic polyurethane in the polyurethane alloy complex comprised of a material not ~oluble in the solvent qolution for the polyurethane alloy complex;
and (d) the polyurethane alloy complex being in the form of a qurface layer on the separate polyurethane ~ubstrate~
In another embodiment, the present invention involves a method for producing a thermoplastic polyurethane product possessing long-term antithrombogenlc and antibiotic properties, comprising the steps of (a) selecting a thermoplastic poly-urethane; (b) selecting a material from the group consi~ting of an antithrombogenic material, an antibiotic material and mixtures thereof; (c) selecting a quaternary ammonium compound;
(d) coupling the material from step (b) with the quaternary ammonium compound from step (c); (e) adding the thermoplastic polyurethane from step (a), and the material from step (d) to an organic ~olvent ~olution (f) dispersing the material from step (d) throughout the material from step (a) to form a polyurethane alloy complex solutiono, (g) ~electing a solid article compri3ed of a polyurethane not soluble in the organic ~olven~ solution from step (e); (h~ coating the surface of the solid article from the fourth selecting ~tep with the solution from ~tep (f): and (i) removing the solvent solution ...
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from the co~ted 3urface formed in Qtep ~h) to form a solld sub~trate of the article compri~ed of polyurethane having di~posed on the surface thareof a layer of an alloy complex including polyurethane qeparate from the polyurethane in the article.
The term antithrombogenic agent or material as u3ed herein refers ~o any material which inhibits thrombus formation on its surface, ~uch a~ by reducing ~latelet aggregation, dissolving fibrin, enhancing pas~ivating protein deposition, or inhibiting one or more stepq within ~he coagulation ca~cade and which form an ionic complex with quaternary ammonium salts.
Illustrative antithrombogenic materials may be ~elected from the group con~isting of heparin, prostaglandins, sulfated polysaccharide, and mixture~ thereof. Heparin i~ preferred.
It should be under~tood that the~e material~ are uqed in their natural form or a~ salt~ thereof, ~uch as the sodium, or lithium salt~. In addition to the foregoing antithrombogenic agents, optional qupplemental amounts of antithrombogenic agent~ may al~o be used that are not reactive within the scope of the invention to further enhance the effect~ of the alloy complexed materials. Exemplary materials include urokinase, ~treptokinas2, albumin and so forth.
The term antibiotic agent or material a~ u~ed herein refers to any material ~hich inhibits bacterial infection.
Illu~trative antibiotic materialq may be selected from a ~ide range of material~ that have a reactive carboxylic functionality~
- Exemplary material~ may be ~elected from the group consisting of penicillin, oxacillin, ticarcillin, carbenicillin, cephalosporins, ,.,~, ~

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cefo~itin, cefazolin, dicloxacillin, cloxacillin, and clavulanic acid, and mixtures thereof.
The alloy 3y~telll of thi~ invention i3 an improve-ment o~er other ionic/leachable antithrombog~3nic ~ystems. By combining the quaternary ammoni~m/anti-biotic compleY with the thermopla~tic polyurethane coating the permanerlcy of the coating i~ ~ignificantly enhanced. In vitro permanency testing under seYere ionic condition~ and ln vitro coaqulation testing both demon~trats a sub3tantial increa~e in permanency of the alloy sy~tem over the one-step ionic process with no reduction in antithrombogenic/antibiotic activity. The compo~ition~and proce~ of thi~ invention may be u~ed to effect a durable antithrombogenic/antibiotic coating on polymer ~urface~. The antithrombogenic/antibiotic coated polymer~ impart non-thromobogenic/antibiotic character and have the potential to reduce thrombo-embolic complications and infection~ commonly associated with long term in-dwelling catheter~.
The polyurethane polymer~ u~ed in the invention a~ the support ~tructure may be qelected from ~ wide range of thermopla~tic polyurethane polymer~. The particular formation~ do not constitute a critical aspect of thi~ invention other than to ~erve a~ a support sub3trate for the antithrombogenic/antibiotic alloy complex. The polyurethane~ are preferably preformed into the de~ired ~hape or ~tructure for the particular application prior to treatment according to the invention. Of ~ignificant importance i9 the ability of the polyurethane ~upport to adhere with the antithrombogenic/antibiotic alloy complex without becoming deformed when the complex i~ applied to the ~ub~trate. It ha~ been found that polyurethane polymer~ may be u~eable a~ ~upport~ which have average molecular weight~ different from the polyurethane~ u~ed to form the alloy complex and which permit the polyurethane ~upport to not di~solve in the organic 3L2S~ rj -lol~nt for the complex. Thi~ distinction i9 critical to enable coating of preformed ~upports wlthout ~eformation ~hile permitting a layer Oe alloy complex to b~ chemically co~lpled ~o the support ~ltructure. In th;~ manner, all ;ntegral unit i~ ~orm~d whi~h will not separate upon use~
The antithrombogenic/antibiotic alloy complex i~
formed by di~solving in an organic solvent the antithrombogenic agent and/or antibiotic material and a ~uitable polyurethane polymer. When the preferred an~ithrombogenic agent i~ heparin which i~ ~oluble for all practical purposes only in water, only a poor disper~ion results when lleparin i3 mixed in organic solvent~. Accordingly, it iq nece3~ary to modify the heparin to render it ~oluble in the organic solvent.
Thi~ i3 done by reacting the heparin, in an aqueous solutiont with a primary alkylammonium ~alt in an organic ~olvent to form a heparinalkylammonium complex compound having a low water solubility~ It is desired to let this reaction proceed so far so that substantially all the anionic group~ in the heparin molecule have reacted with the alkylammonium ions. The best way of having the reaction proceed so far as to produce complete blocking iq to have the alkylammonium salt be present in a quantity at least corresponding to the number of heparin anionic groups which are present in the ~olution ~rom which the complex can be ~eparated into th~ organic pha~e.
A particularly preferred family of quaternary ammonium compound~ useable in the invention are long chain alkyl quaternary ammon~um ~alts of heparin. The salt may have 2 to 4 long chain alkyl groups attached to the nitrogen atom, the alkyl groups having from about 10 to about 30 carbon atom~. The alkyl group~
can be like or unlike. The remaining groups may be hydrogen, lower alkyl, aryl and aryl alkyl groups.
The ammonium cation is not critical and ia pre~erably ~S5;~;~5 chlorine. The~e compounds are generally obtained by he~ting together a tertiary amine and an alkyla~ing clgent to thereby produce the quarteLnary ammonium 3alt by ~tand~rd technique~ well known to the ordinary 3killed ~rtiqan~ Preferred quaternary ammonium compound~ are selected from the group con~i~tlng of tridodecylmethyl ammonium salt~, and tetradodecyl ammonium salt~ and mixturea thereof.
The alloy coating sy3tem may be prepared ~rom any suitable organic ~olvent that i~ capable o~ di~solving both the antithrombogenic agent/antibiotic agent and the second polyurethane polymer without chemically modifying either material. Preferred solvents have high vapor pre~ure which aid~ in reducing ~olvent evaporation/drying timeO Exemplary, non-lim~ting compound~ include hexane and methylene chlorideO
The alloy 3y~tem i~ prepared such that the final weight ratio of thermopla~tic polyurethane to antithro~bogenic agent/antibiotic ia 10 1 to 1:5, preferably from 401 to 1:2 and mo~t preferably 2:1 to 1:1. At ratios above 10:1 there is in~ufficient antithro~bogenic agent and/or antibiotic agent pre~ent to provide antithrombogenic and anti-infection efficacy. At ratio~ below 1:5 insufficient polyurethane is present to provide a suitable film caating.
The polyurethane polymers u~ed to form the support a~ well a~ the alloy complex may be selected from a wide range of materials which contain conventional polyi~ocyanate~, low molecular weight qlycols and high molecular weight glycols.
The polyi~ocyanates useful in the invention in introd~cing the urethane linkage into the polymer chain may be selected from a wide range of aliphatic, cycloaliphatic and aromatic polyi~ocyanates. Useable dii~ocyanates may contain noninterfering groups, e.gq, aliphatic hydrocarbon radicals Quch aQ lower alkyl or 12S~ t~

other groups, having ~ubstantially nonreactive hydro~
gens a~ determined by the Zerewitino~f te~t, J. Am.
Chem. Soc. 49,3181 (1927). The dii~ocyanate o~ten ha~
at lea~t 6 carbon atom3 and usually does not have more than about 40 carbon atoms. Dii~ocyanates of about 8 to 20 atoms in the hydrocarbon group are preferred.
Suit~ble dii~ocyanate~ include 2,4-toluene diisocyanate,

2,6toluene diisocyanate; 1,4-cyclohexane dii~ocyanate, dicyclohexylmethane 4,4'-diisocyanate, xylene diisocya-nate 1-isocyanate-3-i~ocyanatomethyl-3,5,5-trimethyl-cyclohexane: hexamethylene dii~ocyanate, methylcyclo-hexyl diisocyanate: 2,4,4-trimethylhexyl-methylene diisocyanate, i30cyanates such a~ m-phenylene dii~ocya nate, mixtures of 2,4- and 2,6 hexamethylene-1,5-dii~o-cyanate; hexahydrotolylen~ diisocyanate (and i~omer~), naphtylene-1,5-dii~ocyanate l-methoxyphenyl 2,4-di330 cyanate, diphenylmethane 4,4'-diisocyanate, 4,4'-biph-enylene diisocyanate, 3,3'-dimethoxy -4.4biphenyl diisocyanate, 3,3' dimethyl - 4,4'-biphenyl diisocyanaté, and 3,3'dimethyl-diphenylmethane - 4,4'dii~ocyanate and mixture~ thereof. The aliphatic and alicyclic diisocyanates employed in the process of thi~ invention - and the products made therefrom generally exhibit good resistance to the degradative effect~ of ultraviolet light.
The polyisocyanate component used to form the prepolymers may contain a portion of polyisocyanates having more than two isocyanate (NC0) group3 per mole-cule providing the urethane polymer compo3itions are not unduly deleteriously affected. The preferred polyiso-cyanate i~ selected from the group consisting of 4,4l_ diphenylmethane diisocyanate, toluene dii~ocyanate, i~ophorone dii~ocyanate and methylene bis (4-cyclo-hexyl) dii~ocyanate.
The low molecular weight glycola may al30 be used to prepare the prepolymer which material~ may have from 2 to 10 carbon atom3. Exemplary of these glycol~ are 1~
ethylene glycol, diethylene glycol, triethylene glycol~q, 1,4-butanediol, neopentyl glycol, 1,6-hexanedLol, 1,2-and 1,3-propylene glycol, 2,3-butylene glycol, cyclo-hexane dimethanol (1,4-bi~ hydroxymethyl cyclohexatle), dip~opylene glycol, and dibutylene glycol.
The high molecular weight glycols useful in the present invention may be a polyether diol or polye3ter diol and range in number average molecular weight from about 400 to about 3,000 and preferably about 500 to about 2,000. Exemplary of the polyols which may be em-ployed to prepare polyester polyolq are l,6-hexanediol!
neopentyl trimethylol propane, ethylene glycol, diethy-lene glycol, triethylene glycol, 1,4-butanediol, 1,4-cyclohexane, 1,2-propanediol, 1,3-propanediol, 1,3-butylene glycol, 1,4-cyclohexane dimethanol, 1,6-hexanediol, and the like, and mixtures thereof.
Illustrati~e polyesters may contain hydroxyl groups, for example, reaction products of polyhydric alcohols reacted with divalent carboxylic acids. It i9 also possible to use the corresponding polycarboxylic acid anhydrides or corresponding polycarbcxylic a¢id esters of lower alcohol3 or mixtures there~f, for producing the polyesters. The polycarboxylic acids may be ali-phatic, cycloaliphatic, aromatic and/or heterocyclic and may optionally be ~ubstituted, for example, by halogen atoms and~or unsaturated. Examples of poly-carboxylic acida of thiq kind include succinic acid, adipic acid, suberic acid, azelaic acid, 9ebacic acid, phthalic acid, phehalis acid anhydride, t~trachloro-phthalic acid anhydride, endomethylene tetrahydro-phthalic acid anhydride, glutaric acid anhydride, maleic acid, maleic acid anhydride, fumaric acid, dimeric and trimeric fatty acids ~uch as oleic acid, optionally in admixture with monomeric fatty acids, terephthalic acid dimethyl e~ter and terephthalic acid dimethyl ester and terephthalie acid bis-glycol ester. Examples of suitable polyhydric alcohol~ are 11 ~2stj~3s ethylene glycoL, 1,2- and 1,3-propylene ~Jlyco1, 1,~-and 2,3-butylene glycol, 1,6-hex~ne diol, 1,9-octdne ~iol, neopentyl glycol, cyclonexclne dime~h~nol (1,~-bi~-hydro~y methyl cyclohexane), 2-methyl-1,3-proparle diol, al.~o diethylene ~lycol, triethylene glycol, tetra-ethylene glycol, polyethylene glycol~, diprcpylene glycol, polypropylene glycol~, dihutylene glycol ancl polybutylene glycols~ Polye~ters of lacton~s, for ~ample, ep~oloncaprolactone or hydroxy carboxylic acids, for example, w-hydroxycaproic acid, may al~o be u~ed.
~ he polyether~ containing at lea~t 2, generally 2 to 8, but p~eferably 2 to 3 hydroxyl group~ used in accordance with the invention are al~o known per se and are obtained, for example, by polymerizing epoxide~, such a~ ethylene oxide, propylene oxide, butylene oxide, tetrahydrofuran, styrene oxide or epichlorohy-drin on their own, for example, in the pre~ence of BF3, or by adding these epoxides, optionally in admixture or in succe~sion, to starter components containing rea~tive hydrogen atoms, 3uch a~ water, alcohols, or amines, for example, ethylene glycol, 1,3- or 1,2-propylene glycol, 4,4'-dihydroxy diphenyl propane, aniline, ammonia, ethanolamine or ethylene diamine~ The most preferred polyether diol are poly(tetramethylene ather) glycols.
While the preferred polyurethane cor.;poRitions of the invention are thermoplastic in order to enable the urethane to be dis~olved qo that the alloy complex may be forméd, it ha~ been found possibl~ to employ ~mall amounts of cros~linking agents to the compo~itions when the alloy complex is being coated onto the ~upport in order to render them thermo~etting. Suitable crosslink-ing agent~ are di~cu~sed above and include the listed dii30cyanate compounds.
Once prepared, the polyurethane and antithrombo-genic agent and~or antibiotic agent are dissolved in a ~olvent at the appropriate concentration of about 0.1~

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to about ~0~, and pre~erably O.S to 5% respectivQly, the polyurethane aub~trate i9 contacted with the alloy sy~tam to form a layer of alloy upon the polymer ~ub~trate. The ~ime needed to perform the contacting may vary widely depending upon the sub~trate 901vent~
and alloy thicknesA desired. It ha~ been found that coating thickneq~es, i.e., films of 0.1 to 5 mil3 are -obtained when the polyurethane subqtrate i~ dipped into the alloy ~yqtem and depending upon the withdrawn rate.
Obviously, fa~ter withdrawals result in thicker films while slow~r withdrawals re~ult in thinner film~.
Once the polyurethane product i9 withdrawn, the ~olvent i9 removed, auch as by flaqhing off in the presence or ab~ence of heat~
While the present invention ha~ been described in term~ of using polyurethane polymers a~ the ~upport surface, it ~hould be recognized that other 301id eupport materials could be u~ed. Exemplary materialq include polyamides, polyesters, polyvinyl chlorides, metal or gla~.
It should be recognized that the thermopla~tic polyurethane product~ of this invention are uqeable in a wide variety of device~ designed for contacting body fluids. Exemplary articles which can be in contact with body fluid~ such a~ blood, include artificial organs, vascular graft~, probes, cannulas, catheter~, hemodialysis tubing, hyperalimentation catheterq and other long indwelling vascular catheter~, and the like.
A particularly preferred application for the thermo-plastic polyurethane products of the invention is incatheter type devices wherein the alloy complex may be coated on either or both interior and exterior surfaces of the catheter.
The invention will be further illu~trated by the following non-limiting example~. All parts and percentages given throughout the ~pecification are by weight unle~s otherwi~e indicated.
Figures 1 and 2 illustrate the results o~ examples 1 and 2.

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Thiq e~ample demonqtrate9 the preparation and leach rate of structure~ of the invention u~ing heparin coupled with tri~odecylmethyl ammonium chloride (TDMAC ) a~ the antithrombogenic agent compared to surface treated material.
The anticoagulant alloy was prepared by the follow-ing procedure: Heparin (4.5 g) was di~solved in 100 ml.
of water and placed with TDMAC (7.0 g) dissolved in toluene/petroleum either (1:1 by volume) into a separa-tory funnel. The 301utions were vigorously mlxed for two minute~ The reaction ve~3el wa~ allowed to ~tand overnight and then the organic pha3e containing the TOMAC-heparin was collected and evaporated into a beaker under nitrogen.
A thermopla~tic polyurethane was formulated su~h that it could be dissolved in a solvent which would not de~troy the integrity of the item to be coated, in this case polyurethane catheter tubing. An appropriate solvent such as methylene chloride was chosen a~ the ~Alloy" solvent.
The alloy ~olution wa~ prepared ~uch that the final concentration wa~ 1~ TPU and 1% TDMAC-heparin i90topically labeled)~ Polyurethane catheter tubing (16 gauge) was dipped into the alloy ~olution and with-drawn at the rate of 21 cm/9ec. Thi3 resulted in a coating thicknes3 of approximately 0.7 mil. The coated polyurethane catheter tubing was allowed to stand 30 minutes to flash off residual solvent. Catheter sections (12 cm.) were placed in 3M NaCl for up to ten days. At specified interval9 sections were removeds rinsed in distilled water, and placed into scintil lation vials. Ten milliliter~ of solvent were then added to dissolve thQ p~lymer and alloy. After dis~olution, 10 ml. of 3cintillation solution were added and the sample placed in a Packard Tricarb scintillation counter for analysis.

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Figure 1 ghow9 the re9ult9. The Alloy System i3 compared to the one-9tep proces3 9urface coating where both systems ~tarted with approximately the same amount of heparin. In khe comparative example the polyurethane ~urface wa~ treated with TDMAC-Heparin ~ollowed by treatment with the antithrombogenic agent. The result3 ~hows a ~ub~tantial increase in permanency over the comparative proces~. After 10 days of leaching, ~4~ of the heparin in the alloy coating remains whereas the 10 compara~ive proce~ contained less than 3~6.

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Thi~ example demonstrates the low ~u~tained release o the ~tructure~ of thi~ invention using the ~ame alloy as that of the previous example. Thermo pla~tio polyurethane "thimbles" were solution ca~t to form the te3t environment~ The~e thimble~ were then coated with a T~MAC-heparin complex (comparative ~y~tem). The amount of heparin wa~ found to be 33.5 g/cm2. An alloy of TPU and TDMAC-heparin complex waq prepared. The thimble were cast ~rom an 18~
thermopla3tic polyurethane solution in THF onto glass test tubes. The thimble~ were manually dipp*d in a 1 ~olution of the alloy in methylene chloride. After drying, the thimble~ were stripped from the gla~
tubes, inverted~ and cut to ~ize, leaving the alloy coating on the inner ~urface of the thimbles.
The amount of heparin applied was very similar to the levels applied u~ing the comparative qy~tem, 32.9 g/cm2. Each ~et of anticoagulant coated thimbles were placed in a 3eparate 1.0 liter container of 3Molar NaCl solution. The 301utions were then agitated at room temperature and the samples were removed a~ needed for testing. The thimble~ were examined at intervals from 2 to 3~ days.
Figure 2 shows the results ~ After three to four days in 3Molar saline, the release of heparin level~
out to a low leach rate of 2.92 xlO-4~g/cm2 min.
This i9 approximately 100 times less than the comparative ~ystem.

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Thi~ example demonstrate~ the anticoagulant e~ficacy of this invention over long period~ of time.
3Molar saline ~olution is u3ed to challenge the ~ystem o~ thi~ invention. Since blood is 0.85~ ~aline, a ~olar saline solution preqents a much ~tronger challenge to an ionically releasing sy~tem.
Thimble~ of the comparati~e ~ystem and thimbles coated with alloy as de~ribed in Example 2 were prepared. The difference being that no radiolabeled heparin wa~ used in thi~ example.
Both comparative and alloy thimble3 were placed in 3Molar ~aline ~olution. At the appointed test interval, a 3ample wa~ removed from the 3M NaCl ~olution, it wa~ rin~ed with distilled water and dried in a desiccator before testing. Partial thromboplastin times (PTT) were determined for each thimble by the following procedure:
(a~ The thimble was placed in a heating block well in a water bath at 37C.
(b) 0.1 ml. freah, citrated, platelet-poor plasma and 0.1 ml. partial thromboplaqtic reagent were pipetted into a thimble and incubated for five minutes.
(c) 0.1 ml. of 0.02 M CaC12 was added and a stopwatch was ~tarted ~imultaneously.
(d) A nichrome loop was pa~ed through the pla~ma mixture at a rate of two ~weeps per 9econd until the first ~trands o fibrin are detected.
PTT's were performed on glas9 te~t tube~ and un-coated TPU thimble~ on each test day as control~. Table I ~how~ a compari~n of the partial thromboplastin times obtained for the comparati~e ionic proce~q and the Alloy System. Glass and uncoated TPU ~erved as controls.
The study wa~ designed to apply approximately the ~tj~5 same amount of heparin to a polyrner ~ur:Eac~ u~ing both methodq, compar~tlve and the Alloy System. Not only i~
there heparin remaining in the alloy coating af tec 8 months, but it 9ill retain~ its anticoagulant activity.
The partial thromboplaqtin time~ in Table I point out the ad~antage of the alloy system over the comparative Ionic Process. After sixteen dayq in 3M ~aline the ionic coating was unable to extend the PTT beyond that of the TPU controls (x = 161 ~ec.). The alloy coating extended the PTT more than ten times that of the TPU
control even after seven month~ in 3M saline. In ~he ca~e of the PTT te~t, a coagulation time longer than control (uncoated TPU) indicates an anticoagulant effect.

~S~Z3S

TABLE I
TPU/TDMAC--HEPARIN ALLOY VS . IONIC ONE--STEP PROCESS

WITH COATED THIMBLES
.
1~
¦Laach 1~ ' -- ~1 ¦Time~ ¦ Ionic ¦ Alloy ¦ Glass ¦ TPU Only ¦

O I >1800 1>1800 1 58 1 154

3 1 >1800 1> 1~00 1 ~8 1 154 7 i 1128 1>1800 1 61 1 131 1 228 1>1800 1 59 1 153 1 189 1> l~OQ I 62 1 180 17 1 128 1> 1800 1 63 1 139 18 1 167 1>1800 1 67 i 161 21 1 ~ >1800 1 ~ 67 1 161 2~ I> 1800 1 65 1 20 1 1 ~ 1800 1 53 1 168 1 ___ I> 1800 1 58 1 167 210 1 ~ >1800 1 60 1 181 240 ~ 180~ 1 59 1 179 . _. I I _. . . I

.~,.~.

E~AMP1E 4 . Thi~ example demon9tr~te9 the wide latitude ln the ratio o TPU to anticoagul~nt agent which can be employed in thi~ invention. Thimbles o tlle comparative s~qtem and thimble~ coated with alloy aq de3cribed in Example 2 were prepared. Alloy-~olution~ were prepared in four ratios u~ing a low.hard segment thermoplas~ic .
polyure~hane di~olved in methylene chloride and TDMAC-heparin in 50:50 toluene-petroleum ether.
The re~ultq are ~et forth in Table II ~how an anticoagulant effect a~ mea ured by the partial thrombo-pla3tin time (PTT) te~t for all alloy ratio~ of TPU to TDMAC-heparin.

~o .~ZS~j~3~
TABLE II
1- Corltrol - I= co,ltrOl -r r G1a~S ¦ U~1COated ¦ ALLOY COAT~D ~t~lLMBLES
PO1Y~ ~tlEPI\E~IN~--¦
Ure thane ¦ Th:imble ¦ ~1:l 3:1 2~ 2 " I

Plrr¦ G7 ~ec. ¦ l79 ~ec. ¦>1BOO geCI~1800 ~eCI>1BOO ~eCI>1E3OO ~eC ¦
Tim~
.

2~ 5 E:XAMPLE S
This e~arnple demollstrates that the Alloy System of this invellt;on can be crosslinked to achieve a long~r ~ tained rele~qe of anticoagulant. Dii~o-cyanate~ were added to the 1:1 alloy o~ TPU: TDMAC-heparirl in the followin~ ratio~: 0.05~, 0.15~, and 0.50~. Diisocyanate~ can be cho~en ~rom any o~ thoae urrently available commercially by tho~e ~killed in the art. For thi~ exampl~, MDI was choaen. Radio-labeled heparin was used to quantitatc the percentageleached with each ratio of added dii~ocyanateO
Thimbles were coated u~ing ~imilar technique3 to tho~e of Example 2. A~ter fla~hing off the coating ~olvent the sample~ were placed in 3M saline~ A comparison o~
percentage heparin remaining after 240 hour~ i9 shown in Table III~
Thi~ experiment clearly demonstrated the potential for decreaaing the leach rate while still maintaining the anticoagulant effect in the alloy through the additional cro~alinking agent~.

3~

TABLE II I
.~ . ~

-I
¦ MDI in ¦ MDI in ¦ MDI in All~y ¦~Y ¦ Alloy ¦ Alloy ~g Heparin/cm2 149~7 ¦ 42.44 1 39.71 ¦ 36.47 eparin l23.6~6 1 35.89~ 54.i96 1~~~
I remaining @
1240 hr. 1n ¦3M saline l ~ l permanency over l 3 l I .
alloy ¦ PTT ¦ > 1800 r , L ~
1 sec ¦ sec ¦ ~ec ¦(x=161 ~ec) I

23 ~L~25~z3~
E~AMPLE 6 Thi~ example demonstrate~ the urepa~ation of structure~ of th~ invention u~ing cef~zolin coupled with t~idodecylmethyl ammoni-lm chloride (~DM~C) a~ the anti-5 b;otic ~ent.
The antibiotic alloy was prepared by the following procedure: ce~azolin (200g) was di~solved in 100 ml. of water and placed with TDMAC (6.4g3 di~olved in toluene~
petroleum ether (1:1 by volume~ into a separatory funnel. The solutions were vigorou~ly mixed for two minutes. The reaction ve~sel was allowed to ~tand overnight and then the organic phase containing the TDMAC-cefa201in wa~ collected and evaporatea int~ a beaker under nitrogen, A thermopla~tic polyurethane wa~ formulated such tha~ it could be di~solYed in a solvent which would not de~troy the integrity of the item to be coated, in this ca~e polyurethane catheter tubing. An appropriate solvent such as methylene chloride was choaen a~ the "Alloy" solvent~
The alloy solution was prepared such that the final concentration was 1% (weight volume~ TPU znd 1~ (weight-volume) TDMAC-cefazolin. Polyurethane film (2 mil) was prepared using standard techniques ~nown by those skilled in the art~ The film was die cut into 6mm disks. The di3k~ were then coated with the alloy solution. The coated polyurethane film disks were allowed to stand at least 30 minute~ to 1ash off residual solvent.
A Staphlococcu~ aureu~ culture was prepared as follow~: A Staphlococcus aureu~ bactrol disk (ATCC
~25923) i~ placed in 4ml o trypticase soy broth (TSB~
medium and incubated overnight at 37C on a continuous wrist-action shaker. A 0.4ml aliquot of the culture wa~ then transferred into 4ml of TSB medium. This sample was then incubated for 2-5 hour~ at 37C until the visual turbidity was greater than or equal to the t~ ' BaS0~ standar~ (0.5ml of B~S0~ ~ 99.5mo.1.e3 o 1 H2S04 ) .
Sampl~ of the antibiot.ic alloy coated di~k were t~ated by preparing petri dishes contalnin~ Mueller-Hinton agar ~5-6mm in depth). The bacterial broth 3u~pen~ion wa~ streaked evenly in two plane!Y onto the agar plate u3ing a ~terile cotton swab. The ~eeded agar plates were allowed to stand prior to the introduction of the TDMAC-antibiotic coated TPU di~k~
for approximately five minute~. The alloy coated di3ks were placed firmly into the agar near the center of the plate u~ing ~terile ~orceps. The plate~ were the incubated overnight at 37C and checked for a zone of inhibition.
The result~ are shown in Table I~. Efficiency of the alloy coated disk i9 clearly shown ~y the 24.1 mm zone of inhibition~

~ 235 TABLE IV
Zone o Inhlbltlon Te~t ~laterial (average~ mm ~ at.lndard . .. _. ___ __. _ . ~ ~_r _ ~
O~g C'efclzolin Control . No inhibition (~teri.le paper di~) 30~ 9 Cefazolin Control 23.9 ~ O.G
(~terile paper di~k impregnated with 30 g of Cefazolin) 5~ thermopla~tic polyurethane: 24.1 + 1.8 5~ TDMAC-Cefazolin Alloy Z~5 E~A.~PLE 7 __ This example demon9trate~ the wide latltude in the ratio of TPU (thermopla~tic polyuretharle) antibiotic agent which can be employed in this invention. Film~
~ere coated with alloy as de~cribed in Example 6.
ALloy 301utions were prepared in four ratio~ using a low hard segment thermopla~tic polyurethane dis~ol~red in methylene chloride and TDMAC-cefazolin in 50:50 ~by volume) toluene-petroleum ether.
The results ~et forth in Table V ~how an anti-biotic effect a~ mea3ured by the zone of inhibition te~t for all alloy ratio~ of TPU to TDMAC-cefazolin.

27 ~L~S5~Z3~
TABLE V
Zone o Inhl~b~
Te~t ~iaterial (~vera~e, rnm t SD) Of ~ Cefa,~,olin Control ~o inhibit:ion (sterile paper di~k) 30~g Ce~azolin Control 23.9 -~ 0.6 ~sterile paper disk impregnated with 30 of Ce~azolin) 1~ thermoplastic polyurethane: 24.4 + 0.5 58 TD~IAC-Cefazolin Alloy 2% thermopla~tic polyurethane: 22~8 ~ 0~9 5~ TD~AC-Cefazolin Alloy 3% thermoplastic polyurethane~ 23.3 ~ O.S
5~ TDMAC-Cefazolin Alloy

4% thermopla~tic polyurethane: 24.6 ~ 0.4

5~ TDMAC-Cefazolin Alloy 2a ;~ 5~5 _XAMPLE ~
Thi~ e~ample d~monstrate~ the prep~ration of ~t-ructure~ o th~ invention usin~ cloxacillin coupled with tridodecy.lmethyl ~mmonium chloride (TDMAC) aa the antibiotic agent.
The antibiotic ~l.loy was preparecl by th~ following procedure: cloxacillin (2.0g) wa~ di~olved in 100 ml.
of water and placed with TDMAC (6.4g) diasolved in toluene/petroleum ether (1:1 by volume) into a 10 ~eparatory funnel. The solution~ were vi~orously mixed Eor two minute~ The reaction ves~el was allowed to stand overnight and then the organic pha~e containing the TDMAC-cloxacillin was collected and evaporated in~o a beaker under nitrogen.
A thermoplastic polyurethane was formulated a~ notPd in Example 6. Variou3 ratios of TPU to TDMAC-anti-biotic were prepared. Combination~ of %TPU to TDMAC-cloxacillin examined were OoS, 1:5, and 2:5.
15 ml of methylene chloride wa~ then added ~eparately to each of the three combination~ found in Table VI. Polyurethane film (2 mil) wa~ prepared, coated with alloy, and tested a~ in Example 6~
The results are ~hown in Table VI~ A control with no antibiotic present was run 3imultaneously and it qhowed no zone of inhibitionO The efficacy is shown by - the zones of inhibition that resulted from each combination of TPU: TDMAC-antibiotic tested.

TABLE VI
~ 'l`PU to TD~.~C- TDIII\C- Zorle ol~Ft1on cloxacillin TPU ~g) cloxacillin (g) ~verage, n~rrl-~
__ _ Sl:andar.d ~vlation O t:o 5 0 0.75 26.~ ~ 1.2 1 ~o 5 O.l5g0.75 21.0 ~ 1.1 2 to 5 0.30g0.75 21.~3 ~ 1.3 :~2S5'~3~

Thi~ e~ample demonstrate3 the preparation of s~ructure~ o~ the invention u~lng dicloxaci.llin coupled with tridodecylmethyl ammonium chloride (TDM~C) a~ the S ~ntibiotic agent.
T~le antibiotic alloy was prepared by the following procedure: dicloxacillin (~.09) wa~ dis~olved in 100 ml~ of water and placed with TDMAC (6.49) dis301ved in toluene/petroleu~ ethe~ 1 by volume) into a separatory funnel. The solution~ were vigorou31y mixed ~or two minute~. The reaction ve~el was allowed to ~tand. overnight and then the oxganic phase containing the TDMAC-dicloxacillin wa~ collected and evaporated into a beaker under nitrogen~
A thermoplastic polyurethane was formulated as noted in Example 6. Ratios of TPU to dicloxacillin were prepared in the ~ame combinations and manner a3 found in Example 8. Polyurethane film (2 mil) wa~ prepared~
coated with alloy, and tested as in Example 6.
The results are shown in Table VIIo A control with no antibiotic present was tested simultaneously and it showed no zone of inhibition~ The efficacy is shown by the zones of inhibition that re~uited from each combination of TPU: TDMAC-antibiotic tested.

3 ~ 55~3S
TABLE VI I
96 TE'U to TD~lAC- Zone of Inllibitior 9s TPU to ~ TD~AC~-Dicloxacillin Average, mm -1 Standar~ devlatior O to 5 2~ . 1 1 0.6 1 to 5 19.3 1~ 0.~
2 to S 17.E~ -~ 1.2 ~5~5 The invention being thu~ described, .it will be obvious that the same may be varied in many ways.
Such variation~ are not to be regarded a.~ a departure from ~he ~pirit of cope o~ the lnvention and all ~uch modifications are intended to be included within the scope o the claims.

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A thermoplastic polyurethane product possessing long-term antithrombogenic and antibiotic properties, comprising (a) a polyurethane alloy complex formed in a solvent solution;
(b) said polyurethane alloy complex including (1) a thermoplastic polyurethane:
(2) a material dispersed throughout said thermo-plastic polyurethane:
(3) said dispersed material being selected from the group consisting of an antithrombogenic material, an antibiotic material, and mixtures thereof;
(4) said dispersed material ionically bonded to said thermoplastic polyurethane by a quaternary ammonium compound:
(c) a solid polyurethane substrate separate from said thermoplastic polyurethane in said poly-urethane alloy complex comprised of a material not soluble in said solvent solution for said polyurethane alloy complex; and (d) said polyurethane alloy complex being in the form of a surface layer on said separate poly-urethane substrate.

2. The thermoplastic polyurethane product of claim 1, wherein the weight ratio of said thermoplastic polyurethane to said dispersed material is within the range of between about 10:1 and 1:5.

3. The thermoplastic polyurethane product of claim 1 wherein the antithrombogenic material is selected from the group consisting of heparin, prostaglandins, sulfated poly-saccharide, and mixtures thereof.

4. The thermoplastic polyurethane product of claim 1 wherein the antibiotic material is selected from the group consisting of penicillin, oxacillin, ticarcillin, carbenicillin, cephalosporins, cefoxitin, cefazolin, dicloxacallin, cloxacillin, and clavulanic acid, and mixtures thereof.

5. The thermoplastic polyurethane product of claim 1 wherein the quaternary ammonium compound is a long-chain alkyl quaternary ammonium salt having from 2 to 4 alkyl groups each having from about 10 to about 30 carbon atoms.

6. The thermoplastic polyurethane product of claim 1 wherein the quaternary ammonium compound is selected from the group consisting of tridodecylmethyl ammonium salts, tetra-dodecyl ammonium salts and tridodecylbenzyl ammonium salts.

7. The thermoplastic polyurethane product of claim 1 wherein a crosslinking agent is employed to render the poly-urethane product thermosetting in nature.

8. A method for producing a thermoplastic poly-urethane product possessing long-term antithrombogenic and antibiotic properties, comprising the steps of (a) selecting a thermoplastic polyurethane;

(b) selecting a material from the group consisting of an antithrombogenic material, an antibiotic material and mixtures thereof;
(c) selecting a quaternary ammonium compound;
(d) coupling said material from step (b) with said quaternary ammonium compound from step (c);
(e) adding said thermoplastic polyurethane from step (a), and said material from step (d) to an organic solvent solution;
(f) dispersing said material from step (d) through-out said material from step (a) to form a poly-urethane alloy complex solution;
(g) selecting a solid article comprised of a poly-urethane not soluble in said organic solvent solution from step (e):
(h) coating the surface of said solid article from said fourth selecting step with said solution from step (f); and (i) removing said solvent solution from the coated surface formed in step (h) to form a solid sub-strate of said article comprised of polyurethane having disposed on the surface thereof a layer of an alloy complex including polyurethane separate from the polyurethane in said article.

9. The method of claim 8, wherein said article selected in step (g) is a vascular catheter.

10. The method of claim 8 wherein the antithrombo-genic material is selected from the group consisting of heparin, prostaglandins, sulfated polysaccharide, and mixtures thereof.

11. The method of claim 8 wherein the antibiotic material is selected from the group consisting of penicillin, oxacillin, ticarcillin, carbenicillin, cephalosporins, cefoxitin, cefazolin, dicloxacillin, cloxacillin, and clavulanic acid, and mixtures thereof.

12. The method of claim 8 wherein the quaternary ammonium compound is a long chain alkyl quaternary ammonium salt having from 2 to 4 alkyl groups each having from about 10 to about 30 carbon atoms.

13. The method of claim 8 wherein the quaternary ammonium compound is selected from the group consisting of tridodecylmethyl ammonium salts, tetradodecyl ammonium salts, and tridodecylbenzyl ammonium salts.

14. The method of claim 8 wherein the contacting is performed by dipping the substrate into the organic solvent containing the preformed complex.

15. The method of claim 8 wherein the solvent is removed from the polyurethane product by heating the product to volatize the solvent.

16. A vascular catheter which comprises a catheter as the substrate and at least one layer of the product defined in claim 1, 3 or 4.