WO1997025085A1 - Triclosan-containing medical devices - Google Patents
Triclosan-containing medical devices Download PDFInfo
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- WO1997025085A1 WO1997025085A1 PCT/US1996/020932 US9620932W WO9725085A1 WO 1997025085 A1 WO1997025085 A1 WO 1997025085A1 US 9620932 W US9620932 W US 9620932W WO 9725085 A1 WO9725085 A1 WO 9725085A1
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- medical article
- polymer
- chlorhexidine
- catheter
- triclosan
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/28—Materials for coating prostheses
- A61L27/34—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
- A61L29/085—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
- A61L31/10—Macromolecular materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/10—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing inorganic materials
- A61L2300/102—Metals or metal compounds, e.g. salts such as bicarbonates, carbonates, oxides, zeolites, silicates
- A61L2300/104—Silver, e.g. silver sulfadiazine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/202—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with halogen atoms, e.g. triclosan, povidone-iodine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
- A61L2300/206—Biguanides, e.g. chlorohexidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/45—Mixtures of two or more drugs, e.g. synergistic mixtures
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
- Y10T428/1328—Shrinkable or shrunk [e.g., due to heat, solvent, volatile agent, restraint removal, etc.]
- Y10T428/1331—Single layer [continuous layer]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/13—Hollow or container type article [e.g., tube, vase, etc.]
- Y10T428/1352—Polymer or resin containing [i.e., natural or synthetic]
Definitions
- the present invention relates to medical devices comprising synergistic combinations of tri ⁇ closan and chlorhexidine.
- a medical device comes in contact with a patient, a risk of infection is created.
- a contaminated examination 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 which 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 reguired, 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- microbial protection increase with the development of drug-resistant pathogens.
- chlorhexidine and triclosan 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 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 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 porous material such as poly ⁇ propylene
- 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 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 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 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.
- a "beneficial agent” that is at least somewhat soluble in saliva
- a fibrous support material composed of hydrophilic water-insoluble fibers.
- 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.
- 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.
- 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. 4. DETAILED DESCRIPTION OF THE INVENTION
- Chlorhexidine may be provided by way of any form, salt or derivative thereof, including but not limited to chlorhexidine free 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 salts such as chlorhexidine diphosphanilate, chlorhexidine diglu-
- Chlorhexidine may refer to any of such forms, derivatives, or salts, unless specified otherwise. Chlorhexidine salts may be solubilized using polyethylene glycol or propylene glycol, or other solvents known in the art.
- 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 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) .
- urinary catheters and vascular catheters e.g. peri ⁇ pheral and central vascular catheters
- wound drainage tubes e.g. peri ⁇ pheral and central vascular catheters
- arterial grafts e.g. peri ⁇ pheral and central vascular catheters
- soft tissue patches e.g. peri
- 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 2000 ⁇ 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 equivalent 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
- the ratio, by weight, of the total amount of antiinfective agent to polymer in the treatment solution is less than 1.5.
- 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.
- a hydrophilic polymeric medical article i.e., a medical article fabricated from a hydrophilic polymer
- a hydrophilic polymer comprising chlorhexidine and triclosan
- chlorhexidine and triclosan are present in amounts such that their combination, in the treated article, has effective antimicrobial activity.
- hydrophilic polymer refers to polymers which have a water absorption greater than 0.6 percent by weight (and, in preferred embodiments, less than 2 percent by 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 poly- urethanes and ester-based polyurethanes, as set forth in Baker, 1987, in Controlled Release of Biologically Active Agents , John Wiley and Sons, pp. 175-177 and Lelah and Cooper, 1986, Polyurethanes in Medicine , CRC Press, Inc., Fla. pp.
- biomedical polyurethanes e.g. ether-based poly- urethanes and ester-based polyurethanes, as set forth in Baker, 1987, in Controlled Release of Biologically Active Agents , John Wiley and Sons, pp. 175-177 and Lelah and Cooper, 1986, Polyurethane
- polyurethanes comprising substantially aliphatic backbones such as TecoflexTM 93A; polyurethanes comprising substantially aromatic backbones such as TecothaneTM; and PellethaneTM) , polylactic acid, polyglycolic acid, natural rubber latex, and gauze or water-absorbent fabric, including cotton gauze and silk suture material.
- 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.
- the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .5 and 1 percent (more preferably .75 percent).
- 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.
- hydro ⁇ phobic polymer refers to a polymer which has a water absorption of less than 0.6% and includes, but is not limited to, silicone polymers such as biomedical silicones (e.g., Silastic Type A) or elastomers (e.g., as set forth in Baker, 1987, in Con ⁇ trolled 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 copolymers such as silicone-polyurethane copolymers (e.g., PTUE 203 and PTUE 205 polyurethane-silicone interpenetrating polymer) .
- silicone polymers such as biomedical silicones (e.g., Silastic Type A) or elastomers (e.g., as set forth in Baker, 1987, in Con ⁇ trolled Release
- 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; (ii) between l and 5 percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine; and
- the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .5 and 1 percent (more pre ⁇ ferably .75 percent).
- 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.
- 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) 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.
- the treatment solution may further comprise silver sulfadiazine, preferably in a concentration of between .5 and 1 percent (more preferably .75 percent).
- a coating of a hydrophobic polymer may be applied over the treated article. Section 8, below, presents working examples of embodiments set forth in this paragraph.
- 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.
- the medical article is a silicone catheter or Teflon graft which has been 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.
- 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.
- the medical article is a catheter, -li ⁇
- the internal surface and/or external surface of the catheter may be treated according to the invention.
- 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 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.
- 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.
- 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 "impregnating 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.
- THF tetrahy ⁇ drofuran
- the bio ⁇ medical polymer may be hydrophilic or hydrophobic, and includes the various polymers set forth above.
- 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.
- 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.
- 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% THF; (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; (7) 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; (10) 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 in 30% ethanol/70% THF; (13) 1
- 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.
- antiinfective agent and small amounts of polymer when present in the impregnating solution
- the antiinfective agent and biomedical polymer may migrate somewhat toward the surface of the article.
- the article may be rinsed in either water or alcohol and wiped to remove any excess antiinfective agent and/or polymer at the surface.
- 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.
- 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.
- 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.
- a biomedical polymer such as a silicone polymer (e.g., Silastic Type A), poly ⁇ urethane, or polycaprolactone.
- 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.
- the biomedical polymer may be omitted from the first soaking step.
- an antiinfective agent may further be comprised in the polymeric coating.
- 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- tration (but less than 10 percent) of biomedical poly ⁇ mer dissolved in a suitable solvent.
- 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.
- 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.
- the total weight percent of chlorhexidine free 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.
- 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
- articles produced by dipping or soaking are within the scope of the claimed invention.
- CHA chlorhexidine diacetate
- TC triclosan
- the cultures were diluted with drug-inactivating medium (1:100 dilution in LTSB 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 trypticase soy agar plate for the determination of colony counts.
- drug-inactivating medium 1:100 dilution in LTSB 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
- the catheter segments were removed and transferred to fresh media containing IO 6 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.
- Table II 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 combination with AgSD.
- HYDROPHOBIC POLYMER COMPRISING CHLORHEXIDINE AND TRICLOSAN HAVE ANTIMICROBIAL ACTIVITY 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 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.
- 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- cent THF (v/v) containing 5 percent Silastic Type A
- 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) .
- 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.
- 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 these 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 effective than CHA-treated catheters.
- Arterial grafts fabricated from polytetra ⁇ fluoroethylene (“PTFE”) were cut into segments and impregnated with Silastic Type A comprising chlor ⁇ hexidine diacetate or triclosan in 30% methanol/70% THF (v/v) , in proportions set forth below.
- Silastic Type A comprising chlor ⁇ hexidine diacetate or triclosan in 30% 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.
- 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, 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.
- Impregnating Solution Zone Of Inhibition 4% SilA + 5% CHA + 1% TC 12.0
- 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
- 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 was changed daily and drug release was measured as des ⁇ cribed above.
- Table XVII Polyurethane, as set forth below, is Tecoflex 93-A polyurethane. Solution C: 3% polyurethane +
- Solution D 3% polyurethane + 3% TC in 30% reagent alcohol/70%
- Solution E 3% polyurethane + 2% CHA + 2% TC, in 30% reagent alcohol/70% THF
- Solution F 2% CHA in 95% ethanol
- Method 1 METHOD OF RENDERING POLYURETHANE CATHETERS INFECTION-RESISTANT BY IMPREGNATION WITH A SYNERGISTIC COMBINATION OF CHLORHEXIDINE AND TRICLOSAN
- Method 2 A one-step method
- Method 2 a two-step method
- 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%.
- the catheter 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 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.
- Tecoflex polyurethane catheters were prepared using the following 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 for 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 ⁇
- 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
- Method 4 follows the same procedure as Method 1, except that insoluble chlorhexidine free base (CHX) was solubilized with triclosan (1 molar CHX:2 molar triclosan ratio) , which forms a complex with CHX. After soaking for 5-10 minutes the catheters were dried for 1-3 days and then the outer surface was dipped in either a polyurethane solution alone (1-3% poly ⁇ urethane) or a solution of polyurethane containing CHX and triclosan (TC) .
- CHX insoluble chlorhexidine free base
- TC triclosan
- CHX is 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.
- 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.
- 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) Catheters 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.
- 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.
- Catheters were prepared according to Method 3. Specifically, catheters were soaked in a solution containing 5% 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.
- 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 IO 8 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) . TABLE XXI.
- the amount of drug uptake per cm/catheter in catheters prepared using various soaking solutions was measured as set forth above.
- 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.
- TTB trypticase soy broth
- the catheter segments were disconnected and their outer surfaces disinfected with 70% ethanol.
- Each lumen was flushed with 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.
- a 0.5 ml aliquot of the LTSB extract was subcultured on tryp ⁇ ticase soy agar plates. The results are shown in Table XXII.
Abstract
Description
Claims
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
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EP96945335A EP0874655B1 (en) | 1996-01-05 | 1996-12-23 | Triclosan-containing medical devices |
JP9525268A JP2000507842A (en) | 1996-01-05 | 1996-12-23 | Triclosan-containing drug device |
DE69629128T DE69629128T2 (en) | 1996-01-05 | 1996-12-23 | TRICLOSAN CONTAINING MEDICAL DEVICES |
AU15235/97A AU730158B2 (en) | 1996-01-05 | 1996-12-23 | Triclosan-containing medical devices |
US09/101,129 US6106505A (en) | 1996-01-05 | 1996-12-23 | Triclosan-containing medical devices |
AT96945335T ATE245039T1 (en) | 1996-01-05 | 1996-12-23 | MEDICAL DEVICES CONTAINING TRICLOSAN |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/583,239 US5772640A (en) | 1996-01-05 | 1996-01-05 | Triclosan-containing medical devices |
US08/583,239 | 1996-01-05 |
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US48323995A Continuation-In-Part | 1995-06-07 | 1995-06-07 | |
US08/583,239 Continuation-In-Part US5772640A (en) | 1995-06-07 | 1996-01-05 | Triclosan-containing medical devices |
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US09101129 A-371-Of-International | 1996-12-23 | ||
US09/618,432 Continuation US6626873B1 (en) | 1995-06-07 | 2000-07-18 | Tricolosan-containing medical devices |
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PCT/US1996/020932 WO1997025085A1 (en) | 1996-01-05 | 1996-12-23 | Triclosan-containing medical devices |
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US (6) | US5772640A (en) |
EP (2) | EP1273313A3 (en) |
JP (1) | JP2000507842A (en) |
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AU (1) | AU730158B2 (en) |
CA (1) | CA2241461A1 (en) |
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WO (1) | WO1997025085A1 (en) |
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- 1996-12-23 AU AU15235/97A patent/AU730158B2/en not_active Ceased
- 1996-12-23 US US09/101,129 patent/US6106505A/en not_active Expired - Fee Related
- 1996-12-23 AT AT96945335T patent/ATE245039T1/en not_active IP Right Cessation
-
1998
- 1998-04-17 US US09/062,411 patent/US6083208A/en not_active Expired - Fee Related
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2000
- 2000-07-18 US US09/618,432 patent/US6626873B1/en not_active Expired - Lifetime
- 2000-12-22 US US09/746,658 patent/US6706024B2/en not_active Expired - Lifetime
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Also Published As
Publication number | Publication date |
---|---|
EP0874655B1 (en) | 2003-07-16 |
CA2241461A1 (en) | 1997-07-17 |
US20010024661A1 (en) | 2001-09-27 |
US5772640A (en) | 1998-06-30 |
DE69629128T2 (en) | 2004-06-03 |
US6106505A (en) | 2000-08-22 |
EP1273313A3 (en) | 2003-02-05 |
EP0874655A4 (en) | 2001-05-02 |
AU1523597A (en) | 1997-08-01 |
EP1273313A2 (en) | 2003-01-08 |
US6083208A (en) | 2000-07-04 |
US20040039349A1 (en) | 2004-02-26 |
ATE245039T1 (en) | 2003-08-15 |
US6872195B2 (en) | 2005-03-29 |
AU730158B2 (en) | 2001-03-01 |
DE69629128D1 (en) | 2003-08-21 |
EP0874655A1 (en) | 1998-11-04 |
US6706024B2 (en) | 2004-03-16 |
US6626873B1 (en) | 2003-09-30 |
JP2000507842A (en) | 2000-06-27 |
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