CA2241461A1 - Triclosan-containing medical devices - Google Patents

Abstract

The present invention relates to polymeric medical articles comprising the antiinfective agents chlorhexidine and triclosan. It is based, at least in part, on the discovery that the synergistic relationship between these compounds permits the use of relatively low levels of both agents, and on the discovery that effective antimicrobial activity may be achieved when these compounds are comprised in either hydrophilic or hydrophobic polymers. It is also based on the discovery that chlorhexidine free base and triclosan, used together, are incorporated into polymeric medical articles more efficiently.
Medical articles prepared according to the invention offer the advantage of preventing or inhibiting infection while avoiding undesirably high release of antiinfective agent, for example into the bloodstream of a subject.

Description

CA 02241461 1998-06-2~
WO 97/25085 PCTnUS96~093Z

Pescription TRI~LQSAN-CONTAINING MEDICAL DEVICES

1. INTRODUCTION
This application is a continuation in part of United States Patent Application Serial No. 08/483,239, filed January 5, 1996.

2. BACKGROUND OF THE I~v~NllON
The present invention relates to medical devices comprising synergistic combinations of tri-closan and chlorhexidine.
Whenever a medical device comes in contact with a patient, a risk of infection is created. Thus, a cont~ ;n~ted e~ in~tion glove, tongue depressor, or stethoscope could transmit infection. The risk of infection dramatically increases for invasive medical devices, such as intravenous catheters, arterial grafts, intrathecal or intracerebral shunts and pros-thetic 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 ~hich incorporate anti-infective agents into medical devices, none of which have been clinically proven to be completely satis-factory. Such devices desirably provide effective levels of antiinfective agent during the entire period that the device is being used. This sustained release may be problematic to achieve, in that a mechanism for dispersing antiinfective agent over a prolonged period of time may be required, and the incorporation of suf-ficient amounts of antiinfective agent may adversely affect the surface characteristics of the device. The difficulties encountered in providing effective anti-CA 02241461 1998-06-2~
W O 97/25085 PCT~US96~0932 microbial protection increase with the development of drug-resistant pathogens.
One potential solution to these problems is the use of a synergistic combination of antiinfective agents that re~uires relatively low concentrations of individual antiinfective agents which may have dif-fering patterns of bioavailabilit~.
Two well-known antiinfective agents are chlorhexidine and triclosan. The following patents and patent application relate to the use of chlorhexidine and/or triclosan in medical devices.
United States Patent No.4,723,950 by Lee relates to a microbicidal tube which may be incor-porated into the outlet tube of a urine drainage bag.
The microbicidal tube is manufactured from polymeric materials capable of absorbing and releasing anti-microbial substances in a controllable sustained time release m~ch~nism, 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 micro-bicidal agent, and then coated with a hydrophilic polymer which swells upon contact with urine, causing the leaching out of the microbicidal agent; (2) a porous material, such as high density polyethylene, is impregnated with a hydrophilic polymer and at least one microbicidal agent; and (3) a polymer, such as silicone, is compounded and co-extruded with at least one microbicidal agent, and then coated with a hydro-philic polymer. A broad range of microbicidal agents are disclosed, including chlorhexidine and triclosan, and combinations thereof. The purpose of Lee's device is to allow the leaching out of microbicidal agents into urine contained in the drainage bag; similar CA 02241461 1998-06-2~
W O 97/25085 PCTAJS96~0932 leaching of microbicidal agents into the bloodstream of a patient may be undesirable.
United States Patent 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 agent, such as triclosan. The tubular articles are made of materials which include natural rubber, polyvinyl chloride and polyurethane. Antimi-crobial agent may be distributed throughout thearticle, or in a coating thereon. A condom prepared from natural rubber latex containing 1% by weight of triclosan, then dipped in an a~ueous solution of chlor-hexidine, is disclosed. United States Patents Nos.
5,180,605 and 5,261,421, both by Milner, relate to similar technology applied to gloves.
United States Patents 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. Anti-microbial agents such as chlorhexidine or triclosan may be incorporated into the coated floss.
United States Patent No. 5,200,194 by Edgren et al. relates to an oral osmotic device comprising a thin semipermeable membrane wall surrounding a com-partment 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 3~ agents" which may be incorporated into the oral osmotic device, including chlorhexidine and triclosan.
United States Patent No. 5,019,096 by Fox, Jr. et al. relates to infection-resistant medical devices comprising a synergistic combination of a silver salt (such as silver sulfadiazine) and chlor-hexidine.

CA 02241461 1998-06-2~
WO s7nsoss PCTAJS96/20932 International Patent Application No.
PCT/GB92/01481, Publication No. WO 93/02717, relates to an adhesive product comprising residues of a copoly-merisable emulsifier comprising a medicament, which may be povidone iodine, triclosan, or chlorhexidine.
In contrast to the present invention, none of the above-cited references teach medical articles comprising synergistic combinations of chlorhexidine and triclosan which utilize relatively low levels of these agents.

3. SUMMARY OF THE INV~NTION
The present invention relates to polymeric medical articles comprising the antiinfective agents chlorhexidine and triclosan. It is based, at least in part, on the discovery that the synergistic relation-ship between these compounds permits the use of rela-tively low levels of both agents, and on the discovery that effective antimicrobial activity may be achieved when these compounds are comprised in either hydro-philic or hydrophobic polymers. It is also based on the discovery that chlorhexidine free base and tri-closan, used together, are incorporated into polymeric medical articles more efficiently. Medical articles prepared according to the invention offer the advantage of preventing or inhibiting infection while avoiding undesirably high release of antiinfective agent, for example into the bloodstream of a subject.

-CA 02241461 1998-06-2~
W O 97/2508~ PCT~US96~0932 4. ~T~TT.~ DESCRIPTION OF THE I~V~N'1'10N
The present invention relates to medical articles comprising synergistic combinations of chlor-~ hexidine and triclosan.
Chlorhexidine may be provided by way of any form, salt or derivative thereof, including but not limited to chlorhexidine ~ree base and chlorhexidine salts such as chlorhexidine diphosphanilate, chlorhexidine diglu-conate, chlorhexidine diacetate, chlorhexidine dihy-drochloride, chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidine diperchlorate, chlor-hexidine dinitrate, chlorhexidine sulfate, chlor-hexidine sulfite, chlorhexidine thiosulfate, chlor-hexidine di-acid phosphate, chlorhexidine difluoro-phosphate, chlorhexidine diformate, chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlor-hexidine di-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate, chlorhexidine succinate, 2~ chlorhexidine malate, chlorhexidine tartrate, chlorhexidine dimonoglycolate, chlorhexidine mono-diglycolate, chlorhexidine dilactate, chlorhexidine di-~-hydroxyisobutyrate, chlorhexidine diglucoheptonate, chlorhexidine di-isothionate, chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidine dimandelate, chlorhexidine di-isophthalate, chlorhexidine di-2-- hydroxynapthoate, and chlorhexidine embonate. The term ~Ichlorhexidine~ as used herein, may refer to any of such forms, derivatives, or salts, unless specified 3~ otherwise. Chlorhexidine salts may be solubilized using polyethylene glycol or propylene glycol, or other solvents known in the art.
The term triclosan refers to a compound also known as 2,4,4'-trichloro-2'-hydroxydiphenyl ether.
Medical articles that may be treated according to the invention are either fabricated from -CA 02241461 1998-06-2~

5 PCT~US96/20932 or coated or treated with biomedical polymer and include, but are not limited to, catheters including urinary catheters and vascular catheters (e.g. peri-pheral and central vascular catheters), wound drainage tubes, arterial grafts, soft tissue patches, gloves, shunts, stents, tracheal catheters, wound dressings, sutures, guide wires and prosthetic devices (e.g. heart valves and LVADs). Vascular catheters which may be prepared according to the present invention include, but are not limited to, single and multiple lumen cen-tral venous catheters, peripherally inserted central venous catheters, emergency infusion catheters, percu-taneous sheath introducer systems and thermodilution catheters, including the hubs and ports of such vascu-lar catheters.
The present invention may be further applied to medical articles that have been prepared according to United States Patent No. 5,019,096 by Fox, Jr. et al.
The present invention provides, in various alternative nonlimiting embodiments, for: (1) com-positions which provide a local concentration of chlor-hexidine of between 100 and 2000 ~g/ml and a local con-centration of triclosan of between 250 and 2~00 ~g/ml;
(2) treatment solutions of a polymer comprising between 1 and 5 percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine; and between .5 and 5 percent, and preferably between .5 and 2 percent, of triclosan, wherein a medical article may be dipped or soaked in the polymer solution; (3) medical articles treated with a treatment solution as set forth in (2) above, and articles physically e~uivalent thereto (that is to say, articles prepared by a different method but having essentially the same elements in the same pro-portions); (4) treatment solutions of a polymer com-prising between 1 and 5 percent, and preferably between CA 02241461 1998-06-2~
W O 97/2508S PCTrUS96/20932 1.5 and 2.25 percent, of chlorhexidine; between .5 and 5 percent, and preferably between .5 and 2 percent, o~
triclosan; and between .5 and 1 percent (preferably .75 percent) of silver sulfadiazine, wherein a medical article may be dipped or soaked in the polymer solu-tion; and (53 medical articles treated with a treatment solution set forth in (4) above, and articles physi-cally equivalent thereto (that i5 to say, articles prepared by a different method but having essentially the same elements in the same proportions). Percentages recited herein refer to percent by weight, except as indicated otherwise.
In preferred embodiments, the ratio, by weight, of the total amount of antiinfective agent to polymer in the treatment solution is less than 1.5.
In one particular non-limiting embodiment, the present invention provides for a hydrophilic polymeric medical article (i.e., a medical article fabricated from a hydrophilic polymer) treated by dipping or soaking the article in a treatment solution of a hydrophilic polymer comprising chlorhexidine and triclosan wherein the chlorhexidine and triclosan are present in amounts such that their combination, in the treated article, has effective antimicrobial activity.
The terms ~'treat~', "treated", etc., as used herein, refer to coating, impregnating, or coating and impreg-- nating a medical article with polymer/antiinfective agent. The term "hydrophilic polymer", as used herein, - refers to polymers which have a water absorption grea~er than ~.6 percent by weight (and, in preferred embodiments, less than 2 percent ~y weight; as measured by a 24 hour immersion in distilled water, as described in ASTM Designation D570-81) including, but not limited to biomedical polyurethanes (e.g. ether-based po-y-urethanes and ester-based polyurethanes, as set forth in Baker, 1987, in Controlled Release of Biologically CA 02241461 1998-06-2~
W O 97/25085 PCT~US96~0932 Active Agents, John Wiley and Sons, pp. 175-177 and Lelah and Cooper, 1986, Polyurethanes in Nedicine, CRC
Press, Inc., Fla. pp. 57-67; polyurethanes comprising substantially aliphatic backbones such as Tecoflex~
93A; polyurethanes comprising substantially aromatic backbones such as Tecothane~; and Pellethane~), polylactic acid, polyglycolic acid, natural rubber latex, and gauze or water-absorbent fabric, including cotton gauze and silk suture material. In a specific, nonlimiting embodiment, the hydrophilic medical article is a polyurethane catheter which has been treated with (i.e., dipped or soaked in) a treatment solution com-prising (i) between about 1 and 10 percent, preferably between about 2 and 6 percent, and more preferably about 3 percent, of a biomedical polyurethane; (ii) between 1 and 5 percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine; and (iii) between .5 and 5 percent, and preferably between .5 and 2 percent, of triclosan. In related nonlimiting embodiments of the invention, the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .5 and 1 percent (more preferably .75 percent).
Section 6, below, presents working examples of embodi-ments set forth in this paragraph.
In another particular non-limiting embodi-ment, the present invention provides for a hydrophilic polymeric medical article treated by dipping or soaking the article in a treatment solution of a hydrophobic polymer comprising chlorhexidine and triclosan, wherein the chlorhexidine and triclosan are present in amounts such that their combination, in the treated article, has effective antimicrobial activity. The term "hydro-phobic polymer", as used herein, refers to a polymer which has a water absorption of less than ~.6~ and includes, but is not limited to, silicone polymers such as biomedical silicones (e.g., Silastic Type A) or CA 02241461 1998-06-2~
W O 97~5085 rCT~US96~0932 _g_ elastomers (e.g., as set forth in Baker, 1987, in Con-~rolle~ Release of Biologically Active Agents, John Wiley and Sons, pp.156-162), Dacron, polytetra-fluoroethylene (PTFE, also "Teflon"), polyvinyl chlor-ide, cellulose acetate, polycarbonate, and copolymerssuch as silicone-polyurethane copolymers (e.g., PTUE
203 and PTUE 205 polyurethane-silicone interpenetrating polymer). In a specific, nonlimiting embodiment, the medical article is a polyurethane catheter which has been dipped or soaked in a treatment solution com-prising (i) between about 1 and 10 percent, preferably between about 2 and 6 percent, and more preferably about 3 percent, of a polyurethane - silicone copoly-mer; tii) between 1 and 5 percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine; and (iii) between .5 and 5 percent, and preferably between .5 and 2 percent, of triclosan. In related nonlimiting embodiments of the invention, the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .~ and 1 percent (more pre-ferably .75 percent). Section 7, below, presents working examples of embodiments set forth in this paragraph.
In another particular non-limiting embodi-ment, the present invention provides for a hydrophobic polymeric medical article treated by dipping or soaking the article in a treatment solution of hydrophobic polymer comprising chlorhexidine and triclosan, wherein the chlorhexidine and triclosan are present in amounts such that their combination, in the treated article, has effective antimicrobial activity. In a specific, nonlimiting embodiment, the medical article is a sili-cone catheter or a polyvinylchloride catheter which has been dipped or soaked in a treatment solution com-prising (i) between about 1 and 10 percent, and pre-ferably about 5 percent, of a silicone polymer; (ii) CA 02241461 1998-06-2~
WO 97/25085 PCTnJS96/20932 between 1 and 5 percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine; and (iii) between .5 and 5 percent, and preferably between .5 and 2 percent, of triclosan. In related nonlimiting embodiments of the invention, the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .5 and 1 percent (more preferably .75 percent).
In still other related embodiments a coating of a hydrophobic polymer may be applied over the treated 1~ article. Section 8, below, presents working examples of embodiments set forth in this paragraph.
In another particular non-limiting embodi-ment, the present invention provides for a hydrophobic polymeric medical article treated by dipping or soaking the article in a treatment solution of hydrophilic polymer comprising chlorhexidine and triclosan, wherein the chlorhexidine and triclosan are present in amounts such that their combination, in the treated article, has effective antimicrobial activity. In a specific, 2Q nonlimiting embodiment, the medical article is a silicone catheter or Teflon graft which has ~een dipped or soaked in a treatment solution comprising (i) between about 1 and 10 percent, preferably between about 2 and 6 percent, and more preferably about 3 percent, of a biomedical polyurethane polymer; (ii) between 1 and 5 percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine; and (iii) between .5 and 5 percent, and preferably between .5 and 2 percent, of triclosan. In related nonlimiting embodiments of the 3Q invention, the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .5 and 1 percent ~more preferably .75 percent).
Medical articles prepared according to the invention may be treated on their external surface, internal surface, or both. For example, and not by way of limitation, where the medical article is a catheter, CA 02241461 1998-06-2~
WO 97/25085 PCTAUS~6/20932 the internal surface and/or external surface of the catheter may be treated according to the invention.
For example, where it is desired to treat both internal - and external surfaces, an open-ended catheter may be placed in a treatment solution such that the treatment solution fills the catheter lumen. If only the external surface is to come in contact with treatment solution, the ends of the catheter may be sealed before it is placed in the treatment solution. If only the lo internal surface is to come in contact with treatment solution, the solution may be allowed to pass through and fill the lumen but the catheter is not immersed in the treatment solution.
Successful treatment of a medical article with a polymer comprising an antiinfective agent may be problematic, particularly where the medical article has a hydrophobic surface. The adherence of the polymer may depend upon (1) the polymeric matrix in which the anti-infective agent is suspended; (2) compatibility (or lack thereof) between the agent-polymeric matrix and the surface of the article; (3~ the solvent system; and (4) the thickness of polymer/antiinfective agent desir-ably applied. Furthermore, the rates of release of various antiinfective agents from diverse polymers may differ. For example, the rate of release of chlor-hexidine from a silicone matrix is faster than the rate of release of silver sulfadiazine from the same matrix.
In order to compensate for this difference, one poten-- tial solution would be to increase the amounts of chlorhexidine and silver sulfadiazine in the matrix.
Unfortunately, polymers comprising high levels of chlorhexidine and silver sulfadiazine have been found to adhere poorly to silicone catheters. In order to provide an alternative solution to the problem, two different methods for treating medical articles have CA 02241461 1998-06-2~
W O 97~508~ PCT~US96/20932 been developed: a one step method, and a two-step method, both of which are set forth below.
According to the one-step method of the invention, a polymeric medical article may be treated with a solution comprising one or more antiinfective agent, and optionally containing a biomedical polymer, dissolved in one or more solvents, wherein the sol-vent(s) selected are capable of swelling the polymeric medical article to be treated; such a solution is referred to herein as an 'limpregnating solution", and the process by which the article is treated with anti-infective agent is referred to as "impregnation". Suit-able solvents include, but are not limited to, tetrahy-drofuran ("THF"), dichloromethane, carbon tetra-chloride, methanol, ethanol, methyl ethyl ketone,heptane, and hexane, and mixtures thereof. The bio-medical polymer may be hydrophilic or hydrophobic, and includes the various polymers set forth above.
If a hydrophilic polymeric medical article is to be impregnated with chlorhexidine and triclosan, the impregnating solution may, in specific nonlimiting embodiments, comprise the following (percentages of solvents in this paragraph being volume/volume): (1) 95% ethanol; (2) 70% ethanol/30% water; (3) 50%
ethanol/50~ water; (4) 30% reagent alcohol/70% THF
containing 2-3% of a biomedical polyurethane; (5) 90 reagent alcohol/10% THF; or (6~ 100% reagent alcohol.
Preferred soaking times vary between 5 minutes and 1 hour.
In specific, nonlimiting embodiments of the invention, a hydrophilic medical article such as a polyurethane catheter may be impregnated using a sol-vent mixture of 70-90% ethanol and 10-30% water and chlorhexidine and triclosan for between 10 and 60 minutes. The article may then be dried for 24-48 hours.
If a hydrophobic polymeric medical article is CA 0224l46l l998-06-2~
W O 97/25085 PCT~US96n~932 to be impregnated with chlorhexidine and triclosan, the impregnating solution may, in specific nonlimiting embodiments, comprise the following (percentages of ~ solvents in this paragraph being volume/volume): (1) 10% methanol /90% THF; (2) 10% ethanol/90% T~F; (3~ 30%
methanol/70% THF; (4) 30% ethanol/70% THF; (5) 1-5 percent silicone polymer in 10% methanol/90% THF; (6) 1-5 percent silicone polymer in 10% ethanol/90% THF;
t7) 1-2 percent polylactic acid in 10~ methanol/90%
THF; (8) 1-2 percent polylactic acid in 10% ethanol/90%
THF; (9) 1-5 percent silicone polymer in 30% meth-anol/70% THF; (lO) 1-5 percent silicone polymer in 30%
ethanol/70% THF; (11) 1-2 percent polylactic acid in 30% methanol/70% THF; (12) 1-2 percent polylactic acid ~n 30~ ethanol/70% THF; (13) 1-5 percent silicone polymer in 100% methyl ethyl ketone; and (14) 1-2 percent polyurethane in 30% ethanol/70% THF. For specific examples, see Section 15, below.
In specific embodiments, the impregnating solution comprises between 0.2 and 10 percent antiinfective agent and between 0.5 and 4 percent biomedical polymer.
The medical article, or a portion thereof, may be immersed in the impregnating solution to swell, after which the article may be removed and dried at room temperature until all solvent has evaporated and the article is no longer swollen. During the swelling process, antiinfective agent (and small amounts of polymer when present in the impregnating solution) may be distributed within the polymeric substrate of the article; during drying, the antiinfective agent and biomedical polymer (where present) may migrate somewhat toward the surface of the article. After drying, the article may be rinsed in either water or alcohol and wiped to remove any excess antiinfective agent and/or polymer at the surface. This may leave a sufficient CA 0224l46l l998-06-2~
W O 97/25085 PCT~US96/20932 amount of antiinfective agent just below the surface of the article, thereby permitting sustained release of the agent over a prolonged period of time. Anti-infective agents which may be incorporated by this process include but are not limited to chlorhexidine, triclosan, silver sulfadiazine, parachlorometaxylene, benzalkonium chloride, bacitracin, polymyxin, mico-nasole and rifampicin, as well as combinations thereof.
In preferred, nonlimiting embodiments of the invention, synergistic combinations of chlorhexidine and triclosan may be dissolved in a mixture of methanol and tetrahydrofuran to produce an impregnating solution that may be used to render a silicone catheter anti-infective.
In one specific, nonlimiting example, the amount of chlorhexidine may be between 1 and 5 percent and preferably between 1.5 and 2.25 percent of the impregnating solution, and the amount of triclosan may be between .5 and 5 percent, and preferably between .5 and 2 percent. The resulting impregnating solution may further contain between 1 and 10 percent and preferably between 2 and 4 percent of a biomedical polymer such as a silicone polymer (e.g., Silastic Type A), poly-urethane, or polycaprolactone. Specific examples of the one-step method are provided in Section 12 below.
According to the two-step method of the invention, the one-step method may be used to impreg-nate a medical article with antiinfective agent, and then the medical article may be dipped into a polymeric solution and dried. This method forms a polymeric coating on the article and further controls the rate of release of antiinfective agent. When the two step method is practiced, the biomedical polymer may be omitted from the first soaking step. Optionally, an antiinfective agent may further be comprised in the polymeric coating. In a specific, nonlimiting exampl~, CA 0224l46l l998-06-2~
W O 97~5085 PCTfU~96~0932 a silicone catheter may be dipped in a mixture of methanol and tetrahydrofuran containing between about 1 and 5 percent, and preferably between 1.5 and 2.25 per-- cent, of chlorhexidine; between .5 and 5 percent and preferably between .5 and 2 percent of triclosan; and between 1 and 10 percent, and preferably between 2 and 4 percent, of a biomedical polymer (preferably a sili-cone polymer such as Silastic Type A) for about 30 minutes, dried, and then dipped in a higher concen-lo tration (but less than 10 percent) of biomedical poly-mer dissolved in a suitable solvent. For example, but not by way of limitation, a coating may be applied using a solution of 30% ethanol/70% THF containing 2-3 percent of a biomedical polyurethane, or a solution of 1-5 percent of Silastic Type A.
Alternatively, a hydrophilic medical article, such as a polyurethane catheter, may be impregnated with one or more antimicrobial agent and then coated with a polymer.
Examples of the two-step method are set forth in Sections 8, 16 and 17 below.
As set forth in Section 17, below, it has further been discovered that when medical articles were treated with mixtures of chlorhexidine free base and triclosan, uptake of chlorhexidine and triclosan was enhanced, and the antimicrobial activity of such articles was improved. While not desiring to be bound to any particular theory, it is believed that chlor-- hexidine free base and triclosan form a complex with improved solubility. The foregoing effect was observed when chlorhexidine free base and triclosan were com-bined in a respective molar ratio of 1:2; according to the invention, chlorhexidine free base and triclosan may be dissolved in a solvent or solvent system at chlorhexidine free base:triclosan molar ratios of 1:1 to 1:3. The total weight percent of chlorhexidine free CA 0224l46l l998-06-2~
W O 97~5085 PCTrUSg6nO932 base plus triclosan is between 1 and 10 percent. The chlorhexidine free base and triclosan may be dissolved in a solvent system comprising water, alcohol, or tetrahydrofuran, and mixtures thereof, to produce an impregnating solution. In one specific, non-limiting e~ample of the invention, a 1:2 ratio of chlorhexidine free base and triclosan may be dissolved in a solvent system which is 70 percent tetrahydrofuran and 30 percent reagent alcohol. A medical article, for example, a polyurethane article, may be impregnated with chlorhexidine free base/triclosan by immersing the article in such an impregnating solution so that the medical article swells without losing substantial structural integrity. After impregnation, the article may be dried, and then optionally coated with a poly-meric solution, according to the two-step method set forth above.
Antiinfective medical articles prepared by other methods (e.g., extrusion, casting) but being otherwise substantially the same as articles produced by dipping or soaking, are within the scope of the claimed invention.
4.1 EXAMP~E: COMBINATIONS OF CHLO~TnINE AND
TRICLO5AN EXHIBIT SYNERGISTIC A~l~lvll~Y
IN BACTERIAL CU~TURES
Various concentrations of chlorhexidine diacetate ("CHA") and/or triclosan ("TC") were dispensed in 1.0 ml trypticase soy broth ("TSB") containing 20 percent bovine calf serum("BCS") and inoculated with 107 colony-forming units ("CFU") of Staphylococcus aureus. After one minute, the cultures were diluted with drug-inactivating medium (1:100 dilution in L~SB drug inactivating medium, which is 5%
Tween 80, 2% lecithin, 0.6% sodium oleate, 0.5% sodium thiosulfate, 0.1% protease peptone and 0.1% tryptone) and 0.2 ml of the diluted culture was subcultured on a W O 97/25085 PCT~US96/20932 trypticase soy agar plate for the determination of colony counts. The results, shown in Table I, demon-strate the synergistic activity o~ combinations of chlorhexidine and triclosan. For example, whereas 500 micrograms per milliliter of CHA causes an approx-imately 17-fold decrease in CFU, and 500 micrograms per milliliter of triclosan causes an approximately 2400-fold decrease, the combination of these agents is associated with zero CFU, an at least 1 x 107 -fold 10 decrease.
TABLE I
Antiinfective CFU/ml 15 AqentConcentration (~q/ml) (1 minute kill) CHA 2000 2.1 x 103 CHA 1000 5.0 x 104 CHA 500 6.0 x 105 TC 500 4.2 x 103 TC 250 2.0 x 10 CHA + TC 2000 + 500 0 CHA + TC 2000 + 250 0 CHA + TC 1000 + 250 0 CHA + TC 500 ~ 500 0 CONTROL 1.0 x 107 4.2. EXAMPLE: COMBINATIONS OF CHLO~TnINE AND
TRICLOSAN ARE MORE EFFECTIVE THAN
COMBINATIONS OF CHLO~TDINE AND SILVER
SULFADIAZINE WHEN APPLIED TO HYDROPHILIC
CA~l~n~ KS
Polyurethane central venous catheters fabricated Of Tecoflex 93-A polyurethane were dipped in solutions cont~; n; ng 3 percent of a biomedical poly-CA 0224l46l l998-06-2~
W O 97/25085 PCTrUS96/20932 urethane (Tecoflex 93-A; "PU") and CHA, TC and/or silver sulfadiazine ("AgSD"~ dissolved in 30 percent ethanol and 70 percent tetrahydrofuran ("THF") (v/v) and air-dried. Bacterial adherence on these catheters was measured as follows. A 2 cm segment of dipped catheter was suspended in 3 ml TSB containing lO per-cent BCS and incubated in a water bath shaker at 37~ C.
The media was changed daily. After 2 days the catheter segments were removed and transferred to fresh media containing 106 CFU/ml of Staphylococcus aureus and incubated for 24 hours. The segments were removed, rinsed with saline, and then suspended in LTSB drug-inactivating medium and sonicated for 20 minutes to remove the adherent bacteria. Aliquots from the LTSB
extract were then subcultured on trypticase soy agar plates to determine colony counts. The results are presented in Table II, and demonstrate that com-binations of CHA and TC are superior in preventing bacterial adherence when compared with CHA alone or in 20 combination with AgSD.
TABLE II
Adherent Bacteria Coating fCFU/ml) 3% PU + 2.5% CHA 5 x 104 3% PU + 1.5% CHA + 0.75% AgSD2 x 104 3% PU + 1.5% CHA + 1% TC 5 3% PU + 1.5% CHA + O.75% AgSD + 1% TC 40 In additional experiments, addition segments of the same type of polyurethane catheters coated with CHA, TC and/or AgSD were tested for the ability to pro-duce zones of inhibition in trypticase soy agar plates seeded with 0.3 ml of 106 CFU of Staphylococcus aureus, Enterobacter cloacae, Candi~a albicans, and Pseudomonas CA 0224l46l l998-06-25 W O 97/25085 PCTrUS96/20932 aeruginosa. The coated catheter segments were placed vertically on the seeded plates, which were then incu-bated for 24 hours at 37~ C before the zones of inhi-~ bition were measured. The results, shown in Table III, demonstrate the superior effectiveness of mixtures ofchlorhexidine and triclosan.

TABLE III
Zone Of Inhibition (mm) Coating*: A B C D
Orqanism S. aureus14.5 15.0 13.0 16.5 E. cloacae 9.0 12.0 7.5 3.0 C. albicans 12 .0 12.0 11.5 0 P. aeruginosa 12.5 12.5 12.0 0 * coating A= 3% PU + 2.25% CHA
coating B= 3% PU ~ 1.75% CHA + 0.5% TC
coating C= 3~ PU + 1.75~ CHA + 0.5% AgSD
coating D= 3% PU + 0.5% AgSD + 1.75% TC

4.3. EXAMPLE: HYDROPHILIC CA~ ~S COATED WITH
HYDROPHOBIC POLYMER COMPRISING CHLORHEXIDINE
AND TRICLOSAN HAVE ANTIMICROBIAL A~ V~ Y
The antimicrobial effectiveness of poly-urethane central venous catheters (fabricated from Tecoflex 93-A polyurethane) coated with chlorhexidine diacetate and either triclosan or silver sulfadiazine in two polymeric coatings of differing water absorption were tested. The polymeric coatings, applied as set forth in Section 6 above, comprised either polyurethane 93A ("PU 93A"), a hydrophilic polyurethane having a water absorption of about 1-2 percent or polyurethane-silicone interpenetrating polymer ~"PTUE 205") a hydro-phobic silicone-polyurethane copolymer having a water absorption of only 0.4%. Antibacterial activity was measured by zones of inhibition, using methods as set forth in Section 6, above. The results, as regards antibacterial activity toward Staphylococcus aureus, Enterobacter cloacae, and Candida albicans at days 1 and 3 of culture, are shown in Tables IV, V and VI, respectively, and demonstrate that combinations of chlorhexidine diacetate and triclosan were effective when comprised in hydrophilic ~PU 93A) as well as hydrophobic (PTUE 205) coatings.
TABLE IV
Antibacterial Activity Aqainst S. aureus Zone of Inhibition (mm) Coating Day 1 Day 3 3% PTUE 205 +
1.5% CHA + 1.5% TC 16.0 11.0 3% PTUE 205 2% CHA + 0.75% AgSD 14.5 11.0 3% PU 93A +
1.5% CHA + 1.5% TC 16.0 11.5 3% PU 93A +
2% CHA + 0.75% AgSD 14.5 11.0 TABLE V
Antibacterial Activity A~ainst E. cloacae Zone of Inhibition (mm) 30 Coating Day 1 Day 3 3% PTUE 205 +
1.5% CHA + 1.5% TC 12.0 6.0 3% PTUE 205 2% CHA + 0.75% AgSD 8.5 0 3% PU 93A +
1.5% CHA + 1.5% TC 11.0 7.0 3% PU 93A +
2% CHA + 0.75% AgSD 7.0 o CA 0224l46l l998-06-25 WO 97~5085 PCTAUS96nO932 T ~ LE VI
Antibacterial Activity A~ainst C. albicans Zone of Inhibition (mm) 5 Coating Day 1 DaY 3 3% PTUE 205 +
1.5% CHA + 1.5% TC 11.0 7.0 3% PT~E 205 2% CHA + 0.75% AgSD 12.0 9.5 3% PU 93A +
1.5% CHA + 1.5% TC 12.5 7.0 3% PU 93A +
2% CHA + O.75% AgSD 10.0 6.5 4.4. EXAMPLE: HYDROPHOBIC CAl~l~KS TREATED WITH
HYDROPHOBIC POLYMER COMPRISING cHLo~TnINE
~ND TRICLOSAN HAVF ANTIMICROBIAL A~llvl~lY
Silicone central venous catheters fabricated from Dow Corning Q7-4765A silicone polymer or Q7-4765B
silicone polymer were used to determine the effective--ness of impregnation with hydrophobic polymers com-prising chlorhexidine diacetate and triclosan on hydrophobic substrates. The silicone catheters were soaked for about 30 minutes in a solution of 5 percent methanol and 95 percent THF (v/v) comprising (i) 2 percent medical adhesive Silastic Type A and (ii) chlorhexidine diacetate and either triclosan or silver - sulfadiazine. The dipped catheters were dried and then dipped in a solution of 5 percent methanol and 95 per-- 30 cent THF (v/v) containing 5 percent Silastic Type A
("SilA"), and dried again. The catheter segments were then tested for the production of zones of inhibition on trypticase soy agar plates inoculated with S. aureus or E. cloacae. The results are presented in Table VII.

TABLE VII
Zone Of Inhibition (mm) Treatment S. aureus E.
cloaGae 2% SilA + 1.5% CHA +
0.5% TC, then 5% SilA >50 21 2% SilA + 1.5% CHA +
0.5% AgSD, then 5% SilA 17 15 4.5. EXAMPLE: TRICLOSAN EXHIBITS PROLONGED
.~SE FROM POLYMER COATINGS
Silicone central venous catheters fabricated from Dow Corning Q7-4765A silicone polymer or Q7-4765B
silicone polymer were treated as set forth in Section 8, above, and then, immediately after drying, were extracted in dichloromethane/methanol/water (50%/25%/25%, v/v) in order to determine the amount of agent contained in the catheter segment tested (i.e., the uptake). To determine the rate of drug release, catheter segments were suspended in saline and incu-bated at 37~ C for up to seven days; the saline was col-lected and replaced with fresh saline on the first day and every 48 hours thereafter, and the amount of drug present in the collected saline was measured. The results are presented in Table VIII.

CA 0224l46l l998-06-25 W O 97/25085 PCT~US96~0932 TABLE VIII
Uptake Release ~g/cm) Treatment (~g/cm) DaYl Day3 Dav7 2% SilA +
2% CHA, then - 5% SilA 60 28.0 4.1 3.1 2.6 10 2% SilA +
2% TC, then 5% SilA 1168 lO.0 9.511.1 11.4 Silicone catheters impregnated with Silastic Type A comprising either 2% triclosan or 2~ chlor-hexidine diacetate were then tested for the ability to produce zones of inhibition on trypticase soy agar plates inoculated with S. aureus, E. cloacae, C.
albicans, or P. aeruginosa. The results of the~e experiments are shown in Table IX, and demonstrate that when higher concentrations of triclosan or chlor-hexidine diacetate alone were used, triclosan-treated catheters were found to be equally or more e~fective than CHA-treated catheters.
TABLE IX

Zones Of Inhibition (mm) Treatments: 2%SilA + 2%CHA, 2%SilA + 2%TC, then 5% Si lA then 5% SilA
DaY1 Day3 ~y~ PaY3 Organism 8. aUreUB 17.5 16.0 >50 >50 E. cloacae 15.0 9.O 40.0 40.0 C. albicans 13.5 6.0 13.0 13.0 P. aeruginosa 13.0 O 8.5 O

W O 97/2508~ PCT~US96/20932 4.5. EX~MPLE: UPT~iKE OF CHLO~TnINE
~iND TRICLQS~N IN PTFE GFU~FTS

Arterial grafts fabricated from polytetra-fluoroethylene ("PTFE") were cut into segments and impregnated with Silastic Type A comprising chlor-hexidine diacetate or triclosan in 3096 methanol/70% THF
(v/v), in proportions set forth below. The treated grafts were then extracted with dichloro-methane/methanol/water (50%/25%/25%, v/v), and the amounts of solubilized antiinfective agents were determined. Table X shows the uptake of agent by the treated grafts.
TABLE X
Treatment Aqent Uptake f~q/cm~
2% SilA + 2% CHA 895 2% SilA + 2% TC 2435 4.6. EXAMPLE: ANTIMICROBIAL EFFE~l~lv~ESS OF
MEDICAL ARTICLES FABRICATED FROM TEFLON, DACRON OR NATURAL RUBBER LATEX AND
IMPREGNATED WITH COMBINATIONS OF
cHLoR~TnINE AND TRICLOSAN
Chlorhexidine diacetate and either triclosan or silver sulfadiazine, in proportions set forth below, were dissolved in 5% methanol/95% THF (v/v). Segments of Dacron grafts, PTFE grafts, and natural rubber latex urinary catheters were then soaked in the resulting solutions for 15 minutes to impregnate the segments with antiinfective agents. This procedure allows the polymer substrates of the devices to incorporate anti-infective agent. The segments were then removed from the soaking solution, dried, rinsed with water, and wiped. The ability of the treated segments to produce zones of inhibition on trypticase soy agar plates inoculated with S. aureus and E. cloacae was then tested. The results, shown in Tables XI - XIII, demonstrate that the combination of chlorhexidine and WO 97~5085 PcTnuss6nas32 triclosan produced superior antimicrobial results com-pared to the combination of chlorhexidine and silver sulfadiazine.
TAB~E XI

PTFE Graft Zone Of Inhibition (mm) Im~reqnating Solution S. aureus E. cloacae 5% CHA + 0.5% TC 37.0 22.0 1.5% CHA + 0.75% AgSD 22.0 16.5 TAB~E XII
~acron Graft Zone Of Inhibition (mm) T~pre~nating Solution S. aureus E. clo~cae 5% CHA + 0.5% TC >40 30.0 1.5% CHA + 0.75~ AgSD 26.0 27.0 TABLE XIII
Latex Catheter Zone Of Inhibition (mm) Impreqnating Solution S. aureus E. cloacae 5% CHA + 0.5% TC 26.0 20.0 1.5% CHA + 0.75% AgSD 18.0 12.0 4.7. EXAMPLE: ANTIMICROBIAL EFFE~l~lv~NESS OF
SILICONE CA~ KS PREPARED BY A ONE-STEP
IMPREGNATION METHOD
Silicone catheters, as used in Example 8, were prepared by a one-step impregnation method as follows. Segments of the silicone catheters were soaked for about 30 minutes in impregnating solutions of 90%
THF/10~ methanol ~v/v) containing 2% Silastic Type A, CA 02241461 1998-06-2~
W O 97/25085 PCT~US96/20932 chlorhexidine, and either silver sulfadiazine or tri-closan. The segments were then dried, and tested for their ability to produce zones of inhibition (at one and three days) in trypticase soy agar plates inoculated with S. aureus, E. cloacae, C. albicans, and P. aeruginosa. The results, presented in Table XIV, demonstrate the effectiveness of chlorhexidine and tri-closan-impregnated catheters.
TABL~ XIV

Zones Of Inhibition (mm) Treatments: 2%SilA + 1.5%CHA 2%SilA + 1.5%CHA
+ 0.5% TC ~ 0.5% A~SD
DaYl Day3 Dayl Dav3 Orqanism S. aureus >40 39 17.5 13.5 E. cloacae 21 21 15 8 C. albicans 13.5 7 13.5 6 P. aeruginosa 13.5 6.5 13 O

Additional formulations of impregnating solutions were tested for their ability to render the same type of silicone catheter segments antiinfective against C. albicans, the microorganism which appeared to be inhibited only by relatively high amounts of antiinfective agent. The following impregnating solu-tions comprised chlorhexidine, triclosan and either Silastic Type A, polycaprolactone, or no polymer in a 5% methanol/95%THF solvent. Table XV shows that when both polymer and antiinfective agent were comprised in the impregnating solution, higher antiinfective activity was achieved.

W O 97~508~ PCTAUS96~0932 T ~ LE arv Impregnating Solution Zone Of Inhibition (mm) 54% SilA + 5% CHA + 1% TC 12.0 1% polycaprolactone +
5% CHA + 1% TC 12.0 10 No polymer, 5%CHA + 1% TC 6.5 4.8. EXAMPLE: DIFFUSION OF ANTIINFECTIVE AGENTS
FROM MEDICAL ARTICLES TREATED WITH
IMPREGNATING SOLUTIONS WITH AND WITHOUT
POLYMER
The following impregnating solutions, "A" and ~IB'', were used to impregnate segments of Dacron and PTFE grafts. The treated grafts were then rinsed with saline, and the amounts of antiinfective agent incorporated into the gra~ts were determined, before and after rinsing, by extraction of antiinfective agent with dichloromethane/methanol/water (50%/25%/25%, v/v).
The results, set forth in Table XVI, demonstrate that the addition of a polymer to the impregnating solution produces a treated medical article which exhibits greater retention of antiinfective agent.
Solution A: 1% polycaprolactone + 0.1% CHA + 0.02%
TC, in 5% methanol/95% THF (v/v) Solution B: 0.1% CHA + 0.02% TC, in 5% methanol/ 95% THF (v/v) W O 97/25085 PCT~US96/20932 TABLE arVI
Druq Levels (~q/cm) Dacron Graft PTFE Graft Solution:A B A B
Solution A
Before rinsing 392 548 73 go After rinsing353 547 56 88 Solution B
Before Rinsing 409 573 50 44 After rinsing132 553 24 44 4.9. EXAMPLE: DRUG UPTAKE AND ~T~A~E BY
HYDROPHILIC CA~ KS IMPREGNATED WITH
CHLO~T~INE OR TRICLOSAN
Polyurethane central venous catheter segments fabricated of Tecoflex 93-A polyurethane were impreg-nated with solutions "C", "D", "E", "F" a~d "G" set forth below by soaking the catheter segments for about two minutes followed by drying and rinsing with water.
Drug uptake was measured by extracting the impregnated catheter segments with dichloromethane/methanol/water ~50~J25%/25% v/v). Drug release was measured over a period of six days by suspending the catheter segments in saline (one 2 cm segment in 2 ml saline), and agi-tated in a heated water bath at 37~ C; the saline waschanged daily and drug release was measured as des-cribed above. The results are shown in Table XVII.
Polyurethane, as set forth below, is Tecoflex 93-A
polyurethane.
~0 Soluti~n C: 3% polyurethane +
3% CHA in 30% reagent alcohol/70% THF
Solution D: 3~ polyurethane + 3% TC in 30%
reagent alcohol/70% THF~5 CA 0224l46l l998-06-25 W O 97/25085 PCTAJS96~0932 Solution E: 3% polyurethane + 2% CHA + 2% TC, in 30% reagent alcohol/70% THF
Solution F: 2% CHA in 9~% ethanol Solution G:3% CEIA + 1% TC in 95% ethanol TABLE XVII

Drug Release (~g/cm) Solu- Uptake Day No.
tion Druq (~g/cm) 1 2 3 4 5 6 C CHA 197 78 36 20 2.6 0.8 0.8 D TC 300 0.4 .13 0.1 0.1 0.1 0.1 E CHA 202 66 16.8 7.0 5.0 5.0 5.0 TC 230 0.4 0.3 <.1 <.1 <.1 <.1 F CHA 254 15 9.6 7.8 2.5 2.5 2.5 G CHA 223 7.1 3.5 3.0 0.8 0.8 0.8 TC 368 <.1 <.1 <.1 <.1 <.1 <.1 4.10. EXAMPLE: R~T,~.~E OF CHLORHEXIDINE AND
TRICLOSAN FROM IMPREGNATED SILICONE CA~
SEGMENTS
Segments of silicone central venous catheters fabricated from Dow Corning Q7-4765A silicone polymer or Q7-4765B silicone polymer were impregnated with either solution H or I by soaking for 30 minutes, and then the release of drug was measured daily by methods set forth above. The results of these measurements are presented in Table XVIII.
Solution H: 2% SilA + 5% CHA in 10% methanol/90% THF
(v/v) Solution I: 2% SilA + 5% CHA + 2% TC in 10% methanol/90% THF (v/v) W O 97/Z5085 PCT~US96nO932 TABLE arVIII

Solu- Daily Release (~g/cm) tion ~EU~ ~3y~ Day2 Day3 Day4 Pay5 HCHA 2.7 1.0 0.6 0.9 0.9 ICHA 0.8 0.9 0.6 0.8 0.8 TC 2.6 5.6 2.3 1.5 1.5 4.11. METHOD OF RENDERING POLYURETHANE
CA~ ~S INFECTION-RESISTANT BY
IMPREGNATION WITH A SYNERGISTIC COMBINATION
OF CHLORHEXIDINE AND TRICLOSAN
A one-step method ("Method 1") and a two-step method ("Method 2") were used to treat polyurethane catheters Method 1: An entire polyurethane central venous catheter assembly including the hub, extension line and catheter body may be soaked in an alcoholic solution containing chlorhexidine and triclosan for a specific time period sufficient to impregnate these elements with chlorhexidine and triclosan without altering the integrity of the polyurethane substrate.
The following solvent systems and soaking times are suitable. The concentrations of chlorhexidine and triclosan range from 0.5-5%.

CA 0224l46l l998-06-2~
WO 97/2~085 PCT~US96~a93Z

TABLE XIX.
Solvent system Soakinq time 95% ethanol/ 5~ water 2 - 30 minutes 100% reagent alcohol 2 - 30 minutes 90% reagent alcohol/10% water 5 - 60 minutes ~ 80% reagent alcohol/20% water 5 - 60 minutes 70% reagent alcohol/30% water 10 - 60 minutes 90% ethanol/10% water 5 - 60 minutes 80% ethanol/20% water 5 - 60 minutes 70% ethanol/30~ water 10 - 60 minutes 20% methanol/10% isopropanol /40% reagent alcohol /30% water 10 - 60 minutes Selection of the solvent mixture depends on the type of polyurethane substrate and antimicrobials used for impregnation. After soaking, the catheter is rinsed in water for 24 to 48 hours to allow the catheter to regain its original integrity and size.

Method 2. A catheter impregnated with chlor-hexidine and triclosan according to Method 1 is then dipped in 70% THF/30% reagent alcohol/ 1-3% poly-urethane/ 1-3% chlorhexidine/ 1-3% triclosan.

Catheters prepared by Method 1 provide a relatively slow and steady release rate from the luminal surface and outer surface for a prolonged period of time. This pattern of drug release results from the relatively lower ratio of drug to poly-urethane matrix (0.015).
Catheters prepared by Method 2 exhibit biphasic drug release. The higher ratio of drug to polyurethane in the outer coating (1.3) permits an initial release of large amounts of drugs (which may inactivate bacteria entering through the skin at the time of insertion) followed by slow and steady release CA 02241461 1998-06-2~
W O 97t2~085 PCT~US9G/20932 of drug impregnated in the catheter by Method 1. The outer polyurethane coating acts as a barrier and per-mits the controlled release of drug over a prolonged period of time.
As specific examples, Tecoflex polyurethane catheters were prepared using the ~ollowing method and then tested for antimicrobial efficacy in their luminal and outer surfaces:
i) catheters were soaked in 2% chlorhexidine dissolved in 100% reagent grade alcohol ~or 1 hour, rinsed in water, and dried for 24-48 hours ("Catheter C");
ii) catheters were soaked in 2% chlorhexidine + 2% triclosan dissolved in 100% reagent grade alcohol for 15 minutes, rinsed in water, and dried for 24-48 hours ("Catheter TC");
iii) catheters were soaked in 2% triclosan in 70% reagent alcohol/30% water for 2 minutes, rinsed in water, and dried for 24-48 hours ("Catheter T");
iv) catheter C (above) was dipped in 3% poly-urethane + 2% chlorhexidine dissolved in 70% THF/30%
reagent alcohol ("Catheter C-C");
v) catheter C (above) was dipped in 3% poly-urethane + 2% chlorhexidine + 0.75% AgSD dissolved in 70% THF/30% reagent alcohol ("Catheter C-A");
vi) catheter T (above) was dipped in 2%
chlorhexidine + 2% triclosan dissolved in 70% THF/30%
reagent alcohol ("Catheter T-R");
vii) catheter TC (above) was dipped in 2%
chlorhexidine + 2% triclosan dissolved in 70% THF/30%
reagent alcohol ("Catheter TC-R"); and viii) catheter TC (above) was dipped in 2%
chlorhexidine + 0.75% AgSD dissolved in 70% THF/30%
reagent alcohol.
Trypticase soy agar plates were seeded with 105 CFU StaphylocOCCUs aureus/ml and 0.5 cm segments of W O 97~5085 PCT~US96na93Z

catheter were embedded vertically. The plates were then incubated for 24 hours at 37~C and zones of inhibition were measured. The results are shown in Table XX.
TABLE XX.
5 Catheter type Zone o~ Inhibition ~mm) Lumen Outer surface TC-~ 23 26 17. METHOD OF RENDERING POLYURETHANE CA~ ~S
INFECTION-RESISTANT BY IMPREGNATION WITH A
SYNERGISTIC COMBINATION OF CHLO~T~INE
FREE BASE AND TRICLOSAN
It was further discovered that when catheters were coated using insoluble chlorhexidine free base and triclosan, a soluble chlorhexidine/triclosan complex was formed which improved the drug uptake and, there-fore, the efficacy of the catheter.
Method 3: Catheters prepared by Method 1 (see Section 16) were dried for 24-72 hours and then their outer surfaces were dipped in a polyurethane solution (1-3% polyurethane dissolved in THF/alcohol). Catheters prepared by this method exhibited a large amount of drug release initially followed by a small but syner-gistically effective amount of drug release for a pro-longed period of time.
Method 4: Followed the same procedure asMethod 1, except that insoluble chlorhexidine free base (CHX) was solubilized with triclosan (1 molar CHX:2 molar triclosan ratio), which forms a complex with C~X.
After soaking for 5-10 minutes the catheters were dried for 1-3 days and then the outer surface was dipped in CA 02241461 1998-06-2~
W O 97/25085 PCT~US96/20932 either a polyurethane solution alone (1-3% poly-urethane) or a solution of polyurethane containing CHX
and triclosan (TC).
When relatively soluble chlorhexidine salts such as chlorhexidine acetate (CHA) were used to impregnate catheters, the release was undesirably rapid. We investigated the use of CHX as a substitute for CHA. CHX i5 not soluble is water or alcohol but, surprisingly, we found that when it was combined in a 1:2 molar ratio with triclosan, an alcohol soluble complex formed.
The uptake of chlorhexidine from a solution containing CHX-TC complex was greater than that obtained from a CHA-TC solution despite a higher CHA
concentration in the soaking solution. Due to higher chlorhexidine levels and higher rate of chlorhexidine release from the substrate resulting from impregnation with CHX-TC complex, the infection resistance of the catheters was greater than those containing only CHA.
Method 5: Same as method 4 but the soaking and outer coating solutions also contained soluble chlorhexidine acetate.
As specific examples, the following experiments were performed using Tecoflex catheters:
tl) Catheters were prepared according to Method 3. Specifically, catheters were soaked in 5% CHA
+ 1% TC dissolved in reagent alcohol for 10 minutes, dried for three days, and then the outer surface was dipped in 2.7% Tecoflex polyurethane dissolved in THF~reagent alcohol (70%/30%); the resulting catheters are referred to as type 1, and the polyur-ethane/THF/reagent alcohol solution is referred to as Solution J.
(2) A second group of catheters was prepared as in (1), but instead of using Solution J for the outer coating, another solution was used: 0.5% CHX +

CA 02241461 1998-06-2~
WO 97/2508~ PCT~US96nO932 0.5% TC + 2.7% polyurethane dissolved in 70%THF/30%
reagent alcohol (~Solution K"). The resulting catheters are referred to as type 2.
(3) Catheters were prepared using Method 5.
Specifically, catheters were soaked in a solution containing 2% CHX + 2% CHA + 2% TC dissolved in reagent alcohol for 10 minutes, dried for 3 days and their outer surfaces were dipped in Solution J. The resulting catheters are referred to as type 3.
(4) ~atheters were prepared as in (3) but were dipped in Solution K to produce an outer coating.
The resulting catheters are referred to as type 4.
(5) Catheters were prepared according to Method 4. Specifically, catheters were soaked for 10 minutes in 3% CHX + 3% TC in reagent alcohol, dried for 3 days, and outer surface coated in Solution J. The resulting catheters are referred to as type 5.

(6) Catheters were prepared as in (5) but outer surface coated with Solution K. The resulting catheters are referred to as type 6.

(7) Catheters were prepared according to Method 3. Specifically, catheters were soaked in a solution containing ~ CHA + 1% TC in reagent alcohol for 10 minutes, dried for 3 days and then outer surface coated using Solution J. The resulting catheters are referred to as type 7.
- (8) Catheters were prepared as in (7), except were outer surface coated with 2.7% polyurethane + 3%
CHA in 70% THF/ 30% reagent alcohol. The resulting catheters are referred to as type 8.
Segments of catheter types 1-8 were placed vertically in inoculated trypticase soy agar plates inoculated with 108 CFU of Staphylococcus aureus per plate, and incubated for 24 hours. After measuring the zones of inhibition, the catheters were transferred daily to fresh culture plates (shown in Table XXI~.

CA 0224l46l l998-06-2~

T~BLE XXI.
Catheter tyPe ~ayZone of Inhibition (mm) 1 21 12.0 2 21 13.0 3 21 17.0 4 21 20.0 21 20.0 6 21 23.0 7 21 5.0 8 21 9.0 The amount of drug uptake per cm/catheter in catheters prepared using various soaking solutions was measured as set forth above.
TABLE XXII.
Soakinq Solution Drug UPtake/cm catheter Chlorhexidine Triclosan 5% CHA 2 60--310~g?~] ------5% CHA + 2% TC 280-300 450-480 2% C~HX + 296 TC + 2% CHA 480--520 300--370 3% CHX + 3% TC 550--660 600--700 The luminal adherence of bacteria was quan-tified in catheters impregnated with antimicrobials and then coated with a solution of 2. 7 percent Tecoflex 93A and various antimicrobial agents. Bacteriol adherence was measured as follows. 12 cm segments of test and control 7Fr catheters were each connected to an individual channel of a peristaltic pump via an extension line, hub, and injection cap. The hubs were inoculated initially and after 24 hours with 106cfu of S. aureus which causes the extension line to become colonized thus acting as a continuous source of bac-teria for seeding lumens. The lumens were continuously perfused at a rate of 20ml/hour with trypticase soy broth ~TSB) diluted 1:10 with physiological saline over the course of 7 days. At the end of one week the catheter segments were disconnected and their outer sur~aces disinfected with 70% ethanol. Each lumen was flushed wlth sterile TSB to remove non-adherent bac-teria. Each catheter was then cut into 2 cm segment each of which is further divided into 2 mm subsegments and placed in tubes containing 4 ml of antiseptic inactivating broth (LTSB). The tubes were sonicated for 20 minutes at 4~C to remove bacteria adhering to the lumens. To quantify the adherence, a 0.5 ml aliquot of the LTSB extract was subcultured on tryp-ticase soy agar plates. The results are shown in Table XXII.

TABLE XXIII.
DRUG IN DRUG IN BACTERIAL ADHERENCE

~cfutcm) 5% CHA 3% CHA 3 x 104 5% CHA + O.5% TC 2% CHA + 2% TC 3 x 102 2% CHX + 2% CHA 2% CHA + 2% TC 0 + 2% TC
3% CHX + 3% TC 0.5% CHX + 0.5% TC 0 0 (control) 0 4 x 106 25 2% CHX + 2% CHA no outer coating 5 + 2% TC
Various publications are cited herein, which are hereby incorporated by reference in their entireties.

Claims (75)

WHAT IS CLAIMED IS:

1. A hydrophilic polymeric medical article which has been treated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophilic polymer; (ii) between 1 and 5 percent of an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative; and (iii) between .5 and 5 percent of triclosan.

2. The medical article of claim 1 which is fabricated from a hydrophilic polymer selected from the group consisting of natural rubber latex and biomedical polyurethane.

3. The medical article of claim 1 wherein the hydrophilic polymer in the treatment solution is a biomedical polyurethane.

4. The medical article of claim 2 wherein the hydrophilic polymer in the treatment solution is a biomedical polyurethane.

5. A hydrophilic polymeric medical article having a coating comprising a hydrophilic polymer, triclosan, silver sulfadiazine, and an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative, wherein the triclosan, silver sulfadiazine and antiinfective agent are present in amounts such that their combination, in the article, has effective antimicrobial activity.

6. The medical article of claim 5 which is a catheter.

7. The catheter of claim 6 which is an intravenous catheter.

8. The catheter of claim 7 which is fabricated from a biomedical polyurethane.

9. The catheter of claim 8 wherein the hydrophilic polymer in the coating is a biomedical polyurethane.

10. A hydrophilic polymeric medical article treated with a treatment solution comprising a hydrophobic polymer, triclosan, and an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative, wherein the triclosan and antiinfective agent are present in amounts such that their combination, in the treated article, has effective antimicrobial activity.

11. The medical article of claim 10, further comprising silver sulfadiazine.

12. The medical article of claim 10 wherein the hydrophobic polymer is a biomedical silicone polymer.

13. The medical article of claim 11 wherein the hydrophobic polymer is a biomedical silicone polymer.

14. The medical article of claim 10 wherein the hydrophobic polymer is a silicone-polyurethane copolymer.

15. The medical article of claim 11 wherein the hydrophobic polymer is a silicone-polyurethane copolymer.

16. The medical article of claim 10 which is a catheter.

17. The catheter of claim 16 which is an intravenous catheter.

18. The catheter of claim 17 which is fabricated from a biomedical polyurethane.

19. The catheter of claim 18 wherein the hydrophobic polymer in the solution is a biomedical silicone-polyurethane copolymer.

20. A hydrophilic polymeric medical article which has been treated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophobic polymer (ii) between 1 and 5 percent of an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative; and (iii) between .5 and 5 percent of triclosan.

21. The medical article of claim 20 which is fabricated from a hydrophilic polymer selected from the group consisting of natural rubber latex and biomedical polyurethane.

22. The medical article of claim 20 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

23. The medical article of claim 21 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

24. The medical article of claim 20 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

25. The medical article of claim 21 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

26. A hydrophobic polymeric medical article treated with a treatment solution comprising a hydrophobic polymer, triclosan, and an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative, wherein the triclosan and antiinfective agent are present in amounts such that their combination, in the treated article, has effective antimicrobial activity.

27. The medical article of claim 26, further comprising silver sulfadiazine.

28. The medical article of claim 26 wherein the medical article is fabricated from a hydrophobic polymer selected from the group consisting of polytetrafluoroethylene, Dacron, polyvinylchloride and a silicone polyurethane copolymer.

29. The medical article of claim 27 wherein the medical article is fabricated from a hydrophobic polymer selected from the group consisting of polyvinylchloride, polytetrafluoroethylene, Dacron and a silicone polyurethane copolymer.

30. The medical article of claim 26 wherein the medical article is fabricated from a silicone polymer.

31. The medical article of claim 27 wherein the medical article is fabricated from a silicone polymer.

32. The medical article of claim 26 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

33. The medical article of claim 27 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

34. The medical article of claim 26 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

35. The medical article of claim 27 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

36. The medical article of claim 26 which is a catheter.

37. The catheter of claim 36 which is an intravenous catheter.

38. The catheter of claim 37 which is fabricated from a biomedical silicone polymer.

39. The catheter of claim 38 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

40. A hydrophobic polymeric medical article which has been treated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophobic polymer (ii) between 1 and 5 percent of an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative; and (iii) between .5 and 5 percent of triclosan.

41. The medical article of claim 40 which is fabricated from a hydrophobic polymer selected from the group consisting of polytetrafluoroethylene, Dacron, polyvinylchloride, biomedical silicone polymer, and silicone polyurethane copolymer.

42. The medical article of claim 40 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

43. The medical article of claim 41 wherein the hydrophobic polymer in the treatment solution is a biomedical silicone polymer.

44. The medical article of claim 40 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

45. The medical article of claim 41 wherein the hydrophobic polymer in the treatment solution is a silicone-polyurethane copolymer.

46. A method for rendering a silicone catheter antiinfective, comprising:
(1) placing the silicone catheter in an impregnating solution comprising (a) a solvent which causes the catheter to swell; (b) between 1 and 5 percent of an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative; (c) between .5 and 5 percent of triclosan; and (d) between 1 and 10 percent of a biomedical polymer;
(2) soaking the catheter in the impregnating solution for a period of time sufficient to allow the catheter to swell;
(3) removing the catheter from the impregnating solution; and (4) drying the catheter.

47. The method of claim 46, wherein the biomedical polymer is a biomedical silicone polymer.

48. The method of claim 46, further comprising the step of dipping the catheter, after drying according to step (4), into a second coating solution comprising a biomedical polymer.

49. The method according to claim 48, wherein the biomedical polymer in both the impregnating solution and the second coating solution is a biomedical silicone polymer.

50. A hydrophobic polymeric medical article which has been treated with a treatment solution comprising (i) between about 1 and 10 percent of a hydrophilic polymer; (ii) between 1 and 5 percent of an antiinfective agent selected from the group consisting of chlorhexidine free base, a chlorhexidine salt, and a chlorhexidine derivative; and (iii) between .5 and 5 percent of triclosan.

51. The medical article of claim 50 which is fabricated from a hydrophobic polymer selected from the group consisting of polytetrafluoroethylene, Dacron, polyvinylchloride, biomedical silicone polymer, and silicone polyurethane copolymer.

52. The medical article of claim 50 wherein the hydrophilic polymer is a biomedical polyurethane.

53. A medical article which has been treated by a method comprising:
(1) placing the medical article in an impregnating solution comprising (a) a solvent selected from the group consisting of water, reagent alcohol, tetrahydrofuran, and mixtures thereof; and (b) chlorhexidine free base and triclosan, in a molar ratio between 1:1 to 1:3, wherein the total weight of chlorhexidine free base and triclosan is between 1 and 10 percent of the weight of the impregnating solution;
(2) soaking the catheter in the impregnating solution for a period of time sufficient to allow the medical article to swell;
(3) removing the medical article from the impregnating solution; and (4) drying the medical article.

54. The medical article of claim 53, wherein the solvent in step (1)(a) is a mixture of reagent alcohol and tetrahydrofuran.

55. The medical article of claim 53, wherein the ratio of chlorhexidine free base and triclosan in step (1)(b) is about 1:2.

56. The medical article of claim 53, wherein the total weight percent of chlorhexidine free base and triclosan in step (1)(b) is about 2-10.

57. The medical article of claim 53, which has further been coated with a coating solution comprising a biomedical polymer.

58. The medical article of claim 57, wherein the biomedical polymer in the coating solution comprises an antimicrobial agent.

59. The medical article of claim 53 which is fabricated from polyurethane.

60. The medical article of claim 59 which is a polyurethane catheter.

61. The medical article of claim 60 in which both the external and internal surfaces of the catheter are brought into contact with the impregnating solution.

62. The medical article of claim 60 in which only the external surface of the catheter is brought into contact with the impregnating solution.

63. The medical article of claim 60, in which only the internal surface of the catheter is brought into contact with the impregnating solution.

64. A method of preparing an infection resistant medical article comprising:
(1) placing the medical article in an impregnating solution comprising (a) a solvent selected from the group consisting of water, reagent alcohol, tetrahydrofuran, and mixtures thereof; and (b) chlorhexidine free base and triclosan, in a molar ratio between 1:1 and 1:3, wherein the total weight of chlorhexidine free base and triclosan is between 1 and 10 percent of the weight of the impregnating solution;
(2) soaking the catheter in the impregnating solution for a period of time sufficient to allow the medical article to swell;
(33 removing the medical article from the impregnating solution; and (4) drying the medical article.

65. The method of claim 64, wherein the solvent in step (1) (a) is a mixture of reagent alcohol and tetrahydrofuran.

66. The method of claim 64, wherein the ratio of chlorhexidine free base and triclosan in step (1) (b) is about 1:2.

67. The method of claim 64, wherein the total weight percent of chlorhexidine free base and triclosan in step (1) (b) is about 2-10.

68. The method of claim 64, which has further been coated with a coating solution comprising a biomedical polymer.

69. The method of claim 68, wherein the bio-medical polymer in the coating solution comprises an antimicrobial agent.

70. The method of claim 64 which is fabricated from polyurethane.

71. The method of claim 70 which is a polyurethane catheter.

72. The method of claim 71 in which both the external and internal surfaces of the catheter are brought into contact with the impregnating solution.

73. The method of claim 71 in which only the external surface of the catheter is brought into contact with the impregnating solution.

74. The method of claim 71, in which only the internal surface of the catheter is brought into contact with the impregnating solution.

75. The medical article of claim 53 wherein the impregnating solution of step (1) further comprises chlorhexidine acetate.