Anti-thrombobenic, anti-microbial compositions containing heparin reacted with quaternary ammonium components and bound with water-insoluble polymers are disclosed. Such compositions may also contain additional quaternary ammonium compounds not reacted with heparin and may also contain quaternary ammonium compound(s) reacted with antibiotics.

BACKGROUND OF THE INVENTION 
Many kinds of polymer compositions have been used in the field of medical 
supplies. These compositions have not always exhibited anti-thrombogenic 
characteristics when used in prosthetic and therapeutic apparatuses for 
handling or being in contact with blood or blood components under 
conditions where clotting would tend to occur, such as artificial blood 
vessels, catheters, artificial hearts, and artificial kidneys. 
When blood is brought in contact with metal, glass, plastic or other 
similar surfaces, it tends to clot in a short time unless certain 
precautions are taken. One common precaution currently in widespread use 
is the treatment of the surface with heparin or with heparin reacted with 
quaternary ammonium compounds. Such heparin compounds are known to have 
anti-coagulant effects when in contact with blood. The presence of the 
aforementioned heparin compounds on the surface imparts anti-thrombogenic 
characteristics. However, previously known heparinization or compositions 
have not been adequate because of the short time of anti-thrombogenic 
activity, at most a few days in vivo (I. S. Hersch, et al, J. Biomed., 
Mater. Res. Symposium I, 99-104 (1971); K. Amplatz, "A simple 
Non-Thrombogenic Coating", Invest. Radiology, July, August, 1971, Vol. 6 
or because the anti-thrombogenic characteristic was reduced to a very low 
level in order to make it resistant to removal by reacting it with 
quaternary ammonium polymers (U.S. Pat. No. 3,844,989). 
It is therefore, an object of the present invention to provide novel 
anti-thrombogenic polymer/heparin compound compositions or mixtures which 
prevent blood clotting for a relatively long period of time (over one 
month), and which have the same high degree of anti-thrombogenic 
characteristics as the non-polymerized heparin-quaternary ammonium 
compounds, and thus provide excellent properties for use as medical 
materials for coatings on artificial blood vessels, catheters, artificial 
hearts, artificial kidneys, etc. 
Another object of the present invention is to provide novel anti-microbial 
surfaces which contain antibiotic agents which are entrained in the 
surface in such a way as to be gradually released in vivo to provide 
effective anti-microbial action over a longer time than was previously 
possible when using these agents. Typical agents useful in this embodiment 
of the invention include penicillins, cephalosporins, etc. 
SUMMARY OF THE INVENTION 
The anti-thrombogenic, anti-microbial compositions (mixtures) of this 
invention comprise heparin-quaternary ammonium compounds mixed with 
water-insoluble polymers. They may also contain some hydrophilic polymers, 
but the mixture would still be water-insoluble after coating and drying. 
The water-insoluble polymers of this invention range from hydrophobic 
polymers to ones that are fairly hydrophilic, but are nevertheless 
essentially water-insoluble after being coated on a substrate and dried. A 
single polymer or mixture(s) of different polymers may be used to 
accomplish the invention. The heparin-quaternary ammonium compound may be 
mixed in a solution with the water-insoluble polymer, or it may be coated 
on top of a coating of the water-insoluble polymer(s), which is applied to 
the surface beforehand. In the latter case, a solvent must be added that 
is a mutual solvent for both the heparin-quaternary ammonium compound and 
the water-insoluble polymer(s) so that some mixing occurs between the two 
layers. In still another case, it is possible to coat the 
heparin-quaternary ammonium compound directly on the water-insoluble 
plastic surface, and incorporate a mutual solvent for both the plastic 
surface and the heparin-quaternary ammonium compound, so that some mixing 
occurs between the plastic surface and the heparin-quaternary ammonium 
compound. 
Various combinations of these three systems would be obvious to one skilled 
in the art. The mixtures of the water-insoluble polymer(s) and 
heparin-quaternary ammonium compounds of this invention are substantially 
more resistant to removal or deactivation in human and animal body fluids 
such as blood or plasma than the heparin-quaternary ammonium compounds by 
themselves. 
Typical examples of polymers suitable for use with the present invention 
are as follows: Water insoluble cellulose esters such as cellulose 
acetate, cellulose acetate butyrate, cellulose acetate propionate, and 
cellulose nitrate; polyurethane resins including polyether and polyester 
grades. Exemplary of the polyurethane is the reaction product of 
2,4-tolylene diisocyanate and position isomers thereof, 
4,4'-diphenylmethane diisocyanate and position isomers thereof, 
polymethylenepolyphenyl isocyanate, or 1,5-napthylene diisocyanate with 
1,2-polypropylene glycol, polytetramethylene ether glycol, 1,4-butanediol, 
1,4-butylene glycol, 1,3-butylene glycol, poly(1,4-oxybutylene)glycol, 
caprolactone, adipic acid esters, phthalic anhydride, ethylene glycol, 
1,3-butylene glycol, 1,4-butylene glycol or diethylene glycol. Acrylic 
polymers such as ethyl and methyl acrylate and methacrylate; condensation 
polymers such as those produced by sulfonamides such as toluenesulfonamide 
and aldehydes such as formaldehyde; and polyisocyanates. Exemplary of the 
polyisocyanate are polymethylenepolyphenyl isocyanate, 
4,4'-diphenylmethane diisocyanate and position isomers thereof, 
2,4-tolylene diisocyanate and position isomers thereof, 3,4-dichlorophenyl 
diisocyanate and isoferrone isocyanate. Adducts or prepolymers of 
isocyanates and polyols such as the adduct of trimethylolpropane and 
diphenylmethane diisocyanate or tolylene diisocyanate are suitable. For 
further examples of polyisocyanates, see "Encyclopedia of Polymer Science 
and Technology", H. F. Mark, N. G. Gaylord and N. M. Bikales (eds.) (1969) 
incorporated herein by reference. 
Typical quaternary ammonium compounds that can be reacted with heparin for 
use in this invention include benzalkonium chloride, 
tridodecylmethylammonium chloride, cetylpyrrdinium chloride, 
benzyldimethylstearylammonium chloride, benzylcetyldimethylammonium 
chloride, etc. 
DETAILED DESCRIPTION OF THE INVENTION 
The compositions of the present invention are first dissolved in solvent 
mixtures that are co-solvents for the mixtures of non-volatile components 
and which allow compatible homogenous films of the components to be cast. 
Such films when dried will typically appear as a clear film or films of 
very slight turbidity indicating that the non-volatile components have 
been deposited in a substantially homogenous manner. Typical solvents 
comprise alcohols, ketones, esters, aromatics, pyrrollidones, carboxylic 
acids, amides, and other organic solvents used alone or in appropriate 
mixtures as required, and which bring about the basic compatibility of the 
non-volatile components to be expressed. Typical surfaces which can be 
coated include plastic, metal and glass. 
The heparin-quaternary ammonium compounds may be prepared in the 
conventional manner by any known prior art technique. For example, a 
heparin-benzalkonium chloride compound can be prepared by mixing 
approximately equal volumes of a 10% (by wt.) aqueous solution of sodium 
heparin with an approximately 17% (by wt.) solution of benzalkonium 
chloride (i.e., Zephiran from Winthrop-Breon Laboratories), and then 
washing the residual sodium chloride out with distilled or deionized 
water. Such preparations are disclosed in "A Simple Non-Thrombogenic 
Coating", K. Amplatz, Invest., Radiology, July, August, 1971, Vol. 6, 
which is incorporated herein by reference. It should be understood, 
however, that the invention is not limited to the heparin-quaternary 
ammonium compounds cited in the above reference. 
In most cases, all the components are incorporated into a single solution 
so that the surface treatment can be accomplished with a single 
application. However, the treatment can also be applied in two steps. For 
example, the water-insoluble polymer(s) can be applied in one application 
and the heparin-quaternary ammonium compound can be applied to the 
water-insoluble polymer. Some mutual solvent(s) for the water-insoluble 
polymer and heparin-quaternary ammonium compound that makes two components 
compatible should be included in the overcoat application to accomplish 
the objective of the invention. For example, dimethylacetamide (DMA) 
effectively accomplishes this objective as shown in Example 1. A variant 
on this approach would involve application of the water-insoluble 
polymer(s) followed by application of a solution containing some 
water-insoluble polymers and some heparin-quaternary ammonium compound. 
Some heparin-quaternary ammonium compounds may also be added to the first 
application. Typical concentrations of heparin-quaternary ammonium 
compound in the coating solutions range from about 0.1% to 20% by weight. 
Preferred concentrations range from 0.5% up to 4%. Use of higher 
concentrations of heparin-quaternary ammonium compounds in the solutions 
does not enhance performance and is therefore not very useful or desired. 
Lower concentrations than those disclosed above reduce the 
anti-thrombogenicity of the layers. 
Typical concentrations of the water-insoluble polymers in the coating 
solution range from about 0.01% to 20% by weight. Preferred concentrations 
range from about 0.2% to 3%. Higher concentrations tend to mask the 
anti-thrombogenic characteristics of the layers. Lower concentrations tend 
to allow the layer to be extracted more easily. The composition of the 
final coating may have the heparin-quaternary compound present in a 
concentration of about 0.5 to 99.5 percent by weight with the balance of 
the composition comprising essentially the water-insoluble polymer. 
ANTI-THROMBOGENICITY TEST 
The following in vitro test was used to evaluate anti-thrombogenicity: 10 
mm.times.75 mm glass test tubes were charged with 0.5 gm of reconstituted 
human plasma which had been kept refrigerated since collection. The test 
tubes were equilibrated in a 37.degree. C. incubator for 10-30 minutes. 
Next, 0.1 g of 0.10M CaCl.sub.2 was added, and the test tube was manually 
swirled to achieve complete mixing. Immediately after swirling, 41/2" long 
sections of 7 French tubing (either coated with one of the 
anti-thrombogenic systems of the present invention, or uncoated controls) 
were dropped into the plasma in each tube, taking care to ensure that the 
sample pieces were completely immersed in the plasma. The tubes were 
maintained in the 37.degree. C. incubator and were checked for clotting at 
one minute intervals by removing them from the incubator and tilting them. 
Before clotting, the liquid flows in the test tube, but it gels and does 
not flow once it has clotted. Typical clotting times for plasma containing 
untreated polyurethane tubing range from six minutes to 15 minutes. 
Samples made according to this invention prevent clotting in this test. It 
was found that if the plasma did not clot after standing overnight, it 
would usually not clot for up to four weeks. Therefore, tests were usually 
discontinued if they had not clotted after standing overnight. Typical 
samples prepared by this invention did not clot when tested before plasma 
extraction, and retained their anti-clotting activity after 28 or more 
days of extraction in plasma. Devices coated with heparin-benzalkonium 
chloride or heparin-tridodecylmethylammonium chloride do not clot when 
tested before extraction in plasma, but lose their anti-thrombogenicity 
after plasma extraction of two hours or less. Heparinized quaternary 
polymers (HQP), such as those prepared according to U.S. Pat. No. 
3,844,989 and used on catheters marked under the trademark ANTHRON by 
Toray Medical Co. Ltd., show only slight anti-thrombogenicity. For 
example, when tested against heparin-benzalkonium chloride (HBAC), the 
HBAC sample prevented clotting of the plasma overnight, while the control 
clotted in five minutes and the HQP sample clotted in seven minutes before 
plasma extraction, and showed no improvement in anti-thrombogenicity 
compared to the untreated polyurethane control after 12 hours of plasma 
extraction. 
The following examples are intended to illustrate various preferred 
embodiments of the present invention.

EXAMPLE 1 
Polyurethane 7 French tubing was coated with a solution containing the 
following ingredients and dried for 20 minutes at 65.degree. C. 
______________________________________ 
Polyvinylpyrrolidone .006 g 
Isopropanol 1.0 g 
Nitrocellulose 1.6 g 
Ethylacetate 1.2 g 
Rosin ester .5 g 
Butylacetate 4.8 g 
Dimethylacetamide 1.5 g 
Ethyl-3-ethoxy propionate 
6.1 g 
______________________________________ 
The tubing was then overcoated with a solution containing the following 
ingredients and then dried for 20 minutes at 65.degree. C. 
______________________________________ 
Isopropanol 9.85 g 
Dimethylacetamide 1.00 g 
Heparin benzalkonium chloride 
.15 g 
______________________________________ 
This sample was compared to a sample of polyurethane tubing which was 
coated with heparin benzalkonium chloride (1.8% w/v in isopropanol) as 
follows. The samples were dipped in a Gentian Violet dye solution and then 
rinsed in hot running water. The sample coated with heparin-benzalkonium 
chloride (HBAC) in isopropanol lost most of the surface dye stain in less 
than 20 seconds, indicating that most of the HBAC had been washed off. The 
sample of the present invention that had the nitrocellulose undercoat and 
contained DMA in the HBAC overcoat, retained the dye stain much longer 
indicating that it is much more resistant to removal. 
EXAMPLE 2 
Polyurethane 7 French tubing was coated with a solution consisting of: 
______________________________________ 
Methylethylketone 5.0 g 
Heparin-benzalkonium chloride 
0.33 g 
Isopropanol 3.7 g 
Ethyl-3-ethoxy propionate 
.6 g 
Butyl acetate .5 g 
1/2 sec. nitrocellulose .16 g 
Ethyl acetate .1 g 
Rosin ester .05 g 
______________________________________ 
The samples were dried at 75.degree. C. for 30 minutes. Samples were then 
extracted in human plasma at 37.degree. C. for 7, 10, 21, or 28 days and 
then tested for anti-clotting properties. The following results were 
obtained. 
______________________________________ 
Sample Clotting time 
______________________________________ 
Uncoated control 12 minutes 
Above sample, without extraction in plasma 
Did Not Clot 
Above sample, after 7 days extraction in plasma 
Did Not Clot 
Above sample, after 10 days extraction in plasma 
Did Not Clot 
Above sample, after 21 days extraction in plasma 
24 minutes 
Above sample, after 28 days extraction in plasma 
20 minutes 
______________________________________ 
The above results show that the samples are still exhibiting effective 
anti-clotting activity on the device surface where it is most needed and 
that clots are unlikely to form on the treated surfaces, even after 28 
days of extraction. This level of anti-clotting activity is stronger even 
after 28 days of plasma extraction than the anti-clotting levels achieved 
under these test conditions with surfaces treated according to the 
compositions taught by U.S. Pat. No. 3,844,989. 
EXAMPLE 3 
The following solution was coated on polyurethane 7 French tubing and dried 
at 75.degree. C. for 20 minutes. 
______________________________________ 
Methylethylketone 5 g 
8.3% heparin benzalkonium chloride 
5 g 
in isopropanol 
Cellulose Acetate Butyrate - 3A solution* 
1.5 g 
______________________________________ 
*3A solution 
Ethyl-3-ethoxy propionate 
30.3 g 
Butylacetate 24.2 g 
Ethyl acetate 6.1 g 
Rosin ester 1.5 g 
Isopropanol 3.5 g 
1/2 sec. Cellulose acetate 
8.0 g 
butyrate 
Coated samples were tested for anti-clotting activity, and also for 
resistance to removal by dying with Gentian Violet dye and then rinsing 
with hot running water. The sample was compared to a coating of heparin 
benzalkonium chloride without any cellulose ester polymer additive. 
Results: The sample did not clot in the clotting test. In the hot water 
rinse test, the heparin benzalkonium chloride coating without cellulose 
resin was completely removed in a few seconds. Hot water rinsing did not 
remove the above coating which contained cellulose acetate butyrate 
polymer. 
EXAMPLE 4 
Polyurethane 7 French tubing was coated as in Example 3 except that 
cellulose acetate butyrate was replaced with cellulose acetate propionate. 
The sample was tested for anti-clotting activity and resistance to removal 
in hot water. Results were comparable to those with Example 3. 
EXAMPLE 5 
Polyurethane 7 French tubing was coated with the following solution and 
dried at 80.degree. C. for 20 minutes. 
______________________________________ 
Methylethylketone 5 g 
8.3% heparin benzalkonium chloride in 
isopropanol 4 g 
Cellulose acetate propionate 5A solution* 
2 g 
______________________________________ 
*5A solution 
Ethyl-3-ethoxy propionate 
30.3 g 
Butylacetate 24.2 g 
Ethylacetate 6.1 g 
Rosin ester 2.5 g 
Isopropanol 3.5 g 
1/2 sec. cellulose acetate propionate 
8.0 g 
The coated sample was extracted in plasma at 37.degree. C. for four hours 
and tested for anti-microbial activity by pressing it into gelled Difco 
Plate Agar which was spiked with Staphylococcus epidermidis (ATCC 12228) 
and then incubated overnight at 32.degree.-35.degree. C. A sample of 
polyurethane tubing that was coated with heparin-benzalkonium chloride 
without cellulose polymer was extracted in plasma at 37.degree. C. for 
four hours for comparison. The sample which contained cellulose acetate 
propionate (CAP) polymer showed a significant zone of inhibition while the 
sample made without CAP resin showed no zone of inhibition, demonstrating 
that the incorporation of cellulose ester polymer effectively increases 
resistance to removal of the coating when extracted in human plasma. 
EXAMPLE 6 
Example 5 was repeated, except that the solution contained 1.5 gm of 10.7% 
(wt. %) nitrocellulose solution in place of the 2.0 grams of 10.7% (wt. %) 
CAP solution. Samples of polyurethane tubing coated with this solution 
were extracted in plasma at 37.degree. C. for four hours or 18 hours. They 
were then tested for anti-microbial activity using the same zone of 
inhibition test as used in Example 5. The tests showed zones of inhibition 
after both extraction intervals. The sample extracted for four hours has a 
larger zone of inhibition than the sample that was extracted for 18 hours. 
EXAMPLE 7 
The following solution was coated on polyurethane 7 French tubing and dried 
at 80.degree. C. for 20 minutes. A control was made by coating a sample of 
the tubing with a 5% w/v solution of Tridodecylmethylammonium chloride 
(TDMAC). 
______________________________________ 
Methylethylketone 5 g 
8.3% heparin benzalkonium chloride in 
4 g 
isopropanol 
7A solution* 1.5 g 
______________________________________ 
*7A solution 
Ethyl-3-ethoxy propionate 
30.3 g 
Butylacetate 24.2 g 
Ethyl acetate 6.1 g 
Rosin ester 2.5 g 
Isopropanol 3.5 g 
1/2 sec. Nitrocellulose 
8.0 g 
Both samples were then immersed for 30 minutes in a 5% aqueous solution of 
penicillin G and then air dried overnight. The coated samples were then 
extracted for 18 hours in human plasma at 37.degree. C. They were removed 
from the plasma, rinsed in running deionized water and then tested for 
anti-microbial activity as in Example 5. The sample containing 
nitrocellulose showed a strong zone of inhibition while the sample without 
nitrocellulose showed no zone of inhibition. 
EXAMPLE 8 
Example 7 was repeated, except that TDMAC was added to the coating 
solutions as follows: 
______________________________________ 
Example 8 .025 gm TDMAC added 
Example 8A .075 gm TDMAC added 
______________________________________ 
Both samples showed a strong zone of inhibition after the 18 hours plasma 
extraction and appeared to be substantially comparable to Example 7. 
EXAMPLE 9 
Polyurethane 7 French tubing was coated with the following solution. 
______________________________________ 
Heparin tridodecylmethylammonium chloride 
0.2 g 
Isopropanol 2.6 g 
Methylethylketone 2.5 g 
7A Solution 0.7 g 
______________________________________ 
This coated sample was tested for clotting and did not clot. It was very 
resistant to removal in hot running water. 
EXAMPLE 10 
Polyurethane 7 French tubing was coated with a solution containing the 
following ingredients and dried at ambient temperature for 60 minutes: 
______________________________________ 
Methylethylketone 5.3 g 
Heparin-benzalkonium chloride 
0.31 g 
Isopropanol 3.4 g 
Acrylic resin 0.2 g 
Rosin ester 0.2 g 
Tridodecylmethylammonium chloride 
0.4 g 
Xylene 0.14 g 
Butanol 0.05 g 
______________________________________ 
Samples were then extracted in plasma at 37.degree. C. for 4, 24 and 120 
hours and compared to uncoated polyurethane tubing for anti-clotting 
activity. The results were as follows: 
______________________________________ 
Sample Clotting Time 
______________________________________ 
Uncoated control 9 minutes 
Above sample, without extraction in plasma 
Did Not Clot 
Above sample, after 4 hours extraction in plasma 
Did Not Clot 
Above sample, after 24 hours extraction in plasma 
Did Not Clot 
Above sample, after 120 hours extraction in plasma 
Did Not Clot 
______________________________________ 
The above coated sample was resistant to removal by hot running water. 
EXAMPLE 11 
Polyurethane 7 French tubing was coated with a solution containing the 
following ingredients and dried 15 minutes at 75.degree. C.: 
______________________________________ 
Methylethylketone 5.6 g 
Heparin-benzalkonium chloride 
0.33 g 
Isopropanol 3.5 g 
Polyurethane resin 0.24 g 
Polyisocyanate resin 0.19 g 
Ethyl acetate 0.19 g 
______________________________________ 
Samples were extracted in plasma at 37.degree. C. for 72 hours and then 
tested for anti-clotting properties. A sample of polyurethane tubing which 
was coated with heparin-benzalkonium chloride (1.8% w/v in isopropanol) 
was also extracted in plasma at 37.degree. C. for 72 hours for comparison. 
The following results were obtained: 
______________________________________ 
Sample Clotting Time 
______________________________________ 
Uncoated control 13 minutes 
Above sample, after 72 hours extraction in plasma 
Did Not Clot 
Sample coated with heparin-benzalkonium 
7 minutes 
chloride in isopropanol, after 72 hours 
extraction in plasma 
______________________________________ 
The above coating was also resistant to removal by hot running water. 
EXAMPLE 12 
Polyurethane 7 French tubing was coated with a solution containing the 
following ingredients and dried for 20 minutes at 70.degree. C. 
______________________________________ 
Methylethylketone 5.9 g 
Heparin-benzalkonium chloride 
0.32 g 
Isopropanol 3.5 g 
Polyurethane resin 0.14 g 
Polyisoyanate resin 0.07 g 
Ethylacetate 0.07 g 
______________________________________ 
Samples were then extracted in human plasma at 37.degree. C. for 3, 24, and 
48 hours and then tested for anti-clotting properties. The following 
results were obtained: 
______________________________________ 
Sample Clotting Time 
______________________________________ 
Uncoated control 8 minutes 
Above sample, after 3 hours extraction in plasma 
Did Not Clot 
Above sample, after 24 hours extraction in plasma 
Did Not Clot 
Above sample, after 48 hours extraction in plasma 
9 minutes 
______________________________________ 
EXAMPLE 13 
Polyurethane 7 French tubing was coated with a solution containing the 
following ingredients and dried for 20 minutes at 70.degree. C. 
______________________________________ 
Methylethylketone 6.1 g 
Heparin-benzalkonium chloride 
0.32 g 
Isopropanol 3.5 g 
Polyurethane resin 0.07 g 
Polyisoyanate resin 0.04 g 
Ethylacetate 0.04 g 
______________________________________ 
Coated tubing was then extracted in plasma for 3 and 24 hours and then 
tested for anti-clotting behavior. The following results were obtained: 
______________________________________ 
Sample Clotting Time 
______________________________________ 
Uncoated control 8 minutes 
Above sample, after 3 hours extraction in plasma 
Did Not Clot 
Above sample, after 24 hours extraction in plasma 
9 minutes 
______________________________________ 
EXAMPLE 14 
Polyurethane 7 French tubing was coated with a solution containing the 
following ingredients and dried for 20 hours at 55.degree. C. 
______________________________________ 
Heparin tridodecylmethylammonium chloride 
0.32 g 
Dimethylacetamide 6.2 g 
Toluene 2.0 g 
Petroleum ether 1.5 g 
______________________________________ 
The coated tubing was extracted in human plasma at 37.degree. C. for 1, 2, 
3 and 6 days and then tested for anti-clotting properties. 
______________________________________ 
Sample Clotting Time 
______________________________________ 
Uncoated sample 10 minutes 
Above sample, after 1 day extraction in plasma 
Did Not Clot 
Above sample, after 2 days extraction in plasma 
Did Not Clot 
Above sample, after 3 days extraction in plasma 
Did Not Clot 
Above sample, after 6 days extraction in plasma 
Did Not Clot 
______________________________________ 
The preceding examples, together with controls, show clearly that 
heparin-quaternary ammonium compounds that are not polymeric can be made 
more resistant to removal or deactivation in various body fluids such as 
whole blood or plasma (including human) by mixing with appropriate 
water-insoluble polymers. Coatings made from normal heparin-quaternary 
ammonium compounds by themselves using solvents that do not cause mixing 
with the substrate, such as heparin-benzalkonium chloride, or heparin 
tridodecylmethylammonium chloride show little anti-thrombogenicity after 
soaking in human plasma for only a few hours. The heparin-TDMAC compound 
continues to show anti-thrombogenicity somewhat longer than the 
benzalkonium chloride compound, but both exhibit almost no 
anti-thrombogenicity after soaking in human plasma for a few hours. The 
incorporation of water-insoluble polymers according to the present 
invention, and as shown in the examples, greatly extends the time for 
which coating samples can be soaked in human plasma and still show 
substantially levels of anti-thrombogenicity. For instance, some samples 
were found to show anti-thrombogenicity even after soaking in human plasma 
for 28 days. 
On the other hand, when quarternary ammonium polymers are reacted with 
heparin, the coating remains on the surface even after long periods of 
soaking in body fluids such as human plasma, but the anti-thrombogenicity 
is not as strong either before soaking or after soaking for up to 28 days 
in human plasma, as in the samples made according to this invention. It is 
further noted that by water-insoluble polymers we are implying that they 
are water-insoluble after a film is cast and dried, and include 
water-insoluble polymers that may be hydrophilic, but nevertheless cause 
the heparin-quaternary ammonium compounds to remain anti-thrombogenic 
after prolonged soaking in body fluids. 
Other modifications and ramifications of the present invention would appear 
to those skilled in the art upon a reading of this disclosure. These are 
intended to be included within the scope of this invention.