BIO-FILM RESISTANT SURFACES

PRIORITY CLAIM

This application claims priority to U.S. Application Serial No.

14/564,920 filed December 9, 2014, which is hereby incorporated by reference in its entirety herein.

1. INTRODUCTION

The present invention relates to methods and compositions for rendering a surface resistant to bio-film formation by a combination of an alkanediol and an antimicrobial agent (and, optionally, an organic hydroxy acid).

The present invention also relates to methods and compositions for rendering a surface resistant to bio-film formation by a combination of an

antimicrobial agent, an organic acid releasing agent, and a lubricious biomedical polymer. In certain embodiments, the composition may further comprise an alkanediol.

2. BACKGROUND OF THE INVENTION

Whenever a medical article comes in contact with a patient, a risk of infection is created. Thus, a contaminated examination glove, tongue depressor, or stethoscope could transmit infection. The risk of infection dramatically increases for invasive medical articles, such as intravenous catheters, arterial grafts, endotracheal or intracerebral shunts and prosthetic devices, which not only are, themselves, in intimate contact with body tissues and fluids, but also create a portal of entry for pathogens.

A number of methods for reducing the risk of infection have been developed which incorporate anti-infective compounds into medical articles. Ideally, such articles provide effective levels of an anti-infective compound during the entire period that the article is being used. This sustained release may be problematic to achieve, in that a mechanism for dispersing an anti-infective compound over a prolonged period of time may be required, and the incorporation of sufficient amounts of anti-infective compound may adversely affect the surface characteristics of the article. The difficulties encountered in providing effective anti-microbial protection increase with the development of drug-resistant pathogens.

Two well known anti-infective compounds are chlorhexidine and triclosan. The following patents and patent applications relate to the use of anti- microbial compounds in medical articles.

U.S. Pat. No. 4,723,950 by Lee relates to a microbicidal tube which may be incorporated into the outlet tube of a urine drainage bag. The microbicidal tube is manufactured from polymeric materials capable of absorbing and releasing antimicrobial substances in a controllable, sustained, time-release mechanism, activated upon contact with droplets of urine, thereby preventing the retrograde migration of infectious organisms into the drainage bag. The microbicidal tube may be produced by one of three processes: (1) a porous material, such as poly-propylene, is impregnated with at least one microbicidal compound, and then coated with a hydrophilic polymer which swells upon contact with urine, causing the leaching-out of the microbicidal compound; (2) a porous material, such as high density

polyethylene, is impregnated with a hydrophilic polymer and at least one microbicidal compound; and (3) a polymer, such as silicone, is compounded and co-extruded with at least one microbicidal compound, and then coated with a hydrophilic polymer. A broad range of microbicidal compounds are disclosed, including chlorhexidine and triclosan, and combinations thereof. The purpose of Lee's device is to allow the leaching out of microbicidal compounds into urine contained in the drainage bag; similar leaching of microbicidal compounds into the bloodstream of a patient may be undesirable.

U.S. Pat. No. 5,091,442 by Milner relates to tubular articles, such as condoms and catheters, which are rendered antimicrobially effective by the incorporation of a non-ionic sparingly soluble antimicrobial compound, such as triclosan. The tubular articles are made of materials which include natural rubber, polyvinyl chloride and polyurethane. Antimicrobial compound may be distributed throughout the article, or in a coating thereon. A condom prepared from natural rubber latex containing 1% by weight of triclosan, then dipped in an aqueous solution of chlorhexidine, is disclosed. U.S. Pat. Nos. 5,180,605 and 5,261,421, both by Milner, relate to similar technology applied to gloves.

U.S. Pat. Nos. 5,033,488 and 5,209,251, both by Curtis et al, relate to dental floss prepared from expanded polytetrafluoroethylene (PTFE) and coated with microcrystalline wax. Antimicrobial compounds such as chlorhexidine or triclosan may be incorporated into the coated floss.

U.S. Pat. No. 5,200,194 by Edgren et al. relates to an oral osmotic device comprising a thin semipermeable membrane wall surrounding a compartment housing a "beneficial agent" (that is at least somewhat soluble in saliva) and a fibrous support material composed of hydrophilic water-insoluble fibers. The patent lists a wide variety of "beneficial agents" which may be incorporated into the oral osmotic device, including chlorhexidine and triclosan.

International Patent Application No. PCT/GB92/01481, Publication No. WO 93/02717, relates to an adhesive product comprising residues of a co- polymerizable emulsifier comprising a medicament, which may be povidone iodine, triclosan, or chlorhexidine.

U.S. Pat. Nos. 5,019,096 and 5,616,338, both by Fox, Jr. et al. relate to infection-resistant medical articles comprising a synergistic combination of a silver compound (such as silver sulfadiazine) and chlorhexidine and their methods of manufacture, respectively. U.S. Pat. No. 5,334,588 by Fox, Jr. et al. relates to methods of inhibiting transmission of Hepatitis B virus using compositions comprising silver sulfadiazine and preferably further comprising a biguanide such as chlorhexidine and/or a detergent such as sodium deoxycholate.

U.S. Pat. Nos. 5,567,495, 5,772,640, 6,083,208 and 6,106,505 and U.S. patent publication Ser. Nos. 2001/0010016, 2001/0024661, 2002/0122876 and 2002/0173775, all by Modak et al., provide for, inter alia, anti-infective medical devices, either hydrophobic or hydrophilic, impregnated, coated, or impregnated and coated with various combinations of chlorhexidine, a silver salt such as silver sulfadiazine, silver oxide, silver carbonate or silver nitrate among others, a bismuth salt such as bismuth nitrate, bismuth citrate or bismuth salicylate among others, a zinc salt, a cerium salt, triclosan, combinations of chlorhexidine free base and

chlorhexidine acetate, benzalkonium chloride, citrate, povidone iodine,

parachlorometaxylene, gramicidin, polymixin, norfloxacin, tobramycin, sulfamylon, polyhexamethylene biguanide, alexidine, iodine, rifampicin, miconazole, bacitracin, and minocycline.

United States Patent Application Publication No. US 20060099237 Al relates to combinations of octoxyglycerin and anti-infective compounds that synergistically increase the anti-infective properties of medical articles impregnated and/or coated with various combinations of octoxyglycerin and anti-infective compounds relative to the anti-infective properties of medical articles impregnated and/or coated with the same anti-infective compounds without octoxyglycerin.

Salicylic acid, an organic β-hydroxy acid, traditionally used as an antithrombogenic agent, has been recently shown to affect bacterial infection and virulence. In endocarditis, Staphylococcus aureus causes endovascular infections, damaging endothelial cells of valvular tissue. Salicylic acid appears to mitigate the virulent effects, reducing growth and cellular density of S. awrews-induced infective endocarditis in an animal model (Kupferwasser et al., 1999 "Acetylsalicylic Acid Reduces Vegetation Bacterial Density, Hematogenous Bacterial Dissemination, and Frequency of Embolic Events in Experimental Staphylococcus aureus Endocarditis Through Antiplatelet and Antibacterial Effects," Circulation, 99:2791-2797;

Kupferwasser et al., "Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus " J Clin Invest. 2003; 112(2):222-33). In fact, salicylic acid modulates virulence by suppressing expression of adherence factors (Kupferwasser et al., "Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus " J Clin Invest. 2003;112(2):222-33).

U.S. Pat. No. 6,582,719, International Patent Application No.

PCT/US02/03087, and pending U.S. patent application Ser. No. 10/633,204, filed Jul. 30, 2003, all of which are incorporated by reference, disclose antimicrobial compositions comprising antiseptics, such as chlorhexidine, triclosan, and

benzalkonium chloride, and antibiotics, such as minocycline, which may be particularly useful against antibiotic -resistant microorganisms. It has been discovered, however, that although certain of the chlorhexidine-containing solutions exhibited a broad spectrum of activity against many organisms, the solutions became unstable, forming precipitates after a few days at room temperature. Having a short shelf life limits the application of these compositions in coating and impregnating medical devices.

Alkanediols are emollient solvents used in various applications, including in the cosmetics industry. Alkanediols are reported to have anti-fungal activity (Gershon, 2006, J. Pharm. Sci. 69(41:381-384). 3. SUMMARY OF THE INVENTION

The present invention relates to methods and compositions for rendering a surface resistant to bio-film formation by a combination of an alkanediol and an antimicrobial agent (and, optionally, an organic hydroxy acid). It is based, at least in part, on the discovery that a combination of octanediol, chlorhexidine, and lactic acid was observed to inhibit the adherence of certain bacteria and yeast to a catheter surface.

The present invention also relates to methods and compositions for rendering a surface resistant to bio-film formation by a combination of an

antimicrobial agent, an organic acid releasing agent, and a lubricious biomedical polymer. In certain embodiments, the composition may further comprise an alkanediol. In certain embodiments, the composition does not comprise an alkanediol. In certain embodiments, the composition does not comprise an antiinflammatory agent. The present invention is based, at least in part, on the discovery that chlorhexidine free base was soluble in solvents such as tetrahydrofuran (THF) or alcohol, when the chlorhexidine was combined with an organic acid and a lubricious biomedical polymer, such that the chlorhexidine composition prevents adherence of bacteria and biofilm formation on a device surface, but does not release therapeutic amount of antimicrobials to prevent systemic infection.

In one set of non-limiting embodiments, the present invention provides for compositions which may be used to render a surface resistant to bio-film formation. Such compositions may be solutions for impregnating or coating an article, or wipes comprising such solutions.

In another set of non-limiting embodiments, the present invention provides for methods of rendering a surface resistant to bio-film formation which utilize the aforementioned solutions or wipes.

In yet another set of non-limiting embodiments, the present invention provides for articles having a bio-film resistant surface created according to the invention.

In certain embodiments, the surface is an outer surface of a device, for example, a catheter. In certain embodiments, the surface is an inner surface of a device, for example, an inner lumen of a catheter.

The present invention may be used in the context of surfaces of medical articles or other surfaces which are desirably protected from microbe adherence, such as surfaces in an environment associated with child care, food preparation, etc.

4. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows scanning electron microscopic (SEM) images of urinary catheter surfaces that were uncoated (control), coated with a composition comprising chlorhexidine base, silver sulfadiazine and decanediol (CHX+AgSD+D), or coated with Lubri-Sil I.C. (manufactured by BARD medical, C. R. Bard, Inc.) after exposure to artificial urine comprising P. aeruginosa for 10 days, as described by Example 21. Catheters coated with CHX+AgSD+D did not exhibit formation of P. aeruginosa biofilm on the surface of the catheter, while control and Lubri-Sil I.C. coated catheters exhibited P. aeruginosa biofilm formation.

5. DETAILED DESCRIPTION OF THE INVENTION The present invention relates to methods and compositions for rendering a surface resistant to bio-film formation by coating the surface with a combination of an antimicrobial agent and a lubricious biomedical polymer. The present disclosure is based at least in part on the discovery that treating a surface with the compositions described herein provides for a non- or low-leaching antimicrobial surface which prevents the adherence of microbes to the surface, as well as the formation of biofilm on the surface, without leaching therapeutically effective amounts of antimicrobials from the surface. Such an effect is achieved by coating the surface with a composition comprising one or more insoluble antimicrobials, a matrix forming emollient solvent, hydrophilic and/or hydrophobic biomedical polymers, and a releasing agent. In certain embodiments, the releasing agent can be included in the composition in an amount sufficient to induce an initial release of antimicrobials from the surface, for example, the surface of a catheter, to inactivate pathogens, for example, pathogens introduced into a subject through a catheter insertion site into a catheter tract. In certain embodiments, the releasing agent is present in the composition at a concentration of between about 0.05 and 0.5% w/w. In certain embodiments, the releasing agent is present in the composition at a concentration of between about 0.5 and 5% w/w.

Without being bound to any theory, surfaces of devices coated with the compositions described herein exhibit an initial (for example, within 3 days) release of about 20% of the antimicrobials coated on the surface, which inactivate pathogens introduced into a subject from an insertion site of the device into the subject, thus lowering the potential for microbial colonization on the device surface after insertion into the subject. After this initial release, an effective amount of antimicrobials remains on the surface of the device, thereby preventing subsequent microbial adherence and biofilm formation on the device surface. In certain embodiments, catheter surfaces coated with the compositions described herein exhibit antimicrobial activity against, for example, P. aeruginosa and C. albicans, which is greater than the antimicrobial effect exhibited by catheter surfaces coated with other antimicrobial compositions, for example, compositions comprising silver alloy and hydrogel.

The present disclosure is also based at least in part on the discovery that surfaces coated with the compositions described herein are highly lubricious, without the need for a separate hydrogel coating. Accordingly, such catheters can be inserted easily and comfortably into a subject compared to uncoated catheters, without a time consuming and costly step of applying a hydrogel coating onto the surface of the catheter.

In certain embodiments, the solvents included in the formulations described throughout the present disclosure, for example, methanol, ethanol, isopropanol, methyl-ethyl-ketone, acetone, tetrahydrofuran (THF), benzyl alcohol, glycerin, and ethyl hexyl glycerin, are present in concentrations that are % volume by volume (v/v).

For clarity of description and not by way of limitation, the detailed description of the invention is divided into the following subsections:

(i) antimicrobial agents;

(ϋ) organic acid releasing agents;

(iii) solvents;

(iv) lubricious polymeric matrix;

(v) alkanediols;

(vi) hydroxy acids;

(vii) primer coating compositions;

(viii) one-step coating methods;

(ix) two-step coating methods;

(x) compositions for preparing a bio-film resistant surface;

(xii) methods for producing a bio-film resistant surface; and (xii) articles having a bio-film resistant surface.

"Bio-film resistant" as that term is used herein means that adherence of a microbe to the surface is inhibited. 5.1 ANTIMICROBIAL AGENTS

The present invention utilizes one or more biguanide, including, but not limited to, chlorhexidine, either as a free base, or a salt thereof, or a combination of free base and a chlorhexidine salt, poplyhexanide, and alexidine. Non-limiting examples include chlorhexidine diphosphanilate, chlorhexidine digluconate, chlorhexidine diacetate (also known as chlorhexidine acetate or CHA), chlorhexidine dihydrochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate, chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine di-acid phosphate, chlorhexidine difluoro- phosphate, chlorhexidine diformate, chlorhexidine dipropionate, chlorhexidine di- iodobutyrate, chlorhexidine di-n- valerate, chlorhexidine dicaproate, chlorhexidine malonate, chlorhexidine succinate, chlorhexidine malate, chlorhexidine tartrate, chlorhexidine dimonoglycolate, chlorhexidine monodiglycolate, chlorhexidine dilactate, chlorhexidine di-.alpha.-hydroxyisobutyrate, chlorhexidine

diglucoheptonate, chlorhexidine di-isothionate, chlorhexidine dibenzoate,

chlorhexidine dicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate, chlorhexidine di-2-hydroxynaphthoate, and chlorhexidine embonate and combinations thereof. Other examples of biguanides are polyhexamethylene biguanide and alexidine biguanide.

Other antimicrobial agents which may, in addition to a biguanide, be used according to the invention include, but are not limited to, phenoxyethanol, a tetracycline compound such as minocycline, polymixin, octoxyglycerin, a chlorinated phenol such as parachlorometaxylenol (PCMX) or triclosan, silver salts, benzyl benzoate, povidone iodine, nitrofurazone, berberine, alkanediols, and a quaternary ammonium compound such as benzalkonium chloride or benzethonium chloride. Combinations of such agents may also be used.

In preferred non-limiting embodiments, an antimicrobial agent to be used together with a biguanide is a silver compound. The term silver compound, as used herein, refers to a compound comprising silver, either in the form of a silver atom or a silver ion unlinked or linked to another molecule via a covalent or noncovalent (e.g. ionic) linkage, including but not limited to covalent compounds such as silver sulfadiazine ("AgSD") and silver salts such as silver oxide ("Ag ₂ 0"), silver carbonate ("Ag ₂ C03"), silver deoxycholate, silver salicylate, silver iodide, silver nitrate ("AgNOs"), silver paraaminobenzoate, silver paraaminosalicylate, silver acetylsalicylate, silver ethylenediaminetetraacetic acid ("AgEDTA"), silver picrate, silver protein, silver citrate, silver lactate and silver laurate and combinations thereof.

In certain embodiments, the antimicrobial is present in the composition of the present application at a concentration of between about 0.01 and 10.0% w/v; or between about 0.05 and 7.0% w/v; or between about 0.05 and 5.0% w/v; or between about 0.1 and 5% w/v; or between about 0.1 and 2% w/v; or between about 0.1 and 1 % w/v; or between about 0.1 and 0.5 % w/v. In certain embodiments, the

antimicrobial is present in the composition of the present application at a

concentration between about 0.05 and 5.0% w/w.

In certain embodiments, the antimicrobial comprises chlorhexidine, for example, chlorhexidine base (CHX), chlorhexidine acetate (CHA) or CHA+CHX, at a concentration of between about 0.05 and 7.0% w/v. In certain embodiments the composition further comprises a second or more antimicrobial, wherein the second or more antimicrobials are present at a concentration of between about 0.02 and 3.0% w/w, or between about 0.05 and 3.0% w/v. In certain embodiments the second or more antimicrobial is selected from the group consisting of silver salt and/or chlorinated phenol, for example, PCMX.

5.2 ORGANIC ACID RELEASING AGENTS

The term "releasing agent" as used herein refers to an agent that promotes the release of antimicrobial agent(s), or other bioactive agent(s), from a lubricious polymer matrix. In certain embodiments, the antimicrobial agent is released in an amount such that the antimicrobial agent prevents adherence of bacteria and biofilm formation on a device surface, but is not released in an amount to prevent systemic infection. In certain embodiments, once all of the releasing agent has been released from the lubricious polymer matrix (e.g., after at least 1, 2, 3, 4 or 5 days, or between 1-5, 2-4 or 2-3 days following insertion of a device coated with the lubricious polymer matrix into a subject), no further detectable release of

antimicrobials from the lubricious polymer matrix occurs. In certain non-limiting embodiments, the releasing agent can be comprised in the compositions of the present disclosure in an amount sufficient to induce an initial release of antimicrobials from the composition to inactivate pathogens or microbes, for example, pathogens or microbes introduced through an insertion site of a subject into which a device (for example, a catheter) coated with the compositions of the present disclosure is inserted. In certain non-limiting

embodiments, devices coated with the compositions of the present disclosure exhibit an initial (for example, within 2, 3, 4 or 5 days) release of about 10, 15, 20, 25, 30, or 35% of the antimicrobials which inactivate pathogens introduced from the insertion site. In certain non-limiting embodiments, after this initial release, an amount of antimicrobial remains on the surface of the device, which is effective to prevent, reduce or inhibit microbial adherence and biofilm formation on the device. In certain non-limiting embodiments, the device coated with the compositions of the present disclosure exhibit antimicrobial effects against P. aeruginosa and C. albicans. In certain non-limiting embodiments, the coatings described herein do not release a therapeutic amount of antimicrobial agents into systemic circulation when coated onto a medical device that is inserted or implanted into a subject.

In certain embodiments, the releasing agent comprises one or more organic hydroxy acid or fruit acid selected from citric acid, lactic acid, glycolic acid, mandelic acid, benzoic acid, salicylic acid, acetyl salicylic acid, ascorbic acid, and combinations thereof. In certain embodiments, the organic acid is present at a concentration of between about 0.01 and 7% w/v, or between about 0.05 and 5.0% w/v, or between about 0.05 and 4.0% w/v, or between about 0.1 and 5.0% w/v, or between about 0.1 and 2 % w/v, or between about 0.1 and 1 % w/v, or between about 0.1 and 0.5 % w/v, or between about 0.2 and 5.0% w/v; or between about 0.1 and 5.0% w/v of the coating solution. In other non-limiting embodiments, the ratio of releasing agent to antimicrobial agent is between 1:0.5 and 1: 10 and the ratio of releasing agent to the total amount of antimicrobial agent and/or additional bioactive agent is between 1:0.5 and 1:30.

In certain embodiments, the organic acid is present at a concentration of between about 0.2 and 2.05 w/w. 5.3 SOLVENTS

The present invention utilizes one or more solvents. Such solvents can include one or more of methanol, ethanol, isopropanol, methyl-ethyl-ketone, acetone, tetrahydrofuran (THF), benzyl alcohol, glycerin, ethyl hexyl glycerin, or

combinations thereof. In certain embodiments, the one or more solvent is present at a concentration of between about 1 and 80% v/v, or between about 10 and 70% v/v, or between about 2 and 50% v/v, or between about 5 and 30% v/v, or between about 2 and 20% v/v, or between about 10 and 50% v/v, or between about 20 an 70% v/v, or between about 0.05 and 10% v/v, or between about 0.1 and 8% v/v, or between about 0.5 and about 5% v/v, or between about 0.5 and 1% v/v.

In certain embodiments, the solvent comprises tetrahydrofuran (THF), and is present at a concentration of between about 10 and 70% v/v.

In certain embodiments, the solvent comprises methanol and/or ethanol, and is present at a concentration of between about 5 and 30% v/v.

In certain embodiments, the solvent comprises benzyl alcohol, and is present at a concentration of between about 0.5 and 5% v/v.

In certain embodiments, the solvent comprises glycerin, and is present at a concentration of between about 0.5 and 5% v/v.

In certain embodiments, the solvent comprises ethyl hexyl glycerin, and is present at a concentration of between about 0.5 and 5% v/v.

In certain embodiments, the solvents described herein can be combined with other ingredients, such as an antimicrobial and an organic acid releasing agent. In certain embodiments, the solvents described herein can be combined with other ingredients in the absence of a biomedical polymer.

5.4 LUBRICIOUS POLYMERIC MATRIX

A lubricious polymeric matrix as disclosed herein comprises a lubricious matrix system that comprises one or more biomedical polymer.

"Lubricious" means that the matrix system provides a smooth and slippery surface which resists adherence of substances on the surface. In certain embodiments, the lubricious polymeric matrix described herein comprises hydrophilic-hydrophobic polymers that are used as a matrix system to incorporate antimicrobials onto the surface of a device which render the surface highly lubricious and avoids the need for an overcoat with hydrogels to improve surface lubricity. In certain embodiments, the lubricious polymeric matrix does not comprise an anti-inflammatory agent.

In certain embodiments, a device coated with the compositions described herein does not comprise a hydrogel coating.

Non-limiting examples of suitable biomedical polymers include one or more of biomedical polyurethane, for example, hydrophilic polyurethane,

hydrophobic polyurethane, Tecoflex (aliphatic polyether-based polyurethanes), Pellethane or Estane polyurethane (thermoplastic polyurethanes) having Shore hardness of, for example, 70A, 80A, 93A, 100A, 50D, 55D, 60D, 65D, 70D, 70A to 70D durometer, 70A to 100A durometer and a 55D to 70D durometer. In certain embodiments the polyurethane is present at a concentration of between about 0.05 and 50% w/v, or between about 0.2 and 30% w/v, or between about 0.2 and 10.0% w/v, or between about 0.5 and 10% w/v, or between about 1 and 20% w/v, or between about 1 and 10% w/v. In certain embodiments the polyurethane is present at a concentration of between about 0.005 and 10% w/v, or between about 0.05 and 8% w/v, or between about 0.01 and 6% w/v, or between about 0.1 and 4% w/v. or between about 0.5 and 1% w/v.

Additional non-limiting examples of suitable biomedical polymers include one or more urethane adhesive. The urethane adhesive used can be from the medium to high viscosity Loctite Hysol® medical adhesive products, e.g. M-06FL, M-04FL, M-05 FL, M-09FL, M-31C1, M-121HP, M-4981. In certain embodiments the urethane adhesive is present at a concentration of between about 0.05 and 50% w/v, or between about 0.2 and 30% w/v, or between about 0.2 and 10.0% w/v, or between about 0.5 and 10% w/v, or between about 1 and 20% w/v, or between about 1 and 10% w/v. In certain embodiments the urethane adhesive is present at a concentration of between about 0.005 and 10% w/v, or between about 0.01 and 10% w/v, or between about 0.05 and 8% w/v, or between about 0.01 and 6% w/v, or between about 0.1 and 4% w/v. or between about 0.5 and 1% w/v. In certain embodiments the urethane adhesive is Loctite Hysol® M-06FL.

Additional non-limiting examples of suitable biomedical polymers include one or more silicone polymer, such as a hydrophobic silicone polymer or silicone adhesive. The silicone adhesive can be silastic medical adhesive silicone type A (Dow corning), medical adhesive A-100 (Factor II, Inc.), silicone adhesive MDT7- 4502 (Dow corning), and/or any other silicone polymer(s). In certain embodiments the silicone polymer or adhesive is present at a concentration of between about 0.05 and 50% w/v, or between about 0.2 and 30% w/v, or between about 0.2 and 10.0% w/v, or between about 0.5 and 10% w/v, or between about 1 and 20% w/v, or between about 1 and 10% w/v, or between about 5 and 10% w/v. In certain embodiments the silicone polymer or adhesive is present at a concentration of between about 0.005 and 10% w/v, or between about 0.2 and 10.0% w/v or between about 0.05 and 8% w/v, or between about 0.01 and 6% w/v, or between about 0.1 and 4% w/v. or between about 0.5 and 1% w/v.

Additional non-limiting examples of suitable biomedical polymers include one or more water insoluble and/or matrix forming decanediol; biodegradable polymer such as polylactic acid, polyglycolic acid, PLA, PGA, Polycaprolactone (PCL); cellulose polymers such as hydrophilic, hydrophobic or hydrophilic- hydrophobic polymer (e.g., hydroxypropyl methyl-cellulose stearoxy ether

(Sangelose)); one or more hydrogels, for example, polyethylene oxide,

polyvinylpyrolidone, calcium alginate, and chytosan; and hydrophobic matrix forming decanediol either alone or in combination thereof. In certain embodiments the ingredient is present at a concentration of between about 0.05 and 50% w/v, or between about 0.2 and 30% w/v, or between about 0.2 and 10.0% w/v, or between about 0.5 and 10% w/v, or between about 1 and 20% w/v, or between about 1 and 10% w/v. In certain embodiments the ingredient is present at a concentration of between about 0.005 and 10% w/v, or between about 0.05 and 8% w/v, or between about 0.01 and 6% w/v, or between about 0.1 and 4% w/v. or between about 0.5 and 1% w/v.

In certain embodiments, the biomedical polymer is present at a concentration of between about 0.005 and 10% w/v, or between about 0.01 and 6.0% w/v, or between about 0.01 and 5.0% w/v, or between about 0.1 and 1% w/v, or between about 0.05 and 40% w/v, or between about 0.1 and 35% w/v. or between about 0.2 and 30.0% w/v, or between about 0.3 and 20% w/v, or between about 0.2 and 10% w/v, or between about 1 and 10% w/v.

In certain embodiments, the biomedical polymer is present at a concentration of between about 0.2 and 5.0% w/w.

In particular non-limiting embodiments, the ratio of weight of total biomedical polymer to weight of antimicrobial agent(s) and any other bioactive agent(s), or combination thereof, is between 1: 1 to 10: 1. In a non-limiting embodiment, a mixture of biomedical polymers is used to produce the lubricious matrix, said mixture comprising at least 5%, at least 10%, at least 20%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% w/w of the biomedical polymers present.

In certain embodiments, the biomedical polymers are comprised in one or more solvents such as an alcohol (e.g. methanol, ethanol, isopropanol, and mixtures thereof), methyl-ethyl-ketone, acetone or tetrahydrofuran. In certain embodiments, the one or more solvent is present at a concentration of between about 10 and 70% v/v, or between about 2 and 20% v/v, or between about 10 and 50% v/v, or between about 20 an 70% v/v. In certain embodiments, the solvents described herein can be combined with other ingredients, such as an antimicrobial, in the absence of a biomedical polymer.

5.5 ALKANEDIOLS

Examples of alkanediols which may be used, according to the invention, include alkanediols having between about five and twenty-five carbon atoms in the backbone, including but not limited to pentanediol, hexanediol, heptanediol, octanediol, nonanediol, decanediol, undecanediol, dodecanediol, cyclodecanediol, tridecanediol tetradecanediol, pentanedecanediol, hexadecanediol, heptadecanediol, octadecanediol, nonadecanediokl, eicosanediol, heneicosanediol, docosanediol, tricosanediol, and pentacosanediol, where the preferred alkanediols include 1,2 decanediol, 1, 10 decanediol, 1,2 dodecanediol, 1, 12 dodecanediol, cyclododecanediol, 1, 13 tridecanediol, 1,2 tetradecanediol, 1, 14 tetradecanediol, and especially preferred are 1,2 decanediol, 1,2 dodecanediol, 1, 12 dodecanediol, and 1,2 tetradecanediol.

5.6 HYDROXY ACIDS

Organic hydroxy acids which may be used according to the invention include a-hydroxy acids as well as β-hydroxy acids. Non-limiting examples of such hydroxyacids include a-hydroxy acids such as lactic acid, glycolic acid, and citric acid and β-hydroxy acids such as salicylic acid, betahydroxybutanoic acid, tropic acid, and trethocanic acid. 5.7 PRIMER COATING COMPOSITIONS

Also disclosed herein is a "primer" coating composition that may be applied to a device or surface that under usual conditions does not adhere well to standard coatings, for example that shows poor adherence to biomedical polyurethane coatings (for example, where the coating is not sufficiently adherent either in the initial application or under standard testing or clinical use conditions), where the primer coating renders the device or surface capable of being coated with either a standard coating or a lubricious coating as disclosed herein. In particular non-limiting embodiments, devices and surfaces in this category comprise (that is to say, at least a portion is fabricated from) a metal, for example titanium, stainless steel, or nitinol, or a silicone (e.g. a silicone polymer).

Specific non-limiting examples of urethane adhesives which may be used include from low to high viscosity Loctite Hysol® medical adhesive products, e.g. M-06FL, M-04FL, M-05 FL, M-09FL, M-11FL, M-31C1, M-121HP, M-4981. Specific non-limiting examples of silicone adhesives which may be used include Dow Corning Silastic Medical Adhesive Type A, Medical Adhesive MD7-4502, and Medical Adhesive MD7-4602. Said "primer" coating may be used as a base coat to promote adherence of a second coating, e.g. a lubricious coating as disclosed herein, or may be used alone. Said primer coating, whether it underlies another coating layer or not, may optionally comprise one or more antimicrobial agent, one or more antiinflammatory agent, or one or more other bioactive agent, as described above.

The primer coating comprises a mixture of urethane and silicone adhesives, and optionally further comprises decanediol. The weight/weight ratio of urethane to silicone adhesive may be between about 1.25: 1 to 125: 1, or between about 2: 1 and 20: 1, or between about 2: 1 and 6: 1 or about 4: 1, and the ratio of silicone adhesive to decanediol (if present) may be between about between 1: 1 and 20: 1 or between about 3: 1 to 10: 1 or about 5: 1. In one non-limiting embodiment, the ratio of urethane adhesive: silicone adhesive:decanediol (if present) is about 20:5: 1.

In one non-limiting embodiment, a solution for creating the primer coating comprises one or more urethane adhesive present at a concentration of between about 5 and 50% w/v; one or more silicone adhesive present at a

concentration of between about 1 and 10% w/v; and one or more solvent.

In one specific non-limiting embodiment a solution for creating the primer coating is as follows: Ingredient % w/v % w/v Range (%w/v)

Hysol® urethane adhesive 20.0 20.0 5-30

Silicone Medical Adhesive 5.0 5.0 0.2-10

Decanediol 1.0 1.0 0.3-2.0

Tetrahydrofuran 74.0 74.0 60-90

After application, said coating may be allowed to dry (for example, until detectable solvent has evaporated or for at least about 2-3 hours) prior to use either as sole coating agent or as a base for subsequently applied coating(s). In a specific non- limiting embodiment the above solution may be used to coat a urinary catheter. Note that in this and similar tables, the column "% w/v" indicates a specific concentration and the column "Range (%w/v)" shows a range that may be used.

5.8 ONE-STEP COATING METHODS

The compositions described by the present application can be used as coatings that may be applied to a medical device or surface by a one- step method. Use of the term "one-step method" does not mean that it is not possible to apply one or more further coatings to the device or surface, but rather that a coating having the ingredients and properties set forth herein may be achieved in one step.

According to one embodiment, a one-step method comprises coating a device with a solution comprising and antimicrobial agent, alkanediol, and one or more releasing agents in a lubricious polymeric matrix system comprising biomedical polymers and solvents. In certain embodiments, the devices are dipped in the solution and dried at room temperature (e.g., 63-73 degrees Fahrenheit). In certain

embodiments, the coating solution does not comprise alkanediol.

In certain embodiments, a one- step method of coating a surface of a device comprises coating the surface with a solution (e.g., by dipping the device in the solution), comprising (i) chlorhexidine base (0.5-5.0% w/v or 0.05-7.0% w/v), (ii) releasing agent selected from citric acid, lactic acid, salicylic acid, mandelic acid, and a combination thereof (0.2-2.0% w/v), and (iii) decanediol (0.5-5.0% w/v), which are present in a lubricious matrix system comprising (i) Tecoflex polyurethane 93A, polyurethane 60D, or a combination thereof (0.5-5% w/v); (ii) a silicone medical adhesive selected from silicone medical adhesive Type A, medical adhesive MDT7- 4502, and a combination thereof (1-5% w/v ); optionally (iii) with or without urethane adhesive; in a solvent mixture comprising methanol (10-50% v/v) and/or THF (20- 70% v/v). After coating a surface of the device, the coating is dried at room temperature. In certain embodiments, the solution does not comprise an alkanediol.

In certain non-limiting embodiments, a device (e.g., a medical device) coated according to the methods described herein may further comprise one or more additional coatings, for example, a hydrogel coating.

In certain embodiments, the application provides the following non- limiting examples of formulations that may be used in a one-step coating method.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following ranges of ingredients:

Formulation- 1

Ingredients Range (% w/v)

Chlorhexidine base 0.1-5.0

Decanediol 0.1-5.0

Mandelic acid 0.1-5.0

Lactic acid 0-5.0

Silver sulfadiazine 0-2.0

Silver carbonate 0.0-1.0

PU 93A 0.2-5.0

PU 60D 0.1-2.0

Silicone medical adhesive A- 100 0.2 -10.0

Tetrahydrofuran (THF) 50.0-80.0

Methanol 5.0-50.0

In certain embodiments, both latex and silicone catheters can be coated with this solution.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation- 1A

Ingredients % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0 Lactic acid 0.0

Silver sulfadiazine 0.0

Silver carbonate 0.0

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 72.68

Methanol 15.0

In certain embodiments, both latex and silicone catheters can be coated with this solution.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation-2

Ingredients % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.93

Methanol 15.0

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation-3

Ingredients % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 1.0

Lactic acid 1.0 Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.93

Methanol 15.0

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation-4

Ingredients % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0

Silver carbonate 0.3

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 72.38

Methanol 15.0 In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation-5

Ingredient % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 1.0

Lactic acid 1.0

Silver carbonate 0.3

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0 Tetrahydrofuran (THF) 72.38

Methanol 15.0

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation-6

Ingredients % w/v

Chlorhexidine base 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 73.93

Methanol 15.0

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following ranges of ingredients:

Formulation-5 CVC

Ingredients Range (% w/v)

Chlorhexidine base 0.1-5.0

Decanediol 0.1-5.0

Mandelic acid 0.1-3.0

Lactic acid 0.1-3.0

Silver sulfadiazine 0.0-2.0

PU 93A 0.2-8.0

PU 60D 0.1-3.0

Silicone adhesive MDT7- 4502 0.2 -5.0

Tetrahydrofuran (THF) 50.0-80.0

Methanol 5.0-50.0

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients: Formulation-5 CVC A

Ingredients % w/v

Chlorhexidine base 3.0

Decanediol 1.0

Mandelic acid 1.0

Lactic acid 1.0

Silver sulfadiazine 0.0

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF) 71.33

Methanol 16.25

In certain non-limiting embodiments, a composition for coating device is provided comprising the following concentrations of ingredients:

Formulation-6 CVC

Ingredients % w/v

Chlorhexidine base 3.0

Decanediol 1.0

Mandelic acid 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF) 70.58

Methanol 16.25

In certain non-limiting embodiments, a composition for coating device is provided comprising the following ranges of ingredients:

Ingredients Range (% w/v)

Chlorhexidine base 0.1-5.0

Mandelic acid 0.0-5.0 Lactic acid 0.1-5.0

Ethanol 50.0-90.0

Tetrahydrofuran( THF) 10.0-50.0 In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation 1 CVC:

Ingredients % w/v

Chlorhexidine base 2.0

Mandelic acid 1.0

Lactic acid 1.0

Ethanol 76.0

Tetrahydrofuran 20.0

*Ethanol and THF are % volume by volume

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Formulation 2 CVC:

Ingredients % w/v

Chlorhexidine base 2.0

Lactic acid 2.0

Ethanol 76.0

Tetrahydrofuran 20.0

*Ethanol and THF are % volume by volume

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following ranges of ingredients:

Ingredients Range ( w/v)

Decanediol 0.01-5.0

PU 93A 0.1-7.0

PU 60D 0.1-3.0

Silicone medical adhesive A- 100 0.2 -10.0

Tetrahydrofuran (THF) 50.0-98.0 In certain embodiments, both latex and silicone catheters can be coated with the solution described above solution.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Ingredients % w/v

Decanediol 2.0

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 91.68

In certain embodiments, both latex and silicone catheters can be coated with the solution described above solution.

Specific examples of coating solutions and methods set forth in the working example sections below are incorporated by reference into this section.

5.9 TWO-STEP COATING METHODS

The compositions described by the present application can be used as coatings that may be applied to a medical device or surface by a two-step method. Use of the term "two-step method" does not mean that it is not possible to apply one or more further coatings to the device or surface, but rather that a coating having the ingredients and properties set forth herein may be achieved in two steps. The methods described in this section may be used to apply, to a device or surface, a first layer of coating which is a primer coating and a second layer of coating (over at least a portion of the first layer) which is a lubricious coating (for example, the coating described herein that can be used in a one-step coating). In certain non-limiting embodiments, the methods may be used to coat devices that are fabricated from silicone or metal or that comprise one or more silicone or metal surface or area, among other substrates to which conventional biomedical polyurethane does not adequately adhere, although the scope of the disclosure also extends to coating devices or surfaces that could be satisfactorily coated with conventional biomedical polyurethane. According to one embodiment, a two-step method comprises first coating a device with a primer coating comprising a lubricious polymeric matrix. In certain embodiments, the lubricious polymeric matrix primer coating comprises a combination of a urethane adhesive (e.g., at a concentration of between about 0.5 and 50% w/v, or between about 5 and 30% w/v, or between about 10 and 20% w/v), and a silicone adhesive (e.g., at a concentration of between about 0.05 and 50% w/v, or 0.1 and 20% w/v, or between about 0.2 and 10% w/v, or between about 0.2 and 5% w/v) dissolved in a solvent, for example, THF. In certain embodiments, the primer coating comprises an alkanediol, for example, decanediol, (e.g., at a concentration of between about 0.05 and 10% w/v, between about 0.01 and 5.0% w/v, or between about 0.1 and 1% w/v). In certain embodiments, the primer coating does not comprise an alkanediol. In certain embodiments, the primer coating is allowed to dry, for example, at room temperature for 3 hours, or until no detectable solvent is remaining.

In certain embodiments, the device treated with the primer coating is then coated with a second coating solution, wherein the second coating solution is applied over at least a portion of the primer coating layer, and comprises an antimicrobial and a releasing agent in a lubricious polymeric matrix comprising a combination of biomedical polymer and silicone adhesive. In certain embodiments, the coating is dried at room temperature. In certain embodiments, the second coating composition comprises one or more alkanediol. In certain embodiments, the second coating does not comprise an alkanediol.

In certain embodiments, a two-step method of coating a surface of a device comprises (i) coating a surface of a device with a primer coating comprising a combination of a urethane adhesive (e.g., Loctite Hysol® M-06FL) (5-50% (w/v), a silicone adhesive (e.g., silicone medical adhesive A) (1-10% w/v), and optionally with or without decanediol (0.01-5.0% w/v), which is dissolved in solvent (e.g., THF), and then dried at room temperature for 3 hours, or until no detectable solvent is remaining. The method further comprises (ii) coating the device with a second coating solution (e.g., by dipping the device in the second coating solution), wherein the second coating solution is applied over at least a portion of the primer coating layer, and wherein the second coating solution comprises chlorhexidine base (0.5-5.0% w/v or 0.05-7.0% w/v); releasing agent (e.g., citric acid, lactic acid, salicylic acid, mandelic acid, or a combination thereof) (0.2-2.0% w/v or 0.05-4.0% w/v); decanediol (0.5- 2.0% w/v); and a lubricious polymer matrix system comprising a biomedical polymer comprising polyurethane (e.g., Tecoflex polyurethane 93A ,60D) (1-5% w/v) , silicone medical adhesive (silicone medical adhesive Type A, silicone medical adhesive MDT7- 4502, or a combination thereof) ((1-5% w/v); optionally with or without urethane adhesive; in a solvent mixture comprising for example, methanol and or ethanol (5-30% v/v or 10-50% v/v) and THF (10-70% v/v, or 20-70% v/v).

The coated device is then dried at room temperature for 24 -48 hours or at 40-50°C for 3 hours, or until no detectable solvent is remaining.

In certain non-limiting embodiments, a device (e.g., a medical device) coated according to the methods described herein may further comprise one or more additional coatings, for example, a hydrogel coating.

In certain embodiments, the application provides the following non- limiting examples of formulations that may be used in a two-step coating method.

In certain non-limiting embodiments, compositions for coating a device using a two-step method are provided comprising the following ranges of ingredients:

Formulation-7

First primer coating:

Ingredients Range (% w/w)

Hysol® urethane adhesive 5-30

Silicone medical adhesive 0.2-10

Decanediol 0.3-2.0

Tetrahydrofuran 60-90

In certain embodiments, the catheters are dipped in the above mentioned first coating solution and dried at room temperature for 3 hours.

In certain embodiments, the catheters are then dipped in the following second coating solution and dried for 24-48 hours.

Second coating:

Ingredients Range (% w/v)

Chlorhexidine base 0.1-5.0

Decanediol 0.1-5.0

Mandelic acid 0.1-5.0

Lactic acid 0-5.0 Silver sulfadiazine 0-2.0

Silver carbonate 0.0-2.0

PU 93A 0.2-5.0

PU 60D 0.1-2.0

Silicone medical adhesive A-100 0.2 -10.0

Tetrahydrofuran (THF) 50.0-80.0

Methanol 5.0-50.0

In certain non-limiting embodiments, compositions for coating a device using a two-step method are provided comprising the following concentrations of ingredients:

Formulation-7A

First coating:

Ingredients % w/w

Hysol® urethane adhesive 20.0

Silicone medical adhesive 5.0

Decanediol 1.0

Tetrahydrofuran 74.0

In certain embodiments, the catheters are dipped in the above mentioned first coating solution and dried at room temperature for 3 hours.

In certain embodiments, the catheters are then dipped in the following second coating solution and dried for 24-48 hours. Second coating:

Ingredients % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0

Lactic acid 0.0

Silver sulfadiazine 0.0

Silver carbonate 0.0

PU 93A 3.33 PU 60D 0.83

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.84

Methanol 15.0

In certain non-limiting embodiments, compositions for coating a device using a two-step method are provided comprising the following concentrations of ingredients:

Formulation-8

First coating:

Ingredients % w/w Hysol® urethane adhesive 20.0

Silicone medical adhesive 5.0

Decanediol 1.0

Tetrahydrofuran 74.0 In certain embodiments, the catheters are dipped in the above mentioned first coating solution and dried at room temperature for 3 hours.

In certain embodiments, the catheters are then dipped in the following second coating solution and dried for 24-48 hours.

Second coating:

Ingredients % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 3.33

PU 60D 0.83

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.09

Methanol 15.0 In certain embodiments, the two-step method for coating a surface comprises the following method:

(a) exposing the surface to a first composition comprising

(i) one or more urethane adhesive present at a concentration of between about 5 and 50% w/v;

(ii) one or more silicone adhesive present at a concentration of between about 1 and 10% w/v;

(iii) one or more solvent;

(b) allowing the first composition to dry; and

(c) exposing the surface to a second composition comprising

(i) one or more antimicrobial agent present at a concentration of between about 0.05 and 7.0% w/v;

(ii) one or more releasing agent present at a concentration of between about 0.05 and 4.0% w/v; and

(iii) one or more biomedical polymer present at a concentration of between about 0.2 and 30% w/v;;

(iv) decanediol present at a concentration of between about 0.01 and 5.0% w/v; and

(v) one or more solvent present at a concentration of between about 10 and 70% volume/volume (v/v).

Specific examples of coating solutions and methods set forth in the working example sections below are incorporated by reference into this section. 5.10 COMPOSITIONS FOR PREPARING A BIO-FILM RESISTANT SURFACE

The present invention provides for compositions that may be used to prepare a bio-film resistant surface.

In a particular set of non-limiting embodiments, the present invention provides for a composition for preparing a bio-film resistant surface comprising a biguanide, an alkanediol, and a solvent, where the biguanide is present at between about 0.1 and 5 percent (weight/volume), or between about 2.5 and 4 percent

(weight/volume), or between about 0.5 and 3 percent (weight/volume), and the alkanediol is present at between about 0.5 and 5 percent (volume/volume), and the solvent is selected from the group consisting of an alcohol (e.g. methanol, ethanol, isopropanol, and mixtures thereof) and tetrahydrofuran. In preferred non-limiting embodiments of the invention, the biguanide is chlorhexidine, such as chlorhexidine free base, chlorhexidine diacetate, chlorhexidine gluconate, or a mixture thereof, and the alkanediol is octanediol. Such compositions may further comprise one or more additional antimicrobial agent (in an amount between about 0.05 and 3 percent, preferably between about 0.2 and 1.5 percent (weight/volume), one or more hydroxy acid (in an amount between about 0.5 and 3 percent, preferably between about 0.2 and 2 percent (volume/volume), and/or one or more polymer (in an amount between about 1 and 3 percent or between about 1 and 20 percent or between about 1 and 10 percent, or between about 3 and 6 percent (weight/volume). In preferred non-limiting embodiments, the additional antimicrobial agent may be a silver compound, such as, but not limited to, silver sulfadiazine, the hydroxy acid may be lactic acid, and/or the polymer may be 93A polyurethane, 60D polyurethane, silastic medical adhesive type A, or a mixture thereof.

The term "about", as used throughout this document, means plus or minus 20 percent of the recited value.

The term "percent (weight/volume)" means the [weight of the referenced substance divided by the volume of the composition] multiplied by 100, or, in other words, the number of grams of the referenced substance in 100 milliliters of the composition.

As a specific non-limiting example, 100 ml of a composition comprising A percent biguanide (weight/volume), B percent alkanediol

(volume/volume), C percent organic acid (volume/volume), D percent polymer (weight/volume) and E percent non-biguanide antimicrobial (weight/volume), in a solvent (which can be a mixed solvent), may be prepared by providing A grams of biguanide, D grams of polymer, E grams of non-biguanide antimicrobial, B mis of liquid form (e.g. melted) of alkanediol, and C mis of organic acid, adding each of these to solvent to form a solution and then solvent may be used to bring the total volume of the composition to 100 ml.

In non-limiting embodiments of the invention, a composition may be prepared by (i) dissolving biguanide, alkanediol, and optionally organic acid in an alcohol such as ethanol or methanol; (ii) dissolving polymer in tetrahydrofuran or equivalent solvent; and then (iii) mixing the solutions prepared in (i) and (ii). In specific, non-limiting examples, the present invention provides for the following impregnation solutions, which may be used, not by way of limitation, to impregnate catheters such as polyurethane catheters, and also provides for medical articles, such as catheters (e.g. polyurethane catheters) impregnated therewith:

2% CHX + 1.5% CHA + 0.75% AgSD + 1% Lactic acid + 3% 93A PU

+ 1% 60D PU + 30% Methanol + 60.75% THF ("CHX-CHA-AgSD-L");

2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,2 Decanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF ("CHX- CHA- AgSD-L-D");

2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,12 Dodecanediol + 1%

Lactic acid + 3% 93A PU + 1% 60D PU +30% Methanol + 59.75% THF ("CHX- CHA- AgSD-L-1,2 Dod");

2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,12 Dodecanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF ("CHX- CHA- AgSD-L-1,12 Dod");

2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,2 Tetradecanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF ("CHX- CHA- AgSD-L-l,14 TD");

2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,2 Octanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF ("CHX- CHA- AgSD-L-O");

3.5% CHX + 0.75% AgSD + 1% 1,2 Octanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF ("CHX- AgSD-L-O"); and

3.5% CHA + 0.75% AgSD + 1% 1,2 Octanediol + 1% Lactic acid +

3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF ("CHA- AgSD- L-O").

In specific, non-limiting examples, the present invention provides for the following impregnation solutions, which may be used, not by way of limitation, for the impregnation of soft tissue patches (e.g., polytetrafluoroethylene ("PTFE") soft tissue patches ("STPs"), and also provides for medical articles, such as STPs (e.g. PTFE STPs) impregnated therewith:

0.1% Silver carbonate + 0.2% CHX + 0.15% CA + 1% O ("S-CHX-

CHA-O"); 0.1% Silver carbonate + 0.2% CHX + 0.15% CHA + 1% D ("Sl-CHX-

CHA-D"); and

0.05 % Silver carbonate + 0.2% CHX + 0.15% CHA +1% D (S2- CHX-CHA-D), where S = Silver carbonate, D = 1,2 Decanediol, and O = 1,2

Octanediol.

In specific, non-limiting embodiments, the present invention provides for the following impregnation solutions which may be applied to silicone articles, e.g., urinary catheters, for example but not limited to as part of a two-step method, and also provides for medical articles, such as catheters, e.g. urinary catheters, e.g. silicone urinary catheters, impregnated therewith:

CHX-O: 2% (w/v) CHX + 1% O + 15% (w/v) Silastic Medical Adhesive Type A + 1 % glycerin + 81% (v/v) THF;

CHX-D: 2% (w/v) CHX + 1% D + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF;

CHX-l,2Dod:2% (w/v) CHX + 1% 1,2 Dodecandiol + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF;

CHX-l,12Dod: 2% (w/v) CHX + 1% 1,12 Dodecanediol + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF; OR

CHX-TD: 2% (w/v) CHX + 1% TD + 15% (w/v) Silastic Medical

Adhesive Type A + 1% glycerin + 81% (v/v) THF

In specific, non-limiting embodiments, the present invention provides for the following impregnation solutions which may be applied to wound coatings, and also provides for wound coverings impregnated therewith:

Antimicrobial composition 1

Ingredients ( % w/w)

CHA 0.15

CHX 0.15

AgSD 0.30

Lactic Acid 0.50

1,2 Decanediol 0.50

Polyurethane 93A 0.40

Polyurethane 60D 0.10

Methanol 30.00 Tetrahydrofuran 67.90

Antimicrobial composition 2

Ingredients (% w/w) CHA 0.15

CHX 0.15

AgSD 0.30

Lactic Acid 0.50 l,12 Dodecanediol 0.50 Polyurethane 93 A 0.40

Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 67.90 Antimicrobial composition 3

Ingredients (% w/w)

CHA 0.15

CHX 0.15

Silver Carbonate 0.30 Lactic Acid 0.50 l,2 Decanediol 0.50

Polyurethane 93 A 0.40

Polyurethane 60D 0.10

Methanol 30.00 Tetrahydrofuran 67.90

Antimicrobial composition 4

Ingredients (% w/w)

Polyhexamethylene biguanide 0.30 Silver Carbonate 0.30

1,2 Decanediol 0.50

Lactic Acid 0.50

Polyurethane 93 A 0.40

Polyurethane 60D 0.10 Methanol 30.00

Tetrahydrofuran 67.90

Antimicrobial composition 5

Ingredients (% w/w)

CHA 0.15

CHX 0.15

l,2 Decanediol 0.50

Lactic Acid 0.50

Polyurethane 93A 0.40

Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 68.20 Antimicrobial composition 6

Ingredients (% w/w)

Polyhexamethylene biguanide 0.30

l,2 Decanediol 0.50

Lactic Acid 0.50

Polyurethane 93A 0.40

Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 68.20 In a particular, non-limiting set of embodiments, a composition described in this section may be comprised in a wipe or a wound dressing.

In certain embodiments, the composition for use in coating a surface according to a one or two-step method as described herein includes the following:

(a) one or more antimicrobial agent present at a concentration of between about 0.05 and 7.0% weight/volume (w/v);

(b) one or more releasing agent present at a concentration of between about 0.05 and 5.0% w/v; and

(c) one or more biomedical polymer present at a concentration of between about 0.2 and 30% w/v; (d) decanediol present at a concentration of between about 0.01 and

5.0% w/v; and

(e) one or more solvent present at a concentration of between about 10 and 70% volume/volume (v/v).

In certain embodiments, the composition for use in coating a surface according to a one or two-step method as described herein includes the following:

(a) one or more biomedical polymer present at a concentration of between about 0.2 and 30% w/v, wherein the ;

(b) decanediol present at a concentration of between about 0.01 and

5.0% w/v; and

(c) one or more solvent present at a concentration of between about 10 and 70% volume/volume (v/v).

In certain embodiments, the composition for use in coating a surface according to a one or two-step method as described herein includes the following:

(a) one or more antimicrobial present at a concentration of between about 0.05 and 7.0% w/v selected from the group consisting of chlorhexidine base, chlorhexidine acetate, and a combination of chlorhexidine base and chlorhexidine acetate; and

(b) one or more solvent present at a concentration of between about 2 and 20% v/v selected from the group consisting of methyl-ethyl-ketone, methanol, ethanol, isopropanol, acetone, tetrahydrofuran, and combinations thereof; and

(c) optionally a fruit acid present at a concentration between about 0.1 and 5.0% w/v selected from the group consisting of lactic acid, mandelic acid, and combinations thereof.

5.10.1 COMPOSITIONS FOR PREPARING A BIO-FILM RESISTANT

SURFACE: CENTRAL VENOUS CATHETERS The present invention provides for compositions that may be used to prepare a bio-film resistant surface. In certain non-limiting embodiments, the compositions can be used to prepare a bio-film resistant surface of a central venous catheter (CVC). The surface can be, for example, an outer surface of the CVC, or a surface of the inner lumen of the CVC. Although the compositions described by the embodiments of this section are described for use in preparing a bio-film-resistant

CVC, the disclosure of the present application is also directed to the use these compositions for preparing a bio-film resistant surface of other devices or catheters, for example, a urinary catheter. Additionally, the compositions described by the embodiments of this section can be used according to the one-step and two-step coating methods described by the present application.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following ranges of ingredients:

General Formulation for CVC Coating Ex. 22

Ingredients Amount (grams)

Chlorhexidine base 0.5 - 5.0

Decanediol 0.5 - 5.0

Mandelic acid 0.0 - 3.0

Lactic acid 0.0 - 3.0

Silver sulfadiazine 0.0 - 2.0

PU 93A 0.2 - 8.0

PU 60D 0.1 - 3.0

Silicone adhesive MDT7- 4502 0.2 - 5.0

Tetrahydrofuran (THF)* 50.0 - 80.0

Methanol* 5.0 - 50.0

* Methanol and THF are added by volume.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

CVC Formulation Ex. 22.1

Ingredients Amount (grams)

Chlorhexidine base 3.0

Decanediol 1.0

Mandelic acid 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0 Tetrahydrofuran (THF)* 69.58

Methanol* 17.25

* Methanol and THF are added by volume. In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

CVC Formulation Ex. 22.2

Ingredients Amount (grams)

Chlorhexidine base 3.0

Decanediol 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 18.25

Methanol and THF are added by volume. In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

CVC Formulation Ex. 22.3

Ingredients Amount (grams)

Chlorhexidine base 2.5

Decanediol 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 18.75

Methanol and THF are added by volume. In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

CVC Formulation Ex. 22.4

Ingredients Amount (grams)

Chlorhexidine base 3.0

Decanediol 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93 A 3.2

PU 60D 0.8

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 19.67

* Methanol and THF are added by volume.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following ranges of ingredients:

General Formulation for CVC Coating Ex. 23

Ingredients Amount (grams)

Chlorhexidine base 0.1-5.0

Mandelic acid 0.0-5.0

Lactic acid 0.1-5.0

Ethanol* 50.0-90.0

Tetrahydrofuran (THF)* 10.0-50.0

*Ethanol and THF are added by volume.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

CVC Formulation Ex. 23-1:

Ingredients Amount (grams)

Chlorhexidine base 2.0

Mandelic acid 1.0

Lactic acid 1.0

Ethanol* 76.0 Tetrahydrofuran (THF)*

*Ethanol and THF are added by volume.

In certain non-limiting embodiments, a composition for coating device is provided comprising the following concentrations of ingredients:

CVC Formulation Ex. 23-2:

Ingredients Amount (grams)

Chlorhexidine base 2.0

Lactic acid 2.0

Ethanol* 76.0

Tetrahydrofuran (THF)* 20.0

*Ethanol and THF are added by volume 5.10.2 COMPOSITIONS FOR PREPARING A BIO-FILM RESISTANT

SURFACE: URINARY CATHETERS

The present invention provides for compositions that may be used to prepare a bio-film resistant surface. In certain non-limiting embodiments, the compositions can be used to prepare a bio-film resistant surface of a urinary catheter. The surface can be, for example, an outer surface of the catheter, or a surface of the inner lumen of the catheter. Although the compositions described by the

embodiments of this section are described for use in preparing a bio-film-resistant urinary catheter, the disclosure of the present application is also directed to the use these compositions for preparing a bio-film resistant surface of other devices or catheters, for example, a CVC. Additionally, the compositions described by the embodiments of this section can be used according to the one-step and two-step coating methods described by the present application.

In certain embodiments, the catheter is a latex catheter. In certain embodiments, the catheter is a silicone catheter.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following ranges of ingredients: General Formulation for Urinary Catheter Coating Ex. 24

Ingredients Amount (grams)

Decanediol 0.01-5.0

PU 93A 0.1-7.0

PU 60D 0.1-3.0

Silicone medical adhesive A- 100 0.2 -10.0

Tetrahydrofuran (THF)* 50.0-98.0

* THF is added by volume. In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Coating Formulation Ex. 24.1

Ingredients Amount (grams)

Decanediol 2.0

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF)* 91.68

* THF is added by volume.

In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Coating Solution A

Ingredients Amount (grams)

Chlorhexidine base 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF)* 73.93

Methanol* 15.0

*Methanol and THF are added by volume. In certain non-limiting embodiments, a composition for coating a device is provided comprising the following concentrations of ingredients:

Coating Solution B

Ingredients Amount (grams)

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF)* 71.93

Methanol* 15.0

* Methanol and THF are added by volume.

5.11 METHODS FOR PRODUCING A BIO-FILM RESISTANT SURFACE

The present invention provides for methods of producing a bio-film resistant surface, comprising exposing the surface to a composition comprising a biguanide, an alkanediol, and a solvent, where the biguanide is present at between about 0.1 and 5 percent (weight/volume), or between about 2.5 and 4 percent

(weight/volume) (where the article is to be "dipped" in the composition for a period of between about 5 seconds and 5 minutes or between about 5 seconds and 1 minute) or between about 0.5 and 3 percent (weight/volume), and the alkanediol is present at between about 0.5 and 5 percent (volume/volume) (Note that octanediol, for example, is a waxy solid but may be melted prior to adding to the solvent), and the solvent is selected from the group consisting of an alcohol (e.g. methanol, ethanol, isopropanol, and mixtures thereof), tetrahydrofuran and mixtures thereof. In preferred non-limiting embodiments of the invention, the biguanide is chlorhexidine, such as chlorhexidine free base, chlorhexidine diacetate, chlorhexidine gluconate, or a mixture thereof, and the alkanediol is octanediol. Such compositions may further comprise one or more additional antimicrobial agent (in an amount between about 0.05 and 3 percent, preferably between about 0.2 and 1.5 percent (weight/volume), one or more hydroxy acid (in an amount between about 0.5 and 3 percent, preferably between about 0.2 and 2 percent (volume/volume), and/or one or more polymer (in an amount between about 1 and 20 percent or between 1 and 30 percent or between about 1 and 10 percent, or between about 3 and 6 percent (weight/volume). In preferred non-limiting embodiments, the additional antimicrobial agent may be a silver compound, such as, but not limited to, silver sulfadiazine, the hydroxy acid may be lactic acid, and/or the polymer may be 93A polyurethane, 60D polyurethane, silastic medical adhesive type A, or a mixture thereof.

The surface may be exposed to the composition by immersing the surface in the composition or by applying the composition to the surface, for example by a spray, a stream, or a wipe.

In non-limiting embodiments of the invention, the composition may be exposed to the surface for a period of time such that the biguanide impregnates the surface.

In non-limiting embodiments of the invention, the composition may be exposed to the surface for a period of time such that the physical properties of the surface are altered, for example, where there is swelling of the surface; such alteration should not be such that the surface is damaged with regard to its intended use.

For example, where the surface is a surface of a catheter fabricated from a polymer, the catheter may be immersed in the composition and/or the composition may be introduced into the interior of the catheter. In one non-limiting embodiment, the ends of the catheter are sealed to prevent entry of the composition into the lumen. In another non-limiting embodiment, the composition is introduced into the interior of the catheter. In another non-limiting embodiment, the catheter may be briefly dipped into the composition. In non-limiting embodiments, a catheter surface is exposed to the composition for a period of between about 5 seconds and 5 hours, or between about 1 minute and 2 hours, or between about 5 seconds and 5 minutes, or between about 5 seconds and 1 minute.

In one particular set of embodiments, the present invention provides for a two-step method for providing a bio-film resistant surface. In the first step, an additional antimicrobial agent as set forth above, (for example, but not limited to, triclosan or a silver compound such as silver sulfadiazine), may be applied as a first solution comprising the antimicrobial agent at a concentration between about 0.05 and 3 percent (weight/volume), said solution optionally further comprising a hydroxy acid at a concentration between about 0.5 and 3 percent (volume/volume), in a solvent selected from the group consisting of an alcohol (e.g. methanol, ethanol, isopropanol, and mixtures thereof), tetrahydrofuran and mixtures thereof (preferably methanol). Biguanide, alkanediol, polymer and optionally hydroxy acid are applied in the second step, comprised in a solution wherein biguanide is present at between about 0.1 and 5 percent (weight/volume), or between about 0.5 and 3 percent (weight/volume), alkanediol is present at between about 0.5 and 5 percent (volume/volume), polymer is present at a concentration between about 1 and 20 percent or between about 1 and 10 percent or between about 3 and 6 percent (weight/weight) and the solvent is selected from the group consisting of an alcohol (e.g. methanol, ethanol, isopropanol, and mixtures thereof), tetrahydrofuran and mixtures thereof; hydroxy acid, where present, is in an amount of between about 0.5 and 3 percent (volume/volume). In each step, soaking may be for time intervals between about 5 seconds and 5 hours, or between about 1 minute and 2 hours, or between about 5 seconds and 5 minutes, or between about 5 seconds and 1 minute.

In a specific, non-limiting embodiment of the two-step method, in the first step, a solution containing about 30 percent THF (volume/volume), about 65 percent methanol (volume/volume), about 3 percent triclosan (TC) (weight/volume), and about 2 percent lactic acid (L) (volume/volume), may be used, into which a polyurethane catheter may be dipped for a time period of at least about 30 seconds or at least about one minute, and then allowed to dry, for example (but not by way of limitation) 48 hours (or however long drying requires). For the second step, a solution may be prepared containing about 30 percent methanol (volume/volume), about 63 percent THF (volume/volume), about 2 percent octanediol (O)

(volume/volume), about 1 percent lactic acid (L) (volume/volume), about 4 percent chlorhexidine free base (CHX) (weight/volume), about 4 percent 93A polyurethane (weight/volume), and about 1 percent 60D polyurethane (weight/volume). (The polyurethanes may be first dissolved in THF and the other components may be dissolved in methanol and then the two resulting solutions may be mixed). The catheter resulting from the first step may be dipped into this solution for at least about 5 seconds, and then allowed to dry.

In another specific, non-limiting embodiment of the two-step method, in step 1, a silicone article (e.g. a catheter) or portion thereof may be soaked for 1 hour in a solution comprising about 0.3 percent triclosan (weight/volume) and about 1.0 percent lactic acid (volume/volume) in about 30 percent methanol

(volume/volume) / about 67 percent THF (volume/volume). The catheter may be removed, dried, rinsed in water and dried again. In step 2, the catheter resulting from step 1 may be dipped in a solution comprising about 2 percent chlorhexidine free base (weight/volume), about 10 percent Silastic Medical Adhesive Type A

(weight/volume), about 2 percent octanediol (volume/volume) and about 88 percent THF (volume/volume) (where THF is used to bring the volume to 100 percent) and dried.

In yet further specific non-limiting examples of the invention, silicone catheters, for example urinary catheters, may be impregnated by a two-step method as follows. Step 1: Catheters may be soaked for 1 hour in 0.3% Triclosan (T) (w/v) + 1.0 % L (Lactic Acid) (v/v) in 30% Methanol (v/v) + 68.7% (v/v) THF. The catheters may be removed, dried for 1 hour, rinsed in water and dried for another hour. Step 2: Catheters may be dipped in the following solutions and dried for 24 hours and then used for testing:

CHX-O: 2% (w/v) CHX + 1% O + 15% (w/v) Silastic Medical Adhesive Type A + 1 % glycerin + 81% (v/v) THF;

CHX-D: 2% (w/v) CHX + 1% D + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81 % (v/v) THF;

CHX-l,2Dod: 2% (w/v) CHX + 1% 1,2 Dodecandiol + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF;

CHX-l,12Dod: 2% (w/v) CHX + 1% 1, 12 Dodecanediol + 15%

(w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81 % (v/v) THF; OR

CHX-TD: 2% (w/v) CHX + 1% TD + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF. 5.12 ARTICLES HAVING A BIO-FILM RESISTANT SURFACE

The present invention provides for an article having at least one surface which is rendered bio-film resistant using the compositions and methods set forth above.

In non-limiting embodiments, the present invention provides for an article having at least one surface comprising, as active agents, a biguanide (e.g.

chlorhexidine free base or a chlorhexidine salt) at between about 250 and 5000

2 2

μg/cm of surface or between about 500 and 1000 μg/cm of surface and an alkanediol (e.g. octanediol) at between about 200 and 1500 μg/cm of surface, and optionally a hydroxy acid (e.g. lactic acid) at between about 100 and 800 μg/cm of surface, and/or optionally a silver compound (e.g. AgSD) at between about 0-200 μg/cm of surface.

In other non-limiting embodiments, the present invention provides for an article having at least one surface comprising, a biguanide (e.g. chlorhexidine free base), an organic acid releasing agent (e.g. , citric acid, lactic acid, mandelic acid, or a combination thereof), and a lubricious polymer matrix. The surface may also optionally comprise one or more alkanediol, urethane adhesive and/or silicone adhesive.

Medical articles that may be treated according to the invention are either fabricated from or coated (e.g., to the entire device or a portion thereof) or treated with biomedical polymer and include, but are not limited to, indwelling medical devices such as catheters including urinary catheters and vascular catheters (e.g. peripheral and central vascular arterial and venous catheters), wound drainage tubes, arterial grafts, soft tissue patches, gloves, shunts, stents, tracheal catheters, wound dressings, bandages, drapes, intrauterine devices, intravaginal devices, sutures, staples, guide wires and prosthetic devices (e.g. heart valves and LVADs), contact lenses, needleless connectors, endotracheal tubes, mechanical heart valves, pacemakers, peritoneal dialysis catheters, prosthetic joints, tympanostomy tubes and voice prostheses. Vascular catheters that may be prepared according to the present invention include, but are not limited to, single and multiple lumen central venous catheters, peripherally inserted central venous catheters, emergency infusion catheters, percutaneous sheath introducer systems and thermodilution catheters, including the hubs and ports of such vascular catheters.

In non-limiting embodiments, articles made of substrates such as polyurethane, silicone rubber, natural rubber latex, polyvinyl chloride, as well as cotton, silk (wound dressings) can be treated with a composition of the invention.

In certain embodiments, devices coated with the compositions of the present application have a unique drug release pattern ideal for a biofilm resistant antimicrobial medical device, wherein the device prevents adherence of bacteria and biofilm formation on the device surface, but does not release a therapeutic amount of antimicrobials to prevent systemic infection.

In certain embodiments, devices prepared according to the methods described herein release about 30% of the antimicrobials present on a surface of the device (for example, over a period of time of about 2-3 or 2-4 days), which inactivates microbes introduced at the insertion site of the device into a subject. As such, medical devices prepared according to the present application lower the potential for microbial colonization on the surface of device. Once the releasing agent has been released from the coated device (for example, over a period of time of about 2-3 or 2- 4 days), the remaining antimicrobials persist on the surface of the device for a prolonged period of time, thus preventing subsequent microbial adherence and biofilm formation. Furthermore, devices coated according to the present application show higher antifungal activity.

In certain embodiments, the medical device substrates comprise: (i) polymers such as polyurethane, polyvinyl chloride (PVC), acrylonitrile butadiene styrene (ABS), acetals, polycarbonates, pebax, blends and alloys thereof, block Polymers, and Polytetrafluoroethylene (PTFE); (ii) rubber substrates such as silicone rubber, natural rubber latex, neoprene, isoprene, santoprene, and blends thereof; (iii) cotton, rayon, dacron, spandex, woven and non-woven materials; and (iv) metals such as titanium, stainless steel, nitinol, and combinations and alloys thereof.

Below are a series of working examples. The compositions, methods and articles described in the below working examples are hereby incorporated into this detailed description. 6. EXAMPLE 1: EFFECT ON ZONE OF INHIBITION

Polyurethane (PU) 7 Fr. central venous catheters (CVC) were treated with octanediol ("O"), lactic acid ("L") and chlorhexidine ("C")- containing solutions, in the presence or absence of other active agent.

Preparation of coating solution. Two separate solutions were prepared, Solution A and Solution B, as follows:

Solution A: Chlorhexidine, octanediol, with or without lactic acid, in methanol; and

Solution B: 93 A polyurethane and 60D polyurethane in THF,

and then the two solutions were mixed thoroughly prior to treatment. The amounts of active agents are set forth in Table 1, below, and the amount of polymer in the final solution, which was about 65 percent THF (volume/volume ("v/v")) and about 30 percent methanol (v/v) was 4 percent (weight/volume ("w/v")) 93A polyurethane and 1 percent (w/v) 60D polyurethane. Impregnation of catheters. Catheters (6 cm in length, both ends sealed) were dipped in coating solutions prepared as above, containing active ingredients as indicated in Table 1. The catheters were dipped for 5 seconds in the solution and dried at room temperature for 24 hours and then used for testing.

TABLE 1

Group Composition

1) 4% CHX

2) 4% CHX + 3% L

3) 4% CHX + 3% 0

4) 4% CHX + 2% 0 + 1% L

5) 3% CHX + 1% TC

6) 3% CHX + s- TC + 2% 0 + 1% L

7) 3% CHX + s- AgSD

8) 3% CHX + s- AgSD + 2% 0 + 1%

NOTE: CHX = Chlorhexidine free base

Zone of Inhibition (ZOI )Test . Three 0.5cm segments of each group of catheters, prepared as described above, were embedded vertically in modified trypticase soy agar (TSA) media seeded on the surface with 0.3 ml of 10 colony forming units (CFU) per ml of bacteria or 10 ⁵ cfu/ml of yeast and the plates were incubated at 37°C for 24 hours. The diameters of zones of inhibition of bacterial growth around the catheter segments were measured. The results are presented in Table 2.

TABLE 2

Zone of Inhibition (mm)

Group Active

Agents P. aeruginosa S. aureus C. albicans

1) 4% CHX 11.0 13.0 12.0

2) 4% CHX + 3% 0 11.5 13.0 12.0

3) 4% CHX + 3%L 11.0 13.0 12.0

4) 4% CHX + 2%0+l%L 11.0 13.5 12.0

5) 3% CHX + 1% TC* 9.5 14.0 12.0 6) 3% CHX + 1% TC +

2% 0 + 1% L 11.0 15.0 12 .0

7) 3% CHX + 1% AgSD 9.5 12.0 11 .0

8) 3% CHX + 1% AgSD +

2% 0 + 1% L 11.5 13.5 13 .0

9) 5% 0 + 3% L 0 8.0 0

TC is triclosan.

Conclusion: The zone-inhibiting activity was not significantly different between the group containing O + L and the group without O + L.

7. EXAMPLE 2: EFFECT ON MICROORGANISM ADHERENCE

Bacterial adherence on Polyurethane (PU) 7 Fr.( white) central venous catheters (CVC) treated with O + L + C and other antiseptics, as set forth in the preceding section, was evaluated using an in vitro agar track model.

Agar tract model. The medium used was 0.5% agar (w/v) 20% bovine adult serum (BAS) (v/v) + 0.5% milk (v/v) + 0.03 % trypticase soy broth medium powder (TSB) (w/v) in phosphate buffered saline (PBS). First, agar and TSB was dissolved in PBS, and a magnetic stirring rod was included in the flask. The medium was sterilized by autoclaving at 121°C for 20 min. After autoclaving, it was allowed to cool down to 45 - 48° C in a water bath put on a magnetic stirrer. Then, BAS and milk were warmed to room temperature, and 5 ml of milk were mixed with 5 ml BAS in a sterile culture tube and added to the agar/TSB -containing flask with gentle stirring. Then the remaining amount of BAS was added to the flask. The medium was maintained at 45-48° C. 12.5 ml aliquots of medium were dispensed into different culture tubes and allowed to solidify at room temperature.

Evaluation of bacterial adherence. Catheter segments, 4 cm long and sealed at both ends, were inserted vertically into the center of the medium in each tube with 0.5 cm of the catheter protruding out of the medium. The caps of each tube were sealed with parafilm to prevent dessication. 5 catheter segments were used for each test. Untreated catheter segments were used as the control.

After 30 minutes, each catheter segment was lifted up (approximately 0.5 cm) and 25 μΐ of the culture (l-3x 10 ⁸ cfu/ml of P. aeruginosa or l-3xl0 ⁶ cfu/ml C. albicans) was added on the catheter just near the surface of the medium so that the inoculum was also spread on medium surface. The catheter was then placed back to its original position and incubated at 37°C for 7 days.

Then, the catheter segments were removed from the tubes and blotted on tissue. They were rinsed twice in 10 ml saline (6 segments/10 ml saline) and blotted dry. 0.5 cm was then cut off from both the ends of each catheter segment. Each catheter segment was then put in 4 ml LTSB (drug inactivating medium) in a culture tube and sonicated for 20 min. 0.5 ml aliquot from each tube was then plated out on TSA plates and incubated for 24-48 h. The results are shown in Table 3 (adherence of P. aeruginosa) and Table 4 (adherence of C. albicans).

TABLE 3 P . aeruginosa adherence (infected 30 minutes after implantation)

Group Active agents Adherence of P. aeruginosa

CFU/cm LoglO Reduction

from control counts

Control (uncoated) 1.1x10

1) 4% CHX 1.8x10 0.78

2) 4% CHX + 3% L 8.3x10 2 1.14

3) 4% CHX + 3% 0 Ι.δχΙΟ ² 1.78

4) 4% CHX + 2% 0 +

1% L 92 2.08

5) 3% CHX + 1% TC 8.9x10 2 1.04

6) 3% CHX + 1% TC +

7) 3% CHX + 1% AgSD δ.δχΐθ ² 1.28

8) 3% CHX + 1% AgSD +

2% 0 + l% L 4 3.44

9) 3% 0 + 3% L 9xl0 ³ 0.1 TABLE 4

albicans adherence (infected 30 minutes after

implantation)

Active agents Adherence of C. albicans

CFU/cm LoglO Reduction from control

Control (uncoated) 2.9x10'

1) 4% CHX 1.0xl0 ^; 0.5

2) 4% CHX + 3% L 1. Ixl0 ^; 0.46

3) 4% CHX + 3% 0 1.9xl(r 1.2

4) 4% CHX + 2% 0 +

1% L 4 2.9 5) 3% CHX + 1% TC 90 1.5

6) 3% CHX + 1% TC +

2% 0 + 1% L 0 3.5

7) 3% CHX + 1% AgSD 44 1.9

8) 3% CHX + 1% AgSD

2% 0 + l% L 3.5

Conclusions. As regards P. aeruginosa adherence, catheters having surfaces treated with C + O and C + O + L showed lower adherence. Of all the groups C and AgSD with O and L had significantly lower adherence. This result indicates that biofilm formation and bacterial adherence on medical devices can be significantly reduced by treating the device with an antimicrobial solution containing C + O + L.

As regards C. albicans adherence, the group of catheters having surfaces treated with O and L showed significantly lower adherence.

8. EXAMPLE 3: TWO-STEP COATING METHOD

In the preceding sections, catheters were coated with CHX+T+O+L along with a polymer by a dip method. With dipping, the percent of CHX in the solution is preferably in the range of 2.5-4 % , for the catheter to be effective especially against P. aeruginosa ( ZOI more than 10 mm) and C. albicans ( ZOI more than 13 mm). For long term efficacy against S. aureus, a ZOI greater than 15mm is most preferred. The catheters coated by the one step dipping method show effective ZOI against P. aeruginosa and C. albicans. However the ZOI against S. aureus is about 15 mm when CHX+Triclosan is 3%+l% (w/v) in the coating solution. Increasing the Triclosan in the coating solution can increase the efficacy against S. aureus. However, Triclosan has essentially no activity against P. aeruginosa. Furthermore, coating catheters with solutions containing higher concentrations of Triclosan may lower the amount of CHX uptake by the catheter( since the ratio of CHX to Triclosan will be lower) which results in lower efficacy against P. aeruginosa.

In order to provide a catheter which is effective, for extended periods, against P. aeruginosa, C. albicans and S. aureus, a two-step method was developed by which higher concentrations of both triclosan and chlorhexidine could be incorporated along with octanediol and lactic acid.

According to the two-step method, triclosan and lactic acid is applied to the surface in the first step, and chlorhexidine, octanediol, lactic acid and polymer is applied in the second step.

For the first step, a solution containing about 30 percent THF (v/v), about 65 percent methanol (v/v), about 3 percent triclosan (TC) (w/v), and about 2 percent lactic acid (L) (v/v), was prepared. For example, for each about 100 ml of solution to be prepared, 30 ml THF, 65 ml Methanol, 3 g Triclosan, and 2 ml Lactic acid are mixed. A portion of a polyurethane 7 fr. blue catheter, with the top end sealed to prevent entry of liquid into the catheter, was soaked in this solution for 1 minute and then allowed to dry for 48 hours.

For the second step, a solution was prepared containing about 30 percent methanol (v/v), about 63 percent THF (v/v), about 2 percent octanediol (O) (v/v), about 1 percent lactic acid (L)(v/v), about 4 percent chlorhexidine free base (CHX)(w/v), about 4 percent 93A polyurethane (w/v), and about 1 percent 60D polyurethane (w/v). This solution was first prepared by dissolving the chlorhexidine, lactic acid and octanediol in the methanol, dissolving the polyurethanes in the THF, and then mixing the solutions together. For example, for each about 100 ml of solution to be prepared, 2 ml octanediol, 1 ml lactic acid, and 4 mg chlorhexidine are dissolved in 30 ml methanol, and 4 g 93A polyurethane and 1 g 60D polyurethane are dissolved in 63 ml THF, and then the methanol and THF solutions are mixed. Then, the catheter from Step 1 was dipped into this solution for 5 seconds and dried at room temperature overnight.

Control (uncoated) catheters, catheters treated by a one-step method, or by the two-step method described above, were prepared, as follows:

1) Control ( uncoated catheter )

2) Catheter by 2 steps ( Step 1 3% T+2 L) and Step 2( 4% CHX+1 L+

2%0)

3) Catheter by 1 step ( 3% CHX+1.0%T +2% 0+1% L)

The zones of inhibition for each of these catheters were then determined, using methods as set forth in Example 1, above. The results are presented in Table 5.

TABLE 5

Zone of Inhibition (mm)

Group aeruginosa S. aureus C. albicans

1 (control) 0 0 0

2 (2-step) 12.5 17.0 14.5

3 (1-step) 11.0 15.0 12.0 Conclusion : The two- step method produced a catheter which showed higher activity against all the organisms tested.

Bacterial adherence to the three catheters tested above was also determined, using methods described in Example 2. The results are shown in Table 6. TABLE 6

Group P. aeruginosa adherence (cfu/cm)

1 (control) 6.4xl0 ³

2 (2-step) 1.7xl0 ²

3 (1 step) l.OxlO ³

Conclusion Catheters prepared by the two-step method showed lower adherence of P. aeruginosa. 9. EXAMPLE 4. FURTHER BACTERIAL ADHERENCE STUDIES Further studies evaluated bacterial adherence on polyurethane (PU) 4 Fr. peripherally inserted central venous catheters treated with O + L + C and other antiseptics using an in vitro agar tract model. Preparation of catheters, and the agar tract model, were as described in Examples 1 and 2 above, respectively. The results are shown in Table 7.

TABLE 7

P. aeruginosa adherence (infected 30 minutes after implantation)

Group Adherence of P. aeruginosa

( cfu/cm)

Control (uncoated catheters) lxlO ³

2.5% CHX + 1% TC 96

2.5% CHX + 1% TC + 2% L 92

2.5% CHX + 1% TC + 3% 0 23

2.5% CHX + 1% TC + 2% 0 + 1%L 0

Conclusion : Catheters treated with C+O and C+O+L showed significantly lower adherence.

10. EXAMPLE 5: CATHETERS TREATED WITH TWO FORMS OF CHLORHEXIDINE

Studies were performed to evaluate adherence of P. aeruginosa on catheters treated with solutions containing chlorhexidine acetate (CHA) + chlorhexidine free base(CHX)

The method of coating and testing of adherence were the same as described in Examples 1 and 2 above, respectively. The results are shown in Table 8. TABLE 8

P. aeruginosa adherence (infected 30 minutes after implantation)

Group Adherence of P. aeruginosa

( cfu/cm) Control ( uncoated catheters)

2% CHA+1.5% CHX

2% CHA+1.5% CHX+3% 0

2% CHA+1.5%CHX +0.5% TC

2% CHA+1.5%CHX +0.5% TC+3% 0

Conclusion: Catheters Coated with solutions containing CHA + CHX + O or with CHA + CHX + T C+ O showed significantly lower adherence.

11. EXAMPLE 6: COMPARISON OF OCTOXYGLYCERINE AND

OCTANEDIOL

Studies were performed to evaluate adherence of P aeruginosa on central venous catheters (CVC) impregnated with chlorhexidine, with or without either octoxyglycerine ("OCG") or octanediol. The catheters were prepared essentially as described in Example 1 and adherence was measured using the agar tract model as set forth in Example 2. Results, measured 7 days post-infection, are shown in Table 9.

TABLE 9

P. aeruginosa adherence (infected 30 minutes after implantation)

Group ( cfu/cm)

Control (uncoated catheters) 4.1 x 10 ³

3% CHX+3% 0 8

Conclusion The adherence was significantly lower in the Octanediol group 7days post infection. Without being bound by any particular theory, it is believed these results may be caused by octoxyglycerin, which is viscous fluid, remaining on the surface of the catheter as an oily coating which has diffused into the agar by the 7th day. In contrast, octanediol, which is a waxy powder, remains on the catheter surface and does not diffuse into the agar, so that bacteria which comes in contact with the surface of an octanediol coated catheter gets killed . 12. EXAMPLE 7: EVALUATION OF S. AUREUS ADHERENCE

Studies were performed to evaluate adherence of S. aureus to

/?olyurethane( PU) 4 Fr. central venous catheters (CVC) treated with C+ T+O+L (prepared as in Example 1), using an in vitro agar track model (as described below).

Catheter segments, 4 cm long and sealed at both ends, were inserted vertically into the center of medium in each tube with 0.5 cm of the catheter protruding out of the medium (as in Example 2). The caps of each tube were sealed with parafilm to prevent dessication. 5 catheter segments were used for each test. Untreated catheter segments were used as the control.

After 21 days, the catheters were transferred to fresh agar tracts and after 30 minutes each catheter segment was lifted up (approximately 0.5 cm) and 25 ul of the culture (l-3x 10 cfu/ml of S. aureus) was added on the catheter just near the surface of the medium so that the inoculum was also spread on medium surface. The catheter was then placed back into its original position and incubated at 37°C for 7 days

The catheter segments were removed from the tubes and blotted on tissue. They were rinsed twice in 10 ml saline (6 segments/10 ml saline) and blotted dry. 0.5 cm was then cut off from both the ends of each catheter segment. Each catheter segment was then put in 4 ml LTSB (drug inactivating medium) in a culture tube and sonicated for 20 min. 0.5 ml aliquot from each tube was then plated out on TSA plates and incubated for 24-48 h. The results are shown in Table 10.

TABLE 10

S. aureus adherence (infected 21 day post implantation)

Group Adherence of S. aureus

( cfu/cm)

Control (uncoated catheters) 1.0 x 10 ⁴

2.5% CHX+1% TC +2%0+l%L 0

Conclusion: Group containing O + L showed no adherence even after infected 21 days post implantation. 13. EXAMPLE 8: TREATED SILICONE CATHETERS

Studies were performed to evaluate the antimicrobial efficacy of silicone urinary catheters impregnated with chlorhexidine, triclosan, octanediol and lactic acid.

One set of catheter portions was treated by a one-step method, as follows. Catheters were soaked in solutions comprising active agents dissolved in about 60 percent THF(v/v) + about 30 percent methanol (v/v) and the total volume was made up to 100% with THF. The catheters were soaked for 1 hour, dried at room temperature for 1 hour, rinsed in water and then dried for another hour and used for testing.

Another set of catheter portions was treated by a two-step method, as follows. In step 1, portions of silicone urinary catheters were soaked for 1 hour in 0.3% TC (w/v) + 1.0 % L (v/v) in 30% Methanol (v/v) + 67% (v/v) THF. The catheters were removed, dried for 1 hour, rinsed in water and dried for another hour. In step 2, catheters were dipped in 2% CHX (w/v) + 2% O (v/v) + 10% (w/v) Silastic Medical Adhesive Type A THF (THF used to bring the volume to 100%) and air dried at room temperature for 24 hours and then used for testing.

Bacterial adherence was evaluated using an in vitro urinary tract model, as follows. The model consists of two tubes one of which was an open cylindrical tube with one end capped and the other end sealed with a rubber cork with a hole in the center (Tube 1). The tube was crimped from both the sides at the center. The second tube was open at one end and was used for collection of urine (Tube 2). Both the tubes were sterilized with ethylene dioxide. Catheter segments of 6 cm in length, with both the ends sealed with silicone to prevent intraluminal contamination with bacteria, were sterilized and were inserted from top end of Tube 1 after lifting the cap aseptically and placed in the hole of the rubber cork at the end.

The sterile modified Trypticase Soya Agar was cooled to 40°C and then poured along the sides of the tube around the catheter leaving the upper 1cm of the catheter protruding out in the space above the agar tract, which represented the bladder. When the medium solidified in the tube, the cork at the bottom of the tube was removed gently without disturbing the agar column on the top thus exposing the lower end of the catheter. This lower end of the agar column with the catheter protruding represented the meatus and the agar surrounding the catheter simulated the urethra. This tube was then fixed on "Tube 2" to collect small amount of urine that flowed down the agar tract.

The "meatus" was inoculated daily with 20 μΐ of 10 ⁶ cfu/ml of C. albicans after dismantling the collection tube (Tube 2). The "bladder" was filled daily with fresh sterile urine. The "bladder" and the "meatus" were cultured daily on TSA to determine the presence of bacterial growth. On the day a positive "bladder" culture was found, the catheter segment was also processed for determination of bacterial colonization on the catheter surface. This was done by removing the catheter segment from the "bladder" end of the model, rinsing with saline and rolling it on a D/E agar plate followed by incubation for 24 hours at 37°C to semi-quantitatively determine the bacterial growth on the surface of the catheter.

The results are shown in Table 11.

TABLE 11

Duration of activity against C. albicans for

1-step vs 2-step Preparation Method (Days) Active agents 1-step 2-step

Control 1 1

2% CHX + 0.3% TC 3 8

2% CHX + 0.3% TC + 1.% L+2%0 10 30

Conclusion: Silicone urinary catheters treated with C + TC + O + L showed longer activity.

Catheters prepared by the two step method where the CHX was coated on the outer surface along with a silicone matrix showed superior activity. The two-step method was found to be better for releasing CHX from silicone rubber catheters.

Incorporation of chlorhexidine on the outer coating of the silicone matrix appears to release an effective amount of chlorhexidine.

14. EXAMPLE 9: TREATMENT OF PTFE PATCHES

Studies were performed to evaluate the antimicrobial effect of surface treatment of polytetrafluoroethylene ("PTFE") soft tissue patches. In particular, such patches were impregnated with CHX + Silver Carbonate (AgC) and CHX + AgC + O + L. 1 cm pieces were soaked in solutions comprising about 60 percent THF (v/v), about 20 percent Methanol (v/v) and about 20 percent ammonium hydroxide (v/v) as well as the active agents indicated below, then suctioned using a vacuum pump and left for 5 minutes. The pieces were removed, dried and rinsed in water. After 24 hours the patches were tested.

The following Adherence Testing Method was used. 4 pieces of

PTFE tissue patch, each 1cm , were soaked in medium containing 50% TSB + 50%

BAS (v/v) (1ml per 1 cm of each piece) and placed on an orbital shaker at 37° C for 7 days. The pieces were removed, and transferred to a fresh media containing 10 ⁵ cfu of S. aureus/m\ (lml/lcm ) and incubated for 24 hours at 37°C. The pieces were removed and rinsed twice in (2ml/lcm ) saline) by vortexing at low speed, blotted dry and suspended in drug inactivating media (4. ml /lpiece) and sonicated. 0.5 ml aliqouts were plated. The results are shown in Table 12.

TABLE 12

Group Adherence (Cfu/

Control (untreated Patch) >105

0.3% CHX +0.1% AgC 66

0.3%CHX + 0.1% AgC + 1% L+2%+0 5

Conclusion: The Group containing O + L showed lower adherence.

15. EXAMPLE 10: AGENTS AT CATHETER SURFACE

Pre-weighed 7 Fr catheters having an outer diameter measured to be 0.092" or 0.234 cm diameter were dipped in coating solution comprising 1) 4% CHX+2%

Octanediol+1% Lactic acid, in about 30% methanol, about 63% THF and 2) 3.5% CHX+ 0.75% AgSD+ 2% Octanediol+1% Lactic acid in about 30% methanol, about 62.75% THF.

The catheters were dipped and immediately wrapped in pre-weighed aluminum foil to prevent any solvent evaporation and the weight of the coating solution on the catheter was determined.

The coating weights were found to be:

1) 0.022 grams total coating per cm 2)0.021 grams total coating per cm

Based on these weights and the percentages of active agents present, the following amounts of active agents were calculated to be present:

(1) LA = 1% => 220 micro grams/cm Surface

CHX = 4% => 880 micrograms/cm ² Surface

1,2-Octanediol = 2% => 440 micrograms/cm Surface

(2) LA = 1% => 210 micrograms/cm Surface

CHX = 3.5% => 735 micrograms/cm Surface

1,2-Octanediol = 2% => 420 micrograms/cm Surface

AgSD = 0.75% => 158 micrograms/cm ² Surface

16. EXAMPLE 11: ZONES OF INHIBITION

Zones of inhibition associated with catheters treated with the active agents indicated in Table 13 were measured. The methods of preparing the catheters and for measuring zones of inhibition were essentially as set forth in Example 1 (for the particular combinations of active agents tested).

TABLE 13

Zone of Inhibition (mm)

Active A ents P. aeruginosa S. aureus C. albicans

3.5% CHX + 2%0+l%L 11.0 12.5 11.5.

3.5% CHX + 2% O + 1% Salicylic acid 11.0 13.0 13.5.

3.5% CHX + 2% OCG+l%L 11.0 12.5 11.5

3.5% CHX + 1% O + 1% OCG +1% L 11.5 13.0 13.0

Conclusion: The activity of catheters with O+OCG was slightly higher than that with O or OCG alone against C. albicans. 17. EXAMPLE 12: BACTERIAL ADHERENCE TO IMPREGNATED

CATHETERS

Polyurethane catheter segments were impregnated with the following solutions.

1) 2% CHX + 1.5% CHA + 0.75% AgSD + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 60.75% THF (CHX-CHA- AgSD-L) 2) 2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,2 Decanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF (CHX-CHA- AgSD-L-D)

3) 2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,12 Dodecanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU +30% Methanol + 59.75% THF (CHX-CHA- AgSD-L- 1,2 Dod)

4) 2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,12 Dodecanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF (CHX-CHA- AgSD-L- 1,12 Dod)

5) 2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,2 Tetradecanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF (CHX-CHA- AgSD-L- 1,14 TD) 6) 2% CHX + 1.5% CHA + 0.75% AgSD + 1% 1,2 Octanediol + 1% Lactic acid +

3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF (CHX-CHA- AgSD-L-O)

7) 3.5% CHX + 0.75% AgSD + 1% 1,2 Octanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF (CHX- AgSD-L-O)

8) 3.5% CHA + 0.75% AgSD + 1% 1,2 Octanediol + 1% Lactic acid + 3% 93A PU + 1% 60D PU + 30% Methanol + 59.75% THF (CHA- AgSD- L-O) 9) 3.5% CHA + 0.75% AgSD + 3% 93A PU + 1% 60D PU + 30% Methanol + 61.75% THF (CHA- AgSD)

To test bacterial adherence, the following experiments were performed.

Preparation of Agar tract model:

0.5% agar + 20 % bovine adult serum (BAS) + 0.5% milk + 0.03 % trypticase soy broth (TSB) in phosphate buffered saline (PBS). The necessary amounts of agar and TSB were weighed and suspended in PBS with a magnetic stirring bar in the flask. The medium was sterilized by autoclaving at 121° C for 20 min. After autoclaving, the medium was allowed to cool down to 45 - 48° C in a water bath put on a magnetic stirrer. BAS and milk were warmed to room

temperature. 5 ml of milk was mixed with 5 ml BAS in a sterile culture tube and added to the flask with gentle stirring. The remaining amount of BAS was added to the flask. The medium was maintained at 45-48° C. 2.5 ml aliquots of medium were dispensed in different culture tubes and allowed to solidify at room temperature.

Evaluation of bacterial adherence

Catheter segments, 4 cm long and sealed at both ends, were inserted vertically into the center of the medium in each tube with 0.5 cm of the catheter protruding out of the medium. The caps of each tube were sealed with Parafilm to prevent dessication. 5 catheter segments were used for each test. Untreated catheter segments were used as the control. After 30 minutes, each catheter segment was lifted up (approximately 0.5 cm) and 25 ul of the bacterial culture (l-3x 10 cfu/ml) was added on the catheter just near the surface of the medium so that the inoculum was also spread on medium surface. The catheter was then placed back to its original position and incubated at 37°C for 7 days. The catheter segments were removed from the tubes and blotted on tissue. They were rinsed twice in 10 ml saline (6 segments/10 ml saline) and blotted dry. 0.5 cm was then cut off from both the ends of each catheter segment. Each catheter segment was then put in 4 ml LTSB (drug inactivating medium) in a culture tube and sonicated for 20 min. 0.5 ml aliquot from each tube was then plated out on TSA plates and incubated for 24-48 hours. MRSA adherence On central venous catheter coated with various salts of Chlorhexidine along with silver salt and Octanediol was tested, using materials prepared as set forth above. To determine which Chlorhexidine salt would show better efficacy, catheters were coated with CHA, CHX, and a combination of CHA + CHX along with a silver salt and Octanediol and lactic acid was evaluated. Using MRSA as the test organism and adherence was evaluated 21 days post infection. The results are shown in TABLE 14.

TABLE 14: MRSA adherence (21 days after implantation and infection)

Adherence Logio Reduction

Group (Cfu/cm) from Control Counts

Control (uncoated catheters) 3.8xl0 ⁴

CHX- AgSD-L-0 77 2.7

CHX-CHA- AgSD-L-0 38 3.0

CHA-AgSD-L-0 3.9xl0 ² 2.0

CHA-AgSD-L 6.1x102 1.8

These data indicate that the groups containing CHX or CHX + CHA showed higher activity than the groups with CHA alone.

To evaluate bacterial adherence to central venous catheter (CVC) segments coated with various alkanediols along with CHX-CHA- AgSD-L, experiments were performed using the impregnation solutions set forth in TABLE 15, below, which also shows the results of these experiments..

TABLE 15: P. aeruginosa adherence (10 days after implantation and infection)

Logio Reduction

Group Cfu/cm from Control Counts

Control (uncoated catheters) l.OxlO ⁴

CHA-AgSD 3.4xl0 ³ 0.52

CHX-CHA-AgSD-L-0 1.5xl0 ² 1.80

CHX-CHA-AgSD-L-D 20 3.20

CHX-CHA- AgSD-L- 1,2 Dod 15 2.80

CHX-CHA- AgSD-L- 1,12 Dod 18 2.70 CHX-CHA-AgSD-L-TD 32 2.50

These data indicate that each of the alkanediols tested enhanced the efficacy when used along with CHX-CHA-AgSD-L.

18. EXAMPLE 13: BACTERIAL ADHERENCE TO IMPREGNATE

SOFT TISSUE PTFE PATCHES

The following impregnation solutions were prepared:

0.1% Silver carbonate + 0.3% CHA (S-CHA)

0.1% Silver carbonate + 0.2% CHX + 0.15% CHA (S-CHX-CHA)

0.1% Silver carbonate + 0.2% CHX + 0.15% CA (S-CHX-CHA)

0.1% Silver carbonate + 0.2% CHX + 0.15% CA + 1% O (S-CHX-CHA-O)

0.1% Silver carbonate + 0.2% CHX + 0.15% CHA + 1% D (Sl-CHX-CHA-D) 0.05 % Silver carbonate + 0.2% CHX + 0.15% CHA +1% D (S2-CHX-CHA-D) (all of them contain 1% Lactic acid)

(S = Silver carbonate, D = 1,2 Decanediol, O = 1,2 Octanediol)

1 cm ² pieces of PTFE soft tissue patches ("STPs") were soaked in solutions comprising about 60 percent THF (v/v), about 20 percent Methanol (v/v) and about 20 percent ammonium hydroxide (v/v) as well as the active agents indicated above, then suctioned using a vacuum pump and left for 5 minutes. The pieces were removed, dried and rinsed in water. After 24 hours the patches were tested.

To evaluate bacterial adherence to the STPs, the following experiments were performed. Several 3 piece sets of PTFE tissue patch from each group and unimpregnated control, each 1 cm , were soaked in medium containing 50% TSB +

50% BAS (1ml per 1 cm of each piece) and placed on an orbital shaker at 37° C. Adherence was tested after seven days as follows: one set from each group was removed, and transferred to a fresh media containing 10 5 cfu of organisms (1ml/ lcm 2 ) and incubated for 24 hours at 37°C. The pieces were then removed and rinsed twice in saline at the rate of 2ml/cm by vortexing at low speed, blotted dry and suspended in drug inactivating media (4.ml /lpiece) and sonicated. 0.5 ml aliquots were plated. Adherence after 14 days was tested as follows, patches were transferred to fresh media on the 7th day and continued orbital shaking for 14 days and then transferred to fresh media containing bacteria and processed as before. Adherence after 21 days was tested as follows: patches were transferred to fresh media on the 7th and 14th days with continuous shaking. On the 21st day, they were transferred to fresh media containing bacteria and processed as before.

The results obtained using different test organisms and after different periods of time are shown in TABLES 16-18, below.

TABLE 16: P. aeruginosa adherence (cfu/cm ² ) on STPs 7 days after soaking in S.TSB

Adherence

Group (cfu/cm ² )

Control 2.0x10 ⁵

S-CHA 6.0xl0 ⁴

S-CHX-CHA 5.0xl0 ⁴

S-CHX-CHA-0 630

S-CHX-CHA-D 43

TABLE 17: S. aureus adherence (cfu/cm ² ) on STPs various days after soaking in S.TSB

Chlorhexidine

level Bacterial Adherence (cfu/cm ² )

Group ( ug/cm ² ) 7 day 14 day 21 day

Control — - 2.3xl0 ⁵ 1.9xl0 ⁵ 3.6 xlO ⁵ S-CHA 86 0 1.2xl0 ⁵ 2.6xl0 ⁵

S-CHX-CHA 94 0 1.2xl0 ⁵ N.D

51- CHX-CHA-D 96 0 0 6.3x1ο ¹

52- CHX-CHA-D 94 0 73 3.4xl0 ²

ND = Not Determined

TABLE 18: P. aeruginosa adherence (cfu/cm ² ) on STPs, various days after soaking in S.TSB

Group 7 day 14 day

Control 2.0x10 ⁵ 1.5xl0 ⁶ S-CA 6.0xl0 ⁴ 3.7xl0 ⁵

S-CX-CA 5.0xl0 ⁴ 3.0x105

Sl-CX-CA-D 43 3.0xl0 ⁴

S2-CX-CA-D 101 3.1xl0 ⁴

19. EXAMPLE 14. BACTERIAL ADHERENCE TO SILICONE

URINARY CATHETER SEGMENTS

Bacterial adherence to silicone urinary catheters impregnated using a two-step method with various alkanediols along with Chlorhexidine, Silver carbonate and Lactic Acid was evaluated.

Catheter segments were impregnated as follows.

Step 1: Catheters were soaked for 1 hour in 0.3% Triclosan (T) (w/v) + 1.0 % L (Lactic Acid) (v/v) in 30% Methanol (v/v) + 68.7% (v/v) THF. The catheters were removed, dried for 1 hour, rinsed in water and dried for another hour.

Step 2: Catheters were dipped in the following solutions and dried for 24 hours and then used for testing.

CHX: 2% (w/v) CHX + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 82% (v/v) THF

CHX-O: 2% (w/v) CHX + 1% O + 15% (w/v) Silastic Medical Adhesive

Type A + 1% glycerin + 81% (v/v) THF

CHX-D: 2% (w/v) CHX + 1% D + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF

CHX-l,2Dod:2% (w/v) CHX + 1% 1,2 Dodecandiol + 15% (w/v) Silastic Medical Adhesive Type A + 1 % glycerin + 81% (v/v) THF

CHX-l,12Dod: 2% (w/v) CHX + 1% 1,12 Dodecanediol + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF

CHX-TD: 2% (w/v) CHX + 1% TD + 15% (w/v) Silastic Medical Adhesive Type A + 1% glycerin + 81% (v/v) THF

Duration of resistance of adherence of bacteria on the catheters was tested in the in vitro urinary tract model described above in Section 12. The results are shown in TABLE 19. TABLE 19: Duration of activity against S. aureus

Group * (Days)

Control 1

T-CHX-L 8

T-CHX-L-0 30

T-CHX-L-D > 50

T-CHX-L- 1, 2 Dod > 50

T-CHX-L- 1, 12 Dod > 50

T-CHX-L-TD > 50

* The letters for each catheter group denote the anti-infectives in the catheter

These data indicate that silicone urinary catheters containing alkanediols along with T + CHX + L showed longer activity than T + CHX + L.

20. EXAMPLE 15: BACTERIAL ADHERENCE TO IMPREGNATED WOUND DRESSINGS

Wound dressings were impregnated with the following solutions:

Antimicrobial composition 1

Ingredients ( % w/w)

CHA 0.15

CHX 0.15

AgSD 0.30

Lactic Acid 0.50

1,2 Decanediol 0.50

Polyurethane 93A 0.40

Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 67.90 Antimicrobial composition 2

Ingredients (% w/w) CHA 0.15 CHX 0.15 AgSD 0.30 Lactic Acid 0.50 l,12 Dodecanediol 0.50 Polyurethane 93A 0.40 Polyurethane 60D 0.10 Methanol 30.00

Tetrahydrofuran 67.90

Antimicrobial composition 3

Ingredients (% w/w) CHA 0.15 CHX 0.15 Silver Carbonate 0.30 Lactic Acid 0.50 l,2 Decanediol 0.50 Polyurethane 93A 0.40 Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 67.90 Antimicrobial composition 4

Ingredients (% w/w)

Polyhexamethylene biguanide 0.30 Silver Carbonate 0.30 l,2 Decanediol 0.50 Lactic Acid 0.50 Polyurethane 93 A 0.40 Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 67.90 Antimicrobial composition 5

Ingredients (% w/w)

CHA 0.15

CHX 0.15

l,2 Decanediol 0.50

Lactic Acid 0.50

Polyurethane 93A 0.40

Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 68.20

Antimicrobial composition 6

Ingredients (% w/w)

Polyhexamethylene biguanide 0.30

l,2 Decanediol 0.50

Lactic Acid 0.50

Polyurethane 93A 0.40

Polyurethane 60D 0.10

Methanol 30.00

Tetrahydrofuran 68.20

Wound dressings (Dukal Non- Adherent Pad) were dipped into the antimicrobial impregnation solution and dried for 24 hours. The dressings were cut into 1cm pieces and the Zones of Inhibition against various bacteria were determined.

For the Zones of Inhibition Test, 1 cm piece of each dressing was placed on a Trypticase Soy Agar plate seeded on the surface with 0.3mL of 10 colony forming units (CFU)/mL) of the test organism. The plates were incubated at 37°C for 24 hours. The Zone of Inhibition around the dressing was measured. The results are shown in TABLE 20, below. TABLE 20: Zone of Inhibition (mm) testing of Dressings treated with

Antimicrobial Composition (AC) 1, 2, 5 and 6

AC 1 AC 2 AC 5 AC 6

Organism Day 1 Day 2 Day 1 Day 2 Day 1 Day 2 Day 1 Day 2

S. aureus 15.0 15.0 15.0 15.0 14.5 11.0 13.5 6.5 MRSA 15.5 14.0 15.0 12.5 14.5 10.5 13.0 6.5 P aeruginosa 14.0 14.0 15.0 15.0 13.0 5.5 8.5 5.5 C. albicans 16.0 13.0 16.0 13.0 15.5 9.0 12.0 7.0

These data indicate that dressings impregnated with antibacterial agents and alkanediols exhibit broad spectrum antimicrobial activity.

21. EXAMPLE 16: Coating of Urinary catheter by a one- step method

The following formulations were used to coat urinary catheters using one-step method, wherein catheters were coated by dipping a catheter in a solution comprising one of the formulations listed below, and then allowed to dry.

Formulation- 1

Ingredients % w/v Range (% w/v)

Chlorhexidine base 2.0 0.1-5.0

Decanediol 2.0 0.1-5.0

Mandelic acid 2.0 0.1-5.0

Lactic acid 0.0 0-5.0

Silver sulfadiazine 0.0 0-2.0

Silver carbonate 0.0 0.0-1.0

PU 93A 2.66 0.2-5.0

PU 60D 0.66 0.1-2.0

Silicone medical adhesive A- 100 3.0 0.2 -10.0

Tetrahydrofuran (THF) 72.68 50.0-80.0

Methanol 15.0 5.0-50.0

(Both latex and silicone catheters can be coated with this solution) Formulation-2

Ingredients % w/v

Chlorhexidine base 2.0 Decanediol 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66 PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.93

Methanol 15.0

Formulation-3

Ingredients % w/v

Chlorhexidine base 2.0 Decanediol 2.0

Mandelic acid 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75 PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.93

Methanol 15.0

Formulation-4

Ingredients % w/v Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0

Silver carbonate 0.3 PU 93A 2.66

PU 60D 0.66 Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 72.38

Methanol 15.0 Formulation-5

Ingredient % w/v

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 1.0

Lactic acid 1.0

Silver carbonate 0.3

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 72.38

Methanol 15.0

Formulation-6

Ingredients % w/v

Chlorhexidine base 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 73.93

Methanol 15.0

Test 1: Zone of Inhibition Test: Evaluation of the efficacy of latex urinary catheters coated by the one step method.

Method: Three 0.5 cm segments of each group of catheters were embedded vertically in modified trypticase soy agar (TSA) media seeded on the surface with 0.3 ml of 10 colony forming units (CFU) per ml of bacteria and 10 ⁶ cfu/ml of fungi and the plates were incubated at 37°C for 24 hours. The diameters of zones of inhibition of bacterial growth around the catheter segments were measured, and are shown in Table 21.

Table 21: Latex Urinary Catheter: Testing of Zone of inhibition against S. aureus, E.coli, P. auregonosa, C. albicans

Test 2: Evaluation of the efficacy of antimicrobial latex urinary catheter coated by the one step method in preventing bacterial adherence when exposed to contaminated urine Semi-quantitative method).

Latex catheter segments (! cm) sealed at both ends were soaked in a culture tube containing 2 ml. of artificial urine contaminated with 10 ^J CFU/mL of E. coli. The culture tube was kept in a shaker at 37°C for overnight. The catheters were transferred daily to fresh artificial urine contaminated with 10 ^J CFU/mL of E. coli. At different time intervals (1 ^st , 3 ^ra , 6 ^th and 10 ^th day), the catheters were removed, rinsed with saline and rolled on drug neutralizing media (D/E agar), The plates were incubated at 37°C for 24 hours to semi-quantitatively determine the bacterial adherence on the surface of catheter. Uncoated catheter segments were used as the control. Results are shown in Table 22. Table 22: Adherence of E. Coli on latex urinary catheter and bacterial growth in urine culture after exposed to contaminated urine in various days

Number of CFS J/cm catheter* (bad Serial growth in urine)

days

Control Chlorhexidine CHX + D + CHX + D +

(CHX) + AgSD Ag ₂ C0 ₃

Decanediol (D) [Formulation-2] [Formulation-

[Formulation- 1] 4] i > 10,000 (Heavy) 0 (No growth) 0 (No growth) 0 (No growth)

3 > 10,000 (Heavy) 0 (Medium) 0 (No growth) 0

(No growth)

6 > 10,000 (Heavy) 0 (Medium) 0 (Medium) 0

(Medium)

10 >10,000 (Heavy) 27(Heavy) 15 (Heavy) 16

(Heavy)

*Mean of three samples

Conclusion: CHX and silver sulfadiazine released initially to inactivate bacteria in the artificial urine. Subsequently, antimicrobials are not released sufficiently to inactivate bacteria in the urine. As a result, urine culture exhibits bacterial growth. However, the antimicrobial impregnated catheter which is surrounded by heavily contaminated urine showed very negligible count of bacterial adherence on its surface after 10 days soaking in contaminated urine, Test 3: Zone of Inhibition Test: Evaluation of the efficacy of latex urinary catheters coated by the one step method.

The method for zone of inhibition test is the same as described in Test 1. Results are shown in Table 23.

Table 23: Latex Urinary Catheter: Testing of Zone of inhibition against S. aureus, E.coli, P. auregonosa, C. albicans

Test 4: Evaluation of the efficacy of an antimicrobial latex urinary catheter coated by the one step method in preventing bacterial adherence when exposed to contaminated urine (Quantitative method)

Method:

Latex urinary catheter segments (1 cm) sealed at both ends, were placed in a sterile culture tube individually and suspended in 2 ml of artificial urine

contaminated with E.coli (10 ⁵ cfu/ml). The tubes were kept at 37°C incubator in a shaker at low speed for overnight. Uncoated catheter segments were used as the control. Then the catheters were suspended into fresh artificial urine contaminated with E. coli (10 ⁵ cfu/ml) and incubated at 37 ° C incubator shaker for overnight.

Likewise, catheter segments were kept on transferring into fresh artificial urine contaminated with E. coli (10 ⁵ cfu/ml) every day. After 10 days, the catheter segments were removed from the tubes and blotted on tissue paper to drain out the residual artificial urine. They were rinsed twice in 10 ml sterile normal saline and blotted dry. Each catheter segment was then put in 4 ml DNF (drug neutralizing fluid) in a culture tube and sonicated for 20 min. 0.5 ml aliquot from each tube was then plated out on TSA plate and incubated for 24h. Results are shown in table 24.

Table 24: Bacterial adherence on the surface latex urinary catheter and bacterial growth in urine after 10 days soaking in artificial urine

*Mean of three samples

Conclusion: Latex urinary catheter coated with CHX + AgSD + D is more effective than CHX + AgSD in preventing E.coli adherence. 22. EXAMPLE 17: Coating of Central Venous Catheter: by a One Step Method The following formulations were used to coat central venous catheters using a one-step method, wherein catheters were coated by dipping a catheter in a solution comprising one of the formulations listed below, and then allowed to dry.

Formulation-5

Ingredients % w/v Range (% w/v) Chlorhexidine base 3.0 0.1-5.0

Decanediol 1.0 0.1-5.0

Mandelic acid 1.0 0.1-3.0

Lactic acid 1.0 0.1-3.0

Silver sulfadiazine 0.0 0.0-2.0

PU 93A 4.33 0.2-8.0

PU 60D 1.09 0.1-3.0

Silicone adhesive MDT7- 4502 1.0 0.2 -5.0

Tetrahydrofuran (THF) 71.33 50.0-80.0 Methanol 16.25 5.0-50.0

Formulation-6

Ingredients % w/v

Chlorhexidine base 3.0

Decanediol 1.0

Mandelic acid 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF) 70.58

Methanol 16.25 Test 5: Zone of Inhibition Test: Evaluation of the efficacy of polyurethane central venous catheters coated by one step method The method for zone of inhibition test is the same as described in Example 16, Test 1. Results are shown in Table 25.

Table 25: Central venous catheters: Testing of Zone of inhibition against S. aureus, E.coli, P. auregonosa, C. albicans (ONE-STEP METHOD)

Test 6: Evaluation of bacterial adherence on antimicrobial impregnated polyurethane (PU) 7 Fr. central venous catheters (CVC) using an in vitro agar track model:

Method:

Agar tract model: The medium used was 1.0% bacto agar (W/V) + 20 % bovine adult serum (BAS) (V/V) + 0.5% Parmalat milk (V/V) + 0.03 % trypticase soy broth medium powder (TSB) (W/V) in phosphate buffered saline (PBS). First, lOg bacto agar and 0.3 g TSB was dissolved in 795 ml of PBS, and a magnetic stirring rod was included in the flask. The medium was sterilized by autoclaving at 121°C for 20 min. After autoclaving, it was allowed to cool down to 45 - 48°C in water bath. Then, BAS and milk were warmed to room temperature, and 5 ml of Parmalat milk were mixed with 5 ml BAS in a sterile culture tube and added to the agar/TSB-containing flask with gentle stirring. Then the remaining 195 ml of BAS was added to the flask. The medium was maintained at 45-48° C. Finally, 12.5 ml aliquots of medium was dispensed into different culture tubes and allowed to solidify at room temperature.

Evaluation of bacterial adherence: Catheter segments, 4 cm long and sealed at both ends, were inserted vertically into the center of the medium in each tube with 0.5 cm of the catheter protruding out of the medium. The caps of each tube were sealed with parafilm to prevent desiccation. Three catheter segments were used for each test. Uncoated catheter segments were used as the control. The catheter segments were removed after 4hrs and transferred to a fresh media. Each catheter segment was lifted up (approximately 0.5 cm) and inoculated with 25 μΐ of the microbial culture (10 cfu/ml for S. aureus, P. aeruginosa and C. albicans). The inoculum was added on the catheter just near the surface of the medium, so that the inoculum was also spread on medium surface. The catheter was then placed back to its original position and incubated at 37°C for 10 days. Then, the catheter segments were removed from the tubes and blotted on tissue paper. They were rinsed twice in 10 ml saline (3 segments/10 ml saline) and blotted dry. 0.5 cm was then cut off from both the ends of each catheter segment. Each catheter segment was then put in 4 ml of drug inactivating medium in a culture tube and sonicated for 20 min. 0.5 ml aliquot from each tube was then plated out on TSA plates and incubated for 24h. The bacterial adherence to the control and test catheter segments are shown in table 26.

Table 26: Reduction in microbial adherence on antimicrobial impregnated central venous catheter surface 10 days post implantation in subcutaneous agar tract model

*Mean of three samples Conclusion: Central venous catheter coated with CHX + D + AgSD is more effective than CHX + AgSD in preventing microbial adherence.

23. EXAMPLE 18: Coating of the Inner Surface of a Central Venous Catheter by a One-Step Method

The following formulations were used to coat the inner lumen of central venous catheters using a one- step method.

Composition of Coating solution for inner lumen of Central Venous Catheter

(CVC):

Ingredients Range (% w/v)

Chlorhexidine base 0.1-5.0

Mandelic acid 0.0-5.0

Lactic acid 0.1-5.0

Ethanol 50.0-90.0

Tetrahydrofuran( THF) 10.0-50.0

Formulation 1:

Ingredients % w/v

Chlorhexidine base 2.0

Mandelic acid 1.0

Lactic acid 1.0

Ethanol 76.0

Tetrahydrofuran 20.0

Formulation 2:

Ingredients % w/v

Chlorhexidine base 2.0

Lactic acid 2.0

Ethanol 76.0

Tetrahydrofuran 20.0

Ethanol and THF are % volume by volume

Method of evaluation:

The antimicrobial coating solution was exposed to the inner lumen of the central venous catheter (CVC) for 100 sec. Then the coating solution was flushed out from the CVC inner lumen and the catheter was dried. 1 cm segments from both ends of the catheter was cut and removed. The coated inner lumen of the CVC was filled with S. aureus (10 cfu/ml) and both of the open ends of the CVC were locked with a clip, so that the bacterial culture remained inside the lumen. The outer surface of the catheter was wiped with 70% ethanol, and kept in a shaker for overnight at 37°C. After 24 hrs, the bacterial culture was collected from inside the lumen through a syringe. CVC's were refilled with fresh bacterial culture. This procedure was repeated daily for 10 days Cultures were collected daily up to 10 days from the lumen and were diluted with drug neutralization fluid and plated on trypticase soy agar. Lumen of a control uncoated catheter was also exposed to bacterial culture and processed similar to the coated catheter lumen. All the plates were kept at 37°C and the colony counts were enumerated.

Results:

Efficacy of coated luminal surface of CVC on reducing bacterial counts of culture in the lumen:

*Mean of three samples

N.D Not done.

Conclusion. Catheter lumens treated with the formulations 1 and 2 exhibit significant an Abacterial acti vity .

24. EXAMPLE 19: Coating of Silicone Urinary Catheter: Two Step Method

The following formulations were used to coat silicone urinary catheters using a two-step method.

Formulation-7

First coating:

Ingredients % w/w Range (%w/w)

Hysol® urethane adhesive 20.0 5-30 Silicone medical adhesive 5.0 0.2-10

Decanediol 1.0 0.3-2.0

Tetrahydrofuran 74.0 60-90 Dip catheters in the above mentioned first coating solution and leave at room temperature for 3 hours.

Then dip in the following second coating solution and dry for 24-48 hours.

Second coating:

Ingredients % w/v Range (% w/v)

Chlorhexidine base 2.0 0.1-5.0

Decanediol 2.0 0.1-5.0

Mandelic acid 2.0 0.1-5.0

Lactic acid 0.0 0-5.0

Silver sulfadiazine 0.0 0-2.0

Silver carbonate 0.0 0.0-2.0

PU 93A 3.33 0.2-5.0

PU 60D 0.83 0.1-2.0

Silicone medical adhesive A-100 3.0 0.2 -10.0

Tetrahydrofuran (THF) 71.84 50.0-80.0

Methanol 15.0 5.0-50.0

Formulation-8

First coating:

Ingredients % w/w

Hysol® urethane adhesive 20.0

Silicone medical adhesive 5.0

Decanediol 1.0

Tetrahydrofuran 74.0

Dip catheters and leave at room temperature for 3 hours

Then dip in second coating solution and dry for 24-48 hours

Second coating:

Ingredients % w/v

Chlorhexidine base 2.0 Decanediol 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 3.33

PU 60D 0.83

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF) 71.09

Methanol 15.0

Test 7: Zone of Inhibition Test: Evaluation of the efficacy of silicone urinary catheters coated by a two-step method

The method for zone of inhibition test is the same as described in Example 16, Test 1. Results are shown in Table 27.

Table 27: Silicone Urinary Catheter: Testing of Zone of inhibition against S. aureus, E.coli, P. auregonosa, C. albicans (TWO-STEP METHOD)

Test 8: Evaluation of the efficacy of antimicrobial silicone urinary catheter prepared using a two-step method in preventing bacterial adherence when exposed to contaminated urine (semi-quantitative method): Method:

S licone urinary catheter segments (1 cm) were soaked in 4 ml of artificial urine contaminated with E. coli and kept in a rotary shaker at 37°C. For the control, uncoated catheter segments were used. The catheters were transferred dai ly to fresh artificial urine contaminated with E. coli. The urine was also sub-cultured daily to detennine the effect of drug diffused out of the catheter into the contaminated urine. At different time intervals (3 ^rd , 6 ^th , 9 ^th and 12 ^th day) the catheters were removed, rinsed in saline and rolled on drug neutralizing media (D/E agar ). The plates were incubated at 37°C for 24 hours to semi-quantitatively determine the bacterial adherence on the surface of the catheter. Results are shown in tables 28 and 29.

Table 28: Bacterial growth (E.coli) in artificial urine sub-cultured on TSA plate

No growth

Light growth

Medium growth

Heavy growth Table 29: Reduction in bacterial adherence on silicone catheter surface at different time intervals of soaking in artificial urine

*Mean of three samples

Conclusion: In spite of the medium/heavy bacterial growth in the surrounding urine culture medium of the CHX + D + AgSD catheter on the 9 ^th and 12 ^th days post soaking, the CHX + D + AgSD catheter is more effective than the CHX + D catheter in preventing the adherence of E. coli on the 9 and 12 days post exposure to contaminated urine. As CHX + D + AgSD catheter showed higher efficacy than CHX + D catheter against E.coli adherence on catheter surface, the bacterial adherence on the surface of CHX + D + AgSD catheter was re-evaluated by Urinary tract model (see Test 9, below).

Test 9: Bacterial adherence on CHX + D + AgSD [Formulation- 8] silicone urinary catheter implanted in Urinary tract model

Method:

In vitro urinary tract model consisted of two tubes, one of which was an open cylindrical tube with one end capped and the other end sealed with a rubber cork with a hole in the center (Tube 1). The tube was crimped from both the sides at the center. The second tube was open at one end and was used for collection of urine (Tube 2). Both the tubes were sterilized with ethylene dioxide. Catheter segments of 6 cm in length, with both the ends sealed with silicone to prevent intraluminal contamination with bacteria, were sterilized and were inserted from top end of "Tube 1" after lifting the cap aseptically and placed in the hole of the rubber cork at the end. The sterile modified Trypticase Soy Agar was cooled to 40 C and then poured along the sides of the tube around the catheter leaving the upper 1 cm of the catheter protruding out in the space above the agar tract, which represented the bladder. When the medium solidified in the tube, the cork at the bottom of the tube was removed gently without disturbing the agar column on the top thus exposing the lower end of the catheter. This lower end of the agar column with the catheter protruding represented the meatus and the agar surrounding the catheter simulated the urethra. This tube was then fixed on "Tube 2" to collect small amount of urine that flowed down the agar tract.

Inoculation of the meatus and determination of bacterial growth in the bladder was performed as follows. The "meatus" was inoculated daily with 20 μΐ of 10 ⁵ cfu/ml of P. aeruginosa after dismantling the collection tube (Tube 2). The "bladder" was filled daily with fresh sterile urine. The "bladder" and the "meatus" were cultured daily on TSA to determine the presence of bacterial growth.

On the day a positive "bladder" culture was found, the catheter segment was also processed for determination of bacterial colonization on the catheter surface. This was done by removing the catheter segment from the "bladder" end of the model, rinsing with saline and rolling it on a D/E agar plate followed by incubation for 24 hours at 37 °C to semi-quantitatively determine the bacterial growth on the surface of the catheter.

Table 30: Duration (Days) of antimicrobial efficacy of urinary catheters in Urinary tract model

Control 1 : Uncoated catheter

Control 2: Coated only with polymers

25. EXAMPLE 20: Method of Rendering a Urinary Catheter Surface Lubricious for Patient Comfort During Insertion

A one step method of rendering the surface of a urinary catheter highly lubricious for easier insertion and comfort to the patient by dipping the catheter in a coating solution comprising biomedical polymers. The biomedical polymers comprised a combination of hydrophilic polymers selected from polyurethane polymers, and hydrophobic polymers selected from silicone polymers (0.2-30% w/v) and decanediol (0.01-5.0% w/v) dissolved in tetrahydrofuran (50-98% v/v).

Method for preparing lubricious coating on medical devices

One-Step Method: The medical device is dipped in a lubricious matrix system containing hydrophilic polymers (Tecoflex polyurethane 93A, polyurethane 60D, or a combination thereof) (0.2-10% w/v); decanediol (0.01-5.0% w/v); hydrophobic polymers (silicone medical adhesive selected from silicone medical adhesive Type A and medical adhesive MDT7-4502) (0.2-10% w/v); optionally with or without urethane adhesive; in a solvent system containing tetrahydrofuran (50-98% v/v) and dried at room temperature.

Method 1: Coating of Urinary catheter: by one-step method

Ingredients % w/v Range (% w/v)

Decanediol 2.0 0.01-5.0

PU 93A 2.66 0.1-7.0

PU 60D 0.66 0.1-3.0

Silicone medical adhesive A- 100 3.0 0.2 -10.0

Tetrahydrofuran (THF) 91.68 50.0-98.0

(Both latex and silicone catheters can be coated with this solution)

The catheter segment coated with above mentioned lubricious polymeric matrix system was dipped in water. After three days, it was observed that the degree of lubricity on the catheter surface appears to be the same as that of the lubricity obtained immediately after coating.

Balloon inflation test was carried out to evaluate the integrity of the lubricious polymeric coating composition on the urinary catheter surface. The balloon segment of the urinary catheter coated with lubricious coating composition was filled with water. Then the balloon was immersed in water. It was found that the integrity of the coating composition remains intact on the catheter surface even after three days in water. 26. EXAMPLE 21: Decanediol Increases the Antimicrobial Efficacy of a Urinary

Catheter Coated with a Coating Comprising Chlorhexidine and Silver Sulfadiazine -

One Step Method

A one step method was used to coat the surface of a urinary catheter with an antimicrobial composition comprising chlorhexidine and silver sulfadiazine, wherein the addition of decanediol to the coating composition increased the coating's antimicrobial effect.

Coating solution A (Coating solution without Decanediol)

Ingredients Amount (grams)

Chlorhexidine base 2.0

Mandelic acid 2.0

Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF)* 73.93

Methanol* 15.0

*Methanol and THF are added by volume. Coating solution B (Coating solution with Decanediol)

Ingredients Amount (grams)

Chlorhexidine base 2.0

Decanediol 2.0

Mandelic acid 2.0 Silver sulfadiazine 0.75

PU 93A 2.66

PU 60D 0.66

Silicone medical adhesive A- 100 3.0

Tetrahydrofuran (THF)* 71.93

Methanol* 15.0

Methanol and THF are added by volume.

Test 1: Evaluation of the antimicrobial efficacy of a silicone urinary catheter coated with Coating Solution A and B in preventing bacterial adherence to the catheter when exposed to urine contaminated with Pseudomonas aeruginosa.

Method:

Silicone urinary catheter segments (1 cm) sealed at both ends that were coated with Coating Solution A or B were individually placed in a sterile culture tube and suspended in 2 ml of artificial urine contaminated with Pseudomonas aeruginosa, Proteus mirabilis, or Candida albicans (10 ⁴ cfu/ml). The tubes were kept at 37°C with shaking at low speed overnight. Uncoated catheter segments were used as the control. Catheter segments were transferred into fresh artificial urine contaminated with P. aeruginosa, Proteus mirabilis, or Candida albicans (10 ⁴ cfu/ml) each day for 9 days. After 9 days, the catheter segments were removed from the tubes and blotted on tissue paper to drain out the residual artificial urine. Catheter segments were rinsed twice in 10 ml sterile normal saline and blotted dry. Each catheter segment was then placed in a culture tube containing 4 ml of DNF (drug neutralizing fluid) and sonicated in a water bath for 20 min. A 0.5 ml aliquot from each tube was then plated onto a TSA plate and incubated for 24h. Bacterial adherence on the surface of the catheter segments was then determined.

Results

Tables 31A-C show the bacterial adherence on the surface of the silicone urinary catheters coated with Coating Solution A (comprising chlorhexidine base (CHX) and silver sulfadiazine (AgSD), i.e., CHX +AgSD) and Coating Solution B (comprising CHX+AgSD+Decanediol (D)) after 9 days soaking in artificial urine. Table 31 A: Adherence of Pseudomonas aeruginosa

*Mean of three samples

Conclusion: Silicone urinary catheters coated with CHX + AgSD + D are more effective than catheters coated with CHX + AgSD in preventing the adherence of P. aeruginosa, P. mirabilis and C. albicans to the catheters' surfaces. Test 2: Evaluation of drug retention and prevention of biofilm formation on and microbial adherence to catheters coated by a one-step method using Coating Solution B comprising CHX+AgSD+D.

Method

Urinary catheters coated with CHX+AgSD+D were evaluated for drug retention and bacterial adherence on the urinary catheter surface after exposure to urine comprising Pseudomonas aeruginosa for time intervals of between 0-9 days.

To determine the release of chlorhexidine from the catheter surface, 1- cni catheter segments were extracted with 2 ml of methylene dichloride for 20 minutes, with vortexing at every 5 minute interval. After 20 minutes, 4 ml of 50% reagent alcohol was added to the extraction tube and left for another 20 minutes with intermittent vortexing at every 5 minute interval, All the tubes were then centrifuged at 3000 rpm for 10 min. The concentration of chlorhexidine remaining on the upper alcohol layer was determined spectrophotometrically at 259 nm.

Results

Chlorhexidine retention and percentage reduction of Pseudomonas aeruginosa adherence on urinary catheter surfaces coated with CHX+AgSD+D after exposure to urine comprising Pseudomonas aeruginosa for 0-9 days is shown in Table 32.

Table 32. Chlorhexidine retention and percentage reduction of Pseudomonas aeruginosa adherence on urinary catheter surface coated with CHX+AgSD+D.

Conclusion: Urinary catheters coated with CHX+AgSD+D released about 20% of the CHX initially (within 4 days) which can inactivate pathogens introduced from the insertion site of the catheter, thus lowering potential for microbial colonization on the surface of device. Thereafter, a significant amount of the antimicrobials remained on the surface, which helps to prevent subsequent microbial adherence and biofilm formation by releasing a minute amount (1% daily) of CHX for a prolonged period of time of up to at least 9 days. Test 3: Evaluation of biofilm formation and bacterial adherence on the outer surface of urinary catheter 10 days post soaking in artificial urine contaminated with P. aeruginosa Method:

Uncoated catheter segments (control) and catheter segments coated with Lubri-Sil I.C. (manufactured by BARD medical, C. R. Bard, Inc.) comprising silver alloy and hydrogel, or CHX +AgSD+D were soaked in artificial urine comprising P. aeruginosa as described above. After 10 days of soaking, the catheter surface of the uncoated control and coated catheters were imaged using Scanning Electron

Microscopy (SEM) to image bacterial biofilm on the catheter surface.

Results:

As shown in Figure 1, catheters coated with CHX+AgSD+D did not exhibit formation of P. aeruginosa biofilm. In contrast, control and Lubri-Sil I.C. coated catheters exhibited P. aeruginosa biofilm formation.

Example 21 Summary:

Devices coated with a antimicrobial coating comprising CHX, AgSD and D exhibit low-leaching of antimicrobial agents. As such, medical devices (e.g., implantable medical devices) coated with such a composition can prevent biofilm formation on the device thereby reducing blood stream infection, while avoiding release of therapeutic amounts of antimicrobials into the body. 27. EXAMPLE 22: Evaluation of Drug Retention and Microbial Adherence on the Surface of Central Venous Catheters Coated with a Composition Comprising Chlorhexidine base, DecanedioL and Silver Sulfadiazine by a One-Step Method

A one step method was used to coat the surface of urinary catheters with an antimicrobial composition comprising chlorhexidine base (CHX), decanediol (D) and silver sulfadiazine (AgSD). The coating composition comprised the following formulation. General formulation for CVC coating Ex. 22

Ingredients Amount (grams)

Chlorhexidine base 0.5 - 5.0

Decanediol 0.5 - 5.0 Mandelic acid 0.0 - 3.0

Lactic acid 0.0 - 3.0

Silver sulfadiazine 0.0 - 2.0

PU 93A 0.2 - 8.0

PU 60D 0.1 - 3.0 Silicone adhesive MDT7- 4502 0.2 - 5.0

Tetrahydrofuran (THF)* 50.0 - 80.0

Methanol* 5.0 - 50.0 *Methanol and THF are added by volume. CVC Formulation Ex. 22.1

Ingredients Amount (grams)

Chlorhexidine base 3.0

Decanediol 1.0

Mandelic acid 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 17.25

*Methanol and THF are added by volume.

CVC Formulation Ex. 22.2

Ingredients Amount (grams)

Chlorhexidine base 3.0

Decanediol 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75 PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 18.25

Methanol and THF are added by volume.

CVC Formulation Ex. 22.3

Ingredients Amount (grams) Chlorhexidine base 2.5

Decanediol 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 4.33

PU 60D 1.09

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 18.75

*Methanol and THF are added by volume.

CVC Formulation Ex. 22.4

Ingredients Amount (grams) Chlorhexidine base 3.0

Decanediol 1.0

Lactic acid 1.0

Silver sulfadiazine 0.75

PU 93A 3.2

PU 60D 0.8

Silicone adhesive MDT7- 4502 1.0

Tetrahydrofuran (THF)* 69.58

Methanol* 19.67

*Methanol and THF are added by volume. Table 33: Chlorhexidine retention and percentage reduction of Pseudomonas aeruginosa adherence on central venous catheter surfaces coated with a composition comprising CHX (3%), Lactic acid (1%), D (1%) and AgSD (0.75%) (CVC formulation example 22.2) after soaking in artificial urine comprising Pseudomonas aeruginosa for 0-8 days.

Conclusion: Central venous catheters coated with a composition comprising CHX, D and AgSD released about 20% of the CHX initially (within 3 days). The majority of CHX remained on the surface of the catheter during the study preventing P.

aeruginosa adherence and biofilm formation on the coated catheters.

28. EXAMPLE 23: Method of Rendering the Inner Surface of a Catheter Biofilm Resistant and Antimicrobial Coating solutions for coating the inner lumen of a Central Venous

Catheter (CVC) comprise the following formulations:

General formulation Ex. 23

Ingredients Amount (grams)

Chlorhexidine base 0.1-5.0

Mandelic acid 0.0-5.0

Lactic acid 0.1-5.0 Ethanol* 50.0-90.0

Tetrahydrofuran (THF)* 10.0-50.0

*Ethanol and THF are added by volume.

CVC Formulation Ex. 23-1:

Ingredients Amount (grams)

Chlorhexidine base 2.0

Mandelic acid 1.0

Lactic acid 1.0

Ethanol* 76.0

Tetrahydrofuran (THF)* 20.0

*Ethanol and THF are added by volume

CVC Formulation Ex. 23-2:

Ingredients Amount (grams)

Chlorhexidine base 2.0

Lactic acid 2.0

Ethanol* 76.0

Tetrahydrofuran (THF)* 20.0

*Ethanol and THF are added by volume.

Method

The antimicrobial coating solutions were exposed to the inner lumen of a central venous catheter (CVC) for 100 sec. Then the coating solution was flushed out from the CVC inner lumen and the catheter was dried. 1 cm segments from both ends of each catheter were cut and removed. The coated inner lumen of the CVC was filled with S. aureus (10 cfu/ml), and both of the open ends of the CVC were locked with a clip so that the bacterial culture remained inside the lumen. The outer surface of the catheter was wiped with 70% ethanol, and the catheter segments were kept in a shaker overnight at 37°C. After 24 hrs, the bacterial culture was collected from inside the lumen with a syringe. The catheter lumens were refilled with fresh bacterial culture. This procedure was repeated daily for 10 days. The cultures collected from the lumen daily for the 10 days were diluted with drug neutralization fluid (DNF) and plated on trypticase soy agar (TSA) plates. Lumen of a control uncoated catheter was also exposed to bacterial culture and processed similar to the coated catheter lumen. All the plates were kept at 37°C and the colony counts were enumerated.

Results

The antimicrobial efficacy of the coated luminal surface of CVCs on reducing bacterial counts of the culture removed from the lumen is shown in Table 34.

Table 34. Antimicrobial efficacy of CVC Formulations 1 and 2 on bacteria growth over a 10 day culture period

29. EXAMPLE 24: Method of Rendering a Urinary Catheter Surface Lubricious

A one step method of rendering the surface of urinary catheter highly lubricious for easier insertion and comfort to the patient by dipping the catheter in a coating solution comprising biomedical polymers (0.2-30% w/v) comprising a combination of hydrophilic polymers selected from polyurethane polymers, and hydrophobic polymers selected from silicone polymers; and decanediol (0.01- 5.0%w/v) dissolved in tetrahydrofuran (50-98%v/v).

Methods One-Step Coating Method: The medical device is dipped in a lubricious matrix system containing Tecoflex polyurethane 93A, polyurethane 60D, either alone or in combination, (0.2-10% w/v); decanediol (0.01-5.0%w/v); silicone medical adhesive selected from silicone medical adhesive Type A, and medical adhesive MDT7-4502 (0.2-10% w/v); with or without a urethane adhesive in a solvent system containing tetrahydrofuran (50-98% v/v); and then dried at room temperature. The coating composition comprised the following formulation.

Coating Formulation Ex. 24

Ingredients Amount (grams) Amount (grams)

Decanediol 2.0 0.01-5.0

PU 93A 2.66 0.1-7.0

PU 60D 0.66 0.1-3.0

Silicone medical adhesive A- 100 3.0 0.2 -10.0

Tetrahydrofuran (THF)* 91.68 50.0-98.0

*THF is added by volume.

(Both latex and silicone catheters can be coated with this solution)

The catheter segments coated with above lubricious polymeric matrix system were dipped in water. After three days, it was observed that the degree of lubricity on the catheter surfaces appeared to be the same as that of the lubricity obtained immediately after coating.

A balloon inflation test was carried out to evaluate the integrity of the lubricious polymeric coating composition on the urinary catheter surface. The balloon segment of the urinary catheter coated with the lubricious coating composition was filled with water. The balloon was then immersed in water. It was found that the integrity of the coating composition remained intact on the catheter surface even after three days in water.

Various publications are cited herein, the contents of which incorporated by reference in their entireties.