JPH1085320A - Biostatic coatings and processes - Google Patents

Abstract

PROBLEM TO BE SOLVED: To make it possible to hold both the lubricating ability and biological effect for a long time by forming a hydrophilic coating from a hydrophilic polymer layer, into which such an antibacterial agent as agents consisting of 2-hydroxy diphenyl ether halide and the like is dispersed. SOLUTION: As an antimicrobial agent to be put into a hydrophilic coat, an derivative either from 2-hydroxydiphenyl ether halide or 2-acyloxy diphenyl ether halide is used. If the medical equipment surfaces were coated with this derivative, the antimicrobial agent is discharged out at a speed effective to suppress the growth of various infectious microorganisms. A binder polymer is added into the hydrophilic coatings, as required. As an antimicrobial agent, others include the use of 2,4,4'-trichloro-2'-hydroxy diphenyl ether or its same family or derivative. For hydrophilic polymer, either water soluble polymer or its derivative is used.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention relates to a bioactive
coatings (paints, coatings) and methods of applying such coatings (paints) to substrates such as medical devices.

[0002] Most hospital infections result from catheterization procedures. The most common infectious bacteria are, among others, Staphylococc epidermis (Staphylococc
usepidermis), Staphylococcus aureus (Staph
ylococcus aureus), Escherichia
coli), Proteus mirabilis
Is included. Many of these infections are difficult to treat with antimicrobial agents and often require cessation of use of medical devices that cause trauma to the patient and increase medical costs. Furthermore, encrustation of medical equipment
Are urinary tracks and G. I. A significant problem associated with catheterization procedures performed on GI tracks. Mineralization
process) often involves bacterial colonization that requires removal of the implanted device. Also, the presence of encrust on the surface of the device makes it more difficult and more painful to remove the device from the patient. As a result, anti-static coatings suitable for application to the medical device and effective in preventing or reducing the colonization of any of these infectious bacteria on the medical device surface are highly desirable.

A number of antimicrobial agents have been studied for their ability to control infection by incorporation into medical devices. For example, Trooskin et al. (1985) found a lower degree of catheter contamination in laboratory animals due to non-covalent attachment of antibiotics to the catheter. Chlorhexidine (Brook, Douglas and Van Noort, 1986
Years), silver oxide (Schaeffer, Story, and Johnson, 19
88), silver sulfadiazine and chlorhexazine (Ar
row International), Iodine-Povidone
vidone® conjugate (CRBard), reduced bacterial adhesion on medical devices has been reported by incorporating antimicrobial agents such as benzalkonium chloride (Tebbs and Elliott, 1993) on medical devices. . In general, these antimicrobials have the following advantages: (1) they have a relatively high MIC for inhibiting these infectious bacteria;
(Minimum inhibitory concentrations), and thus their bactericidal activity is not sustained, and (2) many of these antimicrobial agents exhibit unacceptable cytotoxicity at the MIC levels required to control infectious bacteria. It has one or both of the two disadvantages.

[0004] Another antimicrobial agent, 2,4,4'-trichloro-2'-hydroxydiphenyl ether (Irga
san DP 300 or Triclosan (registered trademark), a commercial antibacterial agent manufactured by Ciba Geigy) to form it into plastic to make it self-disinfecting. Is reported (K
ingston, Seal, and Hill, 1986). This method is limited by the high molding temperatures that exceed the heat capacity of antimicrobial agents required for many high performance plastics. Moreover, the effectiveness of such compositions is further limited by the rate of diffusion of the antimicrobial agent through the plastic matrix. Yet another concern is the potential deleterious effects of antimicrobial contamination on the physical and mechanical properties of plastic devices. Accordingly, there is a need for an antimicrobial coating for substrates such as medical devices that retains bioefficacy over time, is lubricious, and is applicable to a wide range of materials. .

[0005]

SUMMARY OF THE INVENTION Quite unexpectedly, according to the present invention, when a halogenated hydroxy or acyloxy diphenyl ether (HDPE) is incorporated into a hydrophilic coating, the resulting coating has desirable properties for the control of the aforementioned infectious microorganisms. It turned out that we could show the combination of Even more important features of the hydrophilic coating containing HDPE are:
(1) the coating often exhibits sustained bioavailability against a variety of common infectious microorganisms; (2) the coating has a very low degree of activity compared to the more conventional antimicrobial agents described above. (3) the coating composition is plastic,
Can be used on a variety of substrates, including elastomers, metals, and ceramics; (4) the hydrophilic surface often makes bacterial attachment more difficult;
(5) The coating is preferably lubricious, which makes it easier to insert and remove the medical device and minimizes the potential for injury to the body.

[0006]

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "biostatic" refers to bacteria that are in contact with or in the immediate vicinity of a hydrophilic coating, but kill systemic effects. (Systemic effect), that is, a compound that does not generally affect the body.

The antimicrobial agent of the present invention is derived from halogenated 2-hydroxy-diphenyl ether or halogenated 2-acyloxy-diphenyl ether. The antimicrobial agent is incorporated into the hydrophilic coating where it is released at a rate that is preferably safe but effective to inhibit the growth of many common infectious microorganisms on medical device surfaces. The antimicrobial agent is incorporated into a suitable hydrophilic coating composition so that the medical device also preferably provides a hydrophilic, lubricious, and antistatic surface that is effective in reducing bacterial colonization. .

The antibacterial agent is an active ingredient against microorganisms of the formula 1 in US Pat. No. 3,629,477.
And the following halogenated 2-hydroxy-diphenyl ethers or halogenated 2-acyloxy-
It is preferably one of diphenyl ethers.

[0009]

Embedded image

In the formula 1, each Hal represents the same or different halogen atom, Z represents hydrogen or an acyl group,
w represents a positive integer ranging from 1 to 5, and each of the benzene rings, preferably ring A, has one or several lower alkyl groups (optionally halogenated);
It may have a lower alkoxy group, an allyl group, a cyano group, an amino group, or a lower alkanoyl group.

The lower alkyl group or lower alkoxy group as a substituent on the benzene ring preferably means a methyl group or a methoxy group, respectively, and the lower halogenated alkyl group is preferably a trifluoromethyl group.

The action analogous to the biocidal action of the halogen-o-hydroxy-diphenyl ether of the formula 1 is that its O-form, which partially or completely hydrolyzes under the conditions of practical use.
This is also achieved by using an acyl derivative. Esters of acetic acid, chloroacetic acid, methyl or dimethylcarbamic acid, benzoic acid, chlorobenzoic acid, methylsulfonic acid and chloromethylsulfonic acid are particularly preferred.

The polymer constituting the coating film of the present invention may be any water-soluble or water-swellable synthetic or natural polymer which can be applied by any conventional coating method to obtain an adhesive hydrophilic coating film. And coalescence. As used herein, the term "water-swellable" refers to a substantially hydrophilic polymer that absorbs enough water to make the polymer lubricious in a hydrated state, even if it is not soluble in water. means. In addition, as used herein, the term "hydrophilic" refers to the fact that water droplets do not readily form beads on the surface of such a hydrophilic substance, and instead, the water droplets are 45 ° on the surface. Taking the following contact angles means that they tend to spread easily.

Representative polymers include the following: Synthetic water-soluble or water-swellable polymers Polyacrylates such as poly (acrylic acid), poly (hydroxyethyl acrylate), poly (dimethylamino-ethyl acrylate), and copolymers thereof. 2. Poly (vinyl alcohol) and copolymers thereof with vinyl acetate. 3. Poly (ethylene oxide), poly (ethylene glycol), and copolymers thereof with each of poly (propylene oxide) and poly (propylene glycol). 4. Maleic anhydride polymers such as (maleic anhydride-methyl vinyl ether) copolymer. 5. Polyacrylamides and their copolymers. 6. Poly (vinyl lactams) such as poly (vinyl pyrrolidone) and copolymers thereof. 7. Poly (ethylene imine). 8. Poly (styrene sulfonate) and copolymers thereof. 9. Water-soluble nylon. 10. Poly (methacrylamidopropyltrimethylammonium chloride) and copolymers thereof. 11. Poly (2-acrylamido-2-methylpropanesulfonate) and copolymers thereof. 12. Poly (acrylic acid) -poly (ethylene oxide)
Complexes and polymer complexes such as poly (acrylic acid) -poly (vinylpyrrolidone) complexes.

II. Natural polymers 1. Cellulose polymers such as carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polymers JR and LR® (trade names for quaternized cellulose polymers manufactured by Union Carbide). 2. Polysaccharides such as guar gum, arginic acid, gum arabic, chitosan, hyaluronic acid. 3. Starches such as carboxymethyl starch and dialdehyde starch. 4. Proteins such as gelatin and collagen.

Those skilled in the art will recognize that water-soluble and water-swellable derivatives of the above identified polymers can also be used according to the present invention. Further details regarding the selection and application of suitable coating chemicals are known to those skilled in the art.

When coatings are applied on medical devices made of hydrophobic materials, it is often necessary to impart adhesion to the surface in order to achieve an adhesive coating. This is for example: (1),
Use of a binder polymer such as a reactive primer (such as a polyisocyanate or silane coupling agent); (2) plasma surface treatment or in situ plasma polymerization; (3) addition of a compatible and hydrophobic polymer; (4)
Inter alia, surface etching with chemical reagents known to those skilled in the art. A preferred method is the use of a polyisocyanate primer, as described in US Pat. No. 5,091,205.

The coating of the present invention may comprise, in addition to the binder polymer and the hydrophilic polymer, for example, surfactants, preservatives, viscosity modifiers, pigments, dyes, block inhibitors, and other additives known to those skilled in the art. One or more additives commonly used in coating formulations such as agents can be included. In addition, other functional additives that ionically bond to the hydrophilic polymer can also be used. These additives include, for example, therapeutics and antithrombogens (antithromogens).
mbogenic agents).

In the coating method of the present invention, the binder polymer and the hydrophilic polymer can be supplied from a liquid contained in a solution, dispersion or emulsion of the polymer. In the one-step coating method, the binder polymer and the hydrophilic polymer are contained in the same liquid medium. In the two-stage method, the binder polymer and the hydrophilic polymer are contained in separate liquid media. Additional coating steps can be employed to introduce different polymers or additives. The liquid medium used to supply the binder polymer and the hydrophilic polymer can be an organic substance, an aqueous substance, or an organic-aqueous mixture. The liquid medium used to supply the binder polymer can be selected to have some solubility in the substrate, ie, when the substrate is a polymer. This can enhance the adhesion between the binder polymer and the substrate and promote film formation of the coating material. Preferred liquid media for supplying the binder polymer and the hydrophilic polymer are, for example, esters such as ethyl acetate and isopropyl acetate; ethyl acetate; alcohols such as isopropyl alcohol, ethanol and butanol; Ketones such as diacetone alcohol and methyl isobutyl ketone; amides such as dimethylformamide; toluene; glycol ethers such as butyl glycol ether; chlorinated solvents such as dichloroethane; water; and mixtures thereof. However, it is not limited to them. The liquid medium is preferably selected such that the binder polymer and the hydrophilic polymer evenly wet the surface of the substrate to be coated.

The concentration of the binder polymer and the hydrophilic polymer in the liquid medium is preferably a concentration sufficient to obtain a desired amount of each polymer in the coating film. The concentration of the binder polymer in the liquid medium typically ranges from about 0.05% to 10% by weight, preferably from about 0.2% to 2% by weight, based on the total weight of the liquid medium. Over. The concentration of the hydrophilic polymer typically ranges from about 0.1% to 20%, preferably from about 0.5% to 5% by weight, based on the total weight of the liquid medium. Further details regarding the selection of a liquid medium for supplying the binder polymer and the hydrophilic polymer of the present invention are known to those skilled in the art.

The concentration of the antimicrobial agent in the liquid medium is preferably sufficient to obtain the desired amount of antimicrobial activity in the coating. The concentration of the antimicrobial agent in the liquid medium is typically about 0.000, based on the total weight of the liquid medium.
1% to 10% by weight, preferably about 0.002%
It ranges from 5% to 5% by weight. The concentration of the antimicrobial agent in the cured coating is typically about 0.2% by weight, based on the total weight of the coating, i.e., the solids content of the liquid medium.
To 80% by weight, preferably from about 1% to 50% by weight.

The antimicrobial agent can be incorporated into the coating composition by various methods to achieve a corresponding performance.
For example, the antimicrobial agent can be incorporated into the coating as either a solution, or a dispersion, or an emulsion. The antimicrobial agent can be incorporated into the coating either before, together with, or after application of the hydrophilic polymer. To achieve a more uniform distribution in the coating matrix, it is preferable to incorporate and apply the antimicrobial agent simultaneously with the hydrophilic polymer.

The coating method of the present invention is preferably carried out at atmospheric pressure and in a liquid phase at a temperature of about 10 to 90 ° C. The residence time for contacting the surface of the substrate to be coated with a liquid medium containing a binder polymer or a hydrophilic polymer, or both, is about 1 hour.
It ranges from seconds to 30 minutes, preferably from about 10 seconds to 10 minutes. After application of the coating, it is generally desirable to dry the coating at a temperature of about 20 to 150 ° C, preferably in a forced air oven. If desired, a microwave oven and an infrared heater can be used. Typical drying times range from about 1 minute to 24 hours, preferably from about 10 minutes to 5 hours. When the two-step coating method is adopted, it is preferable to dry the binder polymer before applying the hydrophilic polymer.
If the coating composition contains one or more unsaturated monomers or prepolymers, the curing step can be performed with ultraviolet light, electron beam, gamma radiation, or other suitable radiation source.

The lubricating coating obtained from the coating method of the present invention typically has a thickness of about 0.05 to 10 microns,
Preferably it has a thickness of about 0.1 to about 5 microns. When the two-step coating method is employed, the resulting coating film is rich in the binder polymer contacting the surface of the substrate, that is, the inner layer containing 50% or more of the binder polymer and the hydrophilic polymer contacting the inner layer. It is preferable to comprise an outer layer rich in coalescence, that is, containing an outer layer containing 50% or more of a hydrophilic polymer. The outer layer enriched in the hydrophilic polymer has an outer surface that is preferably lubricious when exposed to an aqueous liquid. If a one-step coating method is employed, the resulting coating preferably comprises a single layer, which is a substantially uniform mixture of a binder polymer and a hydrophilic polymer. However, it is likely that a higher concentration of binder polymer will be present near the surface of the substrate since the binder polymer will often have a greater affinity for the substrate than for the hydrophilic polymer.

The antistatic coating of the present invention can provide a number of important advantages over the prior art "self-sterilizing plastics". First, the coating is independent of the component materials of the equipment to be applied and is therefore widely useful for a variety of substrates. Second, antimicrobial agents are readily available on the outer surfaces of the device where microbial colonization is paramount. Third, the release rate of the antimicrobial agent, and thus the bioavailability of the device, is controlled primarily by the solubility of the antimicrobial agent in the water-swellable coating matrix, without changing with the components of the device. Fourth, the hydrophilic coating is preferably lubricious in the presence of an aqueous liquid, such as a bodily fluid, which makes it more difficult for microorganisms to adhere to the substrate. Fifth, the presence of the antistatic coating preferably results in a bulk property of the substrate material.
rty) will not be adversely affected. Sixth, the antistatic coating of the present invention can reduce the occurrence of encrustation on the surface, thus extending the useful life of the medical device. Thus, the present invention provides for predictable, sustained and safe release of antimicrobial agents to various substrates, regardless of their material and method of construction.

The antistatic coating film of the present invention can be used for any medical device in which suppression of microbial colonization is desired. Representative medical devices suitable for this purpose are urine and ureteral stents, Foley catheters, centralvenous catheters, infusion catheters, endotracheal tubes, introducers, among others. Includes drains, instruments, trauma dressings, pacemaker leads. Medical devices to which the coating of the present invention can be applied, and other devices include polyurethane, poly (vinyl chloride), polyacrylate, polycarbonate, polystyrene, polyester resin, polybutadiene-styrene copolymer, nylon, polyethylene, polypropylene, and polybutylene. , Silicon, poly (vinyl acetate), polymethacrylate, polysulfone, polyisoprene, copolymers and derivatives thereof, glass, metals, ceramics, and mixtures thereof.

The following examples illustrate the formulation of the antistatic coating of the present invention,
It illustrates the coating method, and bioavailability, but does not limit the scope of the claims. Chemicals used in the examples are standard reagents unless otherwise indicated, and are easily obtained from the market.

[0028]

Example 1 This example relates to a high molecular weight water-soluble polymer and 2,
The preparation of a coating solution containing both 4,4′-trichloro-2′-hydroxydiphenyl ether will be described. D in a 2 liter stainless steel reactor equipped with a turbine stirrer, condenser, thermometer, and external heating bath
520 grams of MF (Mallinckrodt) (also described as g), 264 g of MEK (Mallinckrodt), 200 g of tertiary butyl alcohol (Arco), and MYRJ-53 (ICI
0.5 g of ethoxylated stearic acid (manufactured by Seiko Epoxy Co., Ltd.) was charged with stirring. Once a homogeneous solution was obtained, poly (acrylic acid) (Carbopol® 9 from BF Goodrich, a homopolymer having a molecular weight of 12,500,000)
40NF) 15 g of powder were introduced by direct injection into the reactor. The reactor was heated to 50 ° C. and kept at this temperature with stirring at 2,000 RPM for 1 hour. Thereafter, the reactor was cooled to room temperature and the product was removed through a 10 micron polypropylene filter cartridge. A uniform colloidal dispersion was obtained. 180.02 g of the filtered product was transferred to a Waring blender and added to 2,4 over 2 minutes.
4'-trichloro-2-hydroxydiphenyl ether (Irgasan (registered trademark) DP300, manufactured by Ciba Geigy) 1
It was mixed with 0.01 g. The antimicrobial agent dissolved completely in the organic medium of the colloidal dispersion, resulting in a homogeneous fluid.

[0029]

EXAMPLE 2 An 8 French Percuflex.RTM. Catheter (made of ethylene-vinyl acetate copolymer) was placed on a 6 inch stent.
Cut at t). The stent was wiped with freon and air dried for 5 minutes. Next, the catheters were placed in a polyisocyanate primer (Poly-Ion
Immerse in a coating bath containing slip® Coating P-106) for 10 seconds and then in a forced air oven for 6 seconds.
Dry at 5 ° C. for 10 minutes. The stent was then immersed in another coating bath containing the coating solution prepared in Example 1 for 1 second and then dried in a forced air oven at 65 ° C. for 1 hour. The finished coating was uniform.

[0030]

Example 3 This example describes a method for measuring the coefficient of static friction (COF) of a catheter in the presence of water. A sliding block test is employed for this measurement, in which a rectangular block wrapped with a wet membrane is placed on the surface of two parallel mounted catheters in the presence of distilled water. Slowly tilt the platform on which the catheter rests until the block slides out. Measure the angle φ. The static COF is calculated as the tangent φ. Mechanical abrasion by pushing or pulling the catheter ten times or more through a silicone elastomer grommet (having a diameter 10% smaller than the outer diameter of the catheter) to which the wet catheter is secured. To serve. The worn catheter is then measured again to determine the post-wear COF. The COF before and after 10 wear operations on the coated catheter in Example 2 was found to be 0.04 and 0.04, respectively. The COF for the uncoated Parkflex stent was measured to be about 1.0.

[0031]

Example 4 This example illustrates a soft coating formulation. In this formulation, the hydrophilic polymer complex was 2,4,4.
Used with 4'-trichloro-2'-hydroxydiphenyl ether. 250 g of the colloidal dispersion prepared in Example 1, Polylslip® Coating
S-701 (DMFL-MEK- manufactured by Union Carbide)
a mixture of tBOH) 107.5 g, and 2,4,4'-
Trichloro-2-hydroxydiphenyl ether 3.6
1 g of the mixture at 30 ° C. in a Waring mixer
For 2 minutes to produce a uniform dispersion. A 14 French Parkflex catheter was cut into 10 inch stents. The stent was cleaned with isopropyl alcohol and then air dried for 10 minutes. The clean stent was immersed in a coating bath containing Polyslip Coating P-106 for 30 seconds and then dried in a forced air oven at 65 ° C. for 20 minutes. The stent is then immersed in another coating bath containing the solution prepared above for 1 second and then in a forced air oven at 65 ° C for 1 second.
Dried for hours. The stent was prepared using Polyox® WSRN.
It was immersed again in a third coating bath containing a 5% solution of -80 [poly (ethylene oxide) having a molecular weight of 200,000] for 1 second and then dried in a forced air oven at 65 ° C for 12 hours. The coating was uniform and lubricious in the presence of water. The COF in the presence of water measured before and after 100 wear operations was found to be 0.07 and 0.1, respectively. The COF for the uncoated catheter was 1.0.

[0032]

Example 5 Example 4 was repeated except that (1) 2,4,4'-trichloro-2-hydroxydiphenyl ether was used in an amount of 3.
18.8 g instead of 61 g, and (2) the third coating bath contains a 0.75% aqueous solution of PVP K-90 (poly (vinylpyrrolidone) having a molecular weight of 700,000 from ISP) And repeated except that the immersion time was 10 minutes instead of 1 second. The finished coating was uniform and lubricious in the presence of water. The COF in the presence of water measured before and after 100 wear operations was found to be 0.14 and 0.17, respectively. The COF for the uncoated catheter was 1.0.

[0033]

Example 6 Example 5 was repeated except that (1) 2,4,4'-trichloro-2-hydroxydiphenyl ether was used in an amount of 1
(2) Antibacterial agent was replaced with poly (acrylic acid)
Prior to mixing with the colloidal dispersion, first dissolving in the solvent mixture; and (3) increasing the poly (vinylpyrrolidone) concentration from 0.75% by weight to 1.0% by weight, and As chlorine 20p in the form of Clorox®
This was repeated except that pm was also contained. The colloidal dispersion containing both the poly (acrylic acid) and the antimicrobial had a Brookfield viscosity of 3.7 centistokes and an average particle size of 1.2 microns. The finished coating was uniform and lubricious in the presence of water.

[0034]

Example 7 The degree of lubricity and abrasion resistance of the coating film prepared in Example 6 was measured with a force gauge described below.
Measured according to e). The coated catheter is withdrawn in the presence of water through an annular opening punched in the silicone membrane, wherein the inner diameter of the opening is slightly smaller than the outer diameter of the catheter to provide a firm grip during withdrawal, The frictional force generated at this time is a measure of the surface lubricity. The lower the friction force, the greater the lubricity,
The reverse is also true. The measurements were made using a device that could withdraw the catheter through the silicone grommet at a constant rate of 4.5 inches per minute. Using this method, 10
The friction force values before and after the zero wear operation and the friction force value for the uncoated catheter were 4.2, 10.7 and 39.5 g, respectively. These results indicate a high degree of lubricity of the coated catheter.

[0035]

Example 8 Polyslip Coating P-106 was replaced by a higher molecular weight polyisocyanate made from diphenylmethane diisocyanate and a high molecular weight polyester polyol having an isocyanate equivalent weight of 225 and an isocyanate content of 18.7%. Except that Example 6 was repeated. The finished coating was uniform and lubricious in the presence of water. 100 of coated catheter
The friction force values before and after the wear operation and for the uncoated catheter were 4.0, 3.3 and 39.5 g, respectively.
It turned out to be.

[0036]

Example 9 Polyslip Coating P-106 was prepared from toluene diisocyanate and polyol, and had an equivalent weight of 5%.
Example 4 was repeated except that the polyisocyanate was replaced with 25 and a polyisocyanate having an isocyanate content of 8%. The finished coating was uniform and lubricious in the presence of water.
The friction values for the coated catheter before and after 100 wear operations and for the uncoated catheter were found to be 12.2, 14.9 and 28.7, respectively.

[0037]

EXAMPLE 10 A 11.5 inch two-piece piece of a 14 French sized Parkflex catheter was cleaned with isopropyl alcohol and then air dried. A clean catheter was mixed with 1% by weight of a vinyl chloride copolymer (UCAR, (registered trademark) VMCA) manufactured by Union Carbide,
3.5% by weight of 2,4,4′-trichloro-2′-hydroxydiphenyl ether, and ethyl acetate (Mal
linckrodt) for 30 seconds in a coating bath containing 95.5% by weight. The wet catheter was dried in a forced air oven at 65 ° C. for 30 minutes. Then, 0.5% by weight of polymer JR (registered trademark) (quaternized cellulose polymer manufactured by Union Carbide),
Isopropyl alcohol 5% by weight and water 95% by weight
In a second coating bath containing The catheter was fired in a forced air oven at 65 ° C. for 1 hour. The coating was uniform. The coated catheter exhibited a contact angle with distilled water of 36 ° C. as compared to 58 ° C. for the uncoated control. The COF for the coated and uncoated catheters was found to be 0.17 and 0.67, respectively.

[0038]

Example 11 This example demonstrates the excellent biological effectiveness of the anti-static coating composition of the present invention against some common infectious bacteria.
This is demonstrated using the zone of inhibition method. In controlling a given bacterium, the larger the zone, the greater the efficacy of the antimicrobial agent. The results are shown in Table I.

[0039]

TABLE 1 TABLE I zone of inhibition, the type antibacterial agent of mm coating, wt% S.aureus E.coli P.mirabilis Example 6 1 35.3 7 Example 6 2.5> 40 32 13.1 Example 6 3.5> 40 41.8 18.2 Example 8 3.5> 40 27 16.3 without coating 0 0 0 0

[0040]

Example 12 This example relates to 2,4,4'-trichloro-
Figure 2 illustrates the non-hemolytic properties of antistatic coatings containing 2'-hydroxydimethyl ether. In vitro hemolysis tests for hydrogel antistatic coatings containing different levels of antimicrobial agents were performed using rabbitwood containing EDTA to detect NAmSA from Northwood OH.
(Registered trademark). In each case two samples were tested and the results are shown as the average of the two tests.
The results are shown in Table II.

[0041]

Table II Type of coating film Antibacterial agent% Hemolytic% Example 900%, non-hemolytic Example 9 0.1%, non-hemolytic Example 9 10%, non-hemolytic Example 9500%, non-hemolytic

[0042]

Example 13 Examples 13 to 15 demonstrate the long-term bioavailability of antistatic coatings of the present invention in inhibiting the growth of some common infectious bacteria using different bioassays. To illustrate. The long term bioavailability of the anti-static coating prepared according to Example 6 was determined by the 10 ⁵ CFU
Challenge (challenge) by (colony forming unit)
The study was performed according to the inhibition zone in the agar culture tissue. Challenge the same catheter specimen, sterilized with ethylene oxide, with the same bacteria.
) Were transferred daily into fresh cultured tissue until no bioavailability was observed. The study ended at the end of 30 days irrespective of the bioavailability observed at 30 days. The results are shown in Tables III and IV.

[0043]

Table III Bioassay E. coli in Example 13 zone of inhibition data zone of inhibition against coli, mm observed observed sample first day 30th day biofilms discoloration coated non catheter 0 0 Yes Yes coated Yes Yes 0 0 having no antibacterial agent but coating the antimicrobial agent Done 16 15 None None

[0044]

Table IV Bioassay in Example 13 Data suppression band suppression bands for aureus, mm observed observed sample first day 30th day biofilms discoloration coated non catheter 0 0 Yes Yes coated Yes Yes 0 0 having no antibacterial agent but coating the antimicrobial agent Done 16 16.3 None None

[0045]

Example 14 All sterile catheter samples were subjected to trypticase (tr) before they were challenged with infectious bacteria.
ypticase) Example 13 was repeated except that it was cultured in soy broth at 37 ° C for 24 hours. The study was terminated at the end of 30 days regardless of the bioavailability observed on day 30. The results are shown in Tables V and VI.

[0046]

Table V. Bioassay E. coli in Example 13 zone of inhibition data zone of inhibition against coli, mm observed observed sample first day 30th day biofilms discoloration coated non catheter 0 0 Yes Yes coated Yes Yes 0 0 having no antibacterial agent but coating the antimicrobial agent 16.3 15.7 None None

[0047]

TABLE VI Bioassays in Example 14 Data suppression band suppression bands for aureus, mm observed observed sample first day 30th day biofilms discoloration coated non catheter 0 0 Yes Yes coated Yes Yes 0 0 having no antibacterial agent but coating the antimicrobial agent 16 16 None None

[0048]

Example 15 The pieces of the sterile catheter used in Example 13 were placed in three separate sealed flasks containing salt. Samples were placed in a shaking incubator at 37
Incubated at ℃. The protocol described in Example 13 (prot
Samples were taken at three-day intervals to determine the inhibition zone according to ocol). The remaining catheter fragment was transferred to a flask containing fresh salt, returned to the shaking incubator, and the experiment continued. Table VII and Table VII show the results measured up to 30 days.
Summarize in I.

[0049]

Table VII Bioassay E. coli in Example 15 zone of inhibition data zone of inhibition against coli, mm observed observed sample first day 30th day biofilms discoloration coated non catheter 0 0 Yes Yes coated Yes Yes 0 0 having no antibacterial agent but coating the antimicrobial agent 14 14 None None None

[0050]

Table VIII Bioassays Data suppression band suppression bands for aureus, mm observed observed sample first day 30th day biofilms discoloration coated non catheter 0 0 Yes Yes coated Yes Yes 0 0 having no antibacterial agent but coating the antimicrobial agent 17 17 None None None

[0051]

Example 16 In Examples 16 to 19, a method for producing a one-stage antibacterial coating composition containing 2,4,4'-trichloro-2-hydroxyduphenylether and coating on various medical devices were used. Is illustrated.

566.2 g of diacetone alcohol was charged into a 1 liter Waring mixer. While mixing, poly (vinylpyrrolidone) [Sigma poly (vinylpyrrolidone) -360, lot 123-42
3) and 1.16 g of UCAR® VMCA were added and the mixture was stirred for 5 minutes to obtain a homogeneous solution. The solution was then transferred to a glass bottle containing 21 g of the antimicrobial agent, which was then roll milled to obtain a uniform solution.

[0053]

EXAMPLE 17 Four latex Foley catheters (17 French, Baxter Healthcare) were wiped with IPA and air dried. The cleaned catheter was added to the coating solution prepared according to Example 16 for 3 hours.
Dipped for 0 seconds, air dried for 1 minute, and then further dried in a forced air oven at 85 ° C. for 3 hours. A clean and uniform coating was obtained. The finished catheter was sterilized by a standard ethylene oxide method, and no change was observed in physical properties.

[0054]

Example 18 A Foley catheter made of latex was replaced with P
Example 17 was repeated except that a set of VC endotracheal tubes was used and drying was performed at 90 ° C instead of 85 ° C. The sterilized, coated endotracheal tube was clear and uniform.

[0055]

Example 19 A Foley catheter made of latex was replaced with a urological stent (14 French Parkflex stent, manufactured by Boston Scientific) and dried at 65 ° C.
Example 17 was repeated again except that for 3 hours. Sterilized and coated Parkflex
The stent was uniform and smooth.

[0056]

Example 20 Unexpectedly, the antistatic hydrophilic coating film of the present invention
In a test tube model, Proteus mirabilis (Proteu
s Mirabilis) was also found to reduce the encrustation of medical devices exposed to human urine challenged. This is demonstrated by the following example.

In each of the six culture tubes, rehydrated urine (Pr
ichem® 12 ml, 100 Klett Proteus Mirabill
is) 100 microliters and a piece of 17 French latex Foley catheter were added. Three of the sterile catheter pieces were coated with an antistatic coating according to Example 6, and the other three were uncoated. Place all 6 culture tubes in a 37 ° C. incubator,
Cultured for 4 hours. Thereafter, the culture tube was taken out of the incubator and visually inspected for the degree of rust. All three uncoated catheter pieces showed varying degrees of rusting. On the other hand, all of the coated catheter pieces showed no visible rust on the surface.

Although the present invention has been described with respect to particular aspects, those skilled in the art will recognize that other aspects of the invention are within the scope of the claims. For example, antimicrobial agents can be incorporated into hydrophobic coatings or other coatings that are not hydrophilic or lubricious. The antimicrobial coating of the present invention can also reduce the occurrence of rust on medical devices often associated with catheterization procedures performed on urine and GI tracks.

 ──────────────────────────────────────────────────の Continued on the front page (72) Inventor Yu, Lynn, Fan United States, New Jersey 08816, East Brunswick, Heritage Court No. 3

Claims (10)

[Claims] 1. A medical device having a hydrophilic coating on its surface, said hydrophilic coating comprising: (i) a layer of a hydrophilic polymer adhered to the surface of said medical device; and (ii) said layer An antimicrobial agent dispersed therein, wherein the antimicrobial agent is selected from the group consisting of halogenated 2-hydroxydiphenyl ether, halogenated 2-acyloxydiphenyl ether or mixtures thereof. 2. The medical device of claim 1, wherein the coating further comprises a binder polymer. 3. The antibacterial agent is 2,4,4′-trichloro-
The medical device according to claim 1, which is 2'-hydroxydiphenyl ether or a homolog or derivative thereof. 4. The medical device according to claim 1, wherein the hydrophilic polymer is a natural water-soluble polymer or a derivative thereof. 5. The medical device according to claim 1, wherein the hydrophilic polymer is a synthetic water-soluble polymer or a derivative thereof. 6. The medical device according to claim 1, wherein the hydrophilic polymer is selected from the group consisting of poly (acrylic acid), a cellulose polymer, and a mixture thereof. 7. The medical device of claim 1, wherein the hydrophilic polymer comprises a mixture of at least two polymers including at least one water-soluble polymer. 8. A substrate surface, and (i) a hydrophilic polymer composition including a hydrophilic polymer; and (ii) a binder polymer and a hydrophilic polymer capable of binding to the substrate surface. A method of applying a hydrophilic coating film to a substrate surface, which comprises contacting a binder polymer composition with a binder polymer composition; wherein at least one of the binder polymer composition and the hydrophilic polymer composition is a halogenated 2
The above method, further comprising an antimicrobial selected from the group consisting of -hydroxydiphenyl ether, halogenated 2-acyloxydiphenyl ether, or mixtures thereof. 9. The method of claim 8, wherein an amount of the antimicrobial agent effective to inhibit microbial growth is used. 10. A hydrophilic polymer or a binder polymer is coated on a substrate, and then the monomer or prepolymer is polymerized to form the hydrophilic polymer or the binder polymer. At least one of the hydrophilic polymer or the binder polymer
9. The method of claim 8, wherein the seed is formed.