(12) United States Patent
`Darouiche
`
`I 1111111111111111 11111 lllll 111111111111111 111111111111111 IIIIII IIII 11111111
`US006475434Bl
`US 6,475,434 Bl
`Nov. 5, 2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) COMPOSITION AND METHODS FOR
`PREVENTING AND REMOVING BIOFILM
`EMBEDDED MICROORGANISMS FROM
`THE SURFACE OF MEDICAL DEVICES
`
`(75)
`
`Inventor: Rabih 0. Darouiche, Houston, TX
`(US)
`
`(73) Assignee: Baylor College of Medicine, Houston,
`TX (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 09/455,985
`
`(22) Filed:
`
`Dec. 6, 1999
`
`(60)
`
`(51)
`
`(52)
`(58)
`
`(56)
`
`Related U.S. Application Data
`Provisional application No. 60/111,209, filed on Dec. 7,
`1998.
`
`Int. Cl.7 ............................. A61L 2/00; A61L 9/00;
`AOlN 1/00
`U.S. Cl. ............................. 422/28; 422/35; 427/2.1
`Field of Search ................................ 422/8, 28, 35;
`427/2.1
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,749,770 A
`3,947,589 A
`4,305,958 A
`4,710,313 A
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`5,158,684 A
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`5,480,574 A
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`Martin
`Misato et al.
`Fujita et al.
`Miyajima et al.
`Wiatr
`Moulton et al.
`Raad et al.
`................... 623/11
`Carpenter et al.
`Dziabo et al.
`......... 252/187.21
`Richter et al.
`Lindall
`Singerman
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`5,520,746 A
`5,536,258 A
`5,624,704 A *
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`5/1996 Kamiya
`7/1996 Folden
`4/1997 Darouiche et al. ......... 427/2.24
`8/1997 Hann et al.
`8/1997 Abe et al.
`
`(List continued on next page.)
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`WO 91/07090
`WO98/07883
`
`5/1991
`* 2/1998
`
`OTHER PUBLICATIONS
`
`Nickel et al, Tobramycin Resistance of Pseudomas aerugi(cid:173)
`nosa Cells Growing as a Biofilm on Urinary Catheter
`Material, Apr. 1985, Antimicrobial Agents and Chemo(cid:173)
`therapy, vol. 27, No. 4, pp. 619-624.*
`
`(List continued on next page.)
`
`Primary Examiner-Robert J. Warden, Sr.
`Assistant Examiner----Imad Soubra
`(74) Attorney, Agent, or Firm-Anthony F. Matheny;
`Andrews & Kurth L.L.P.
`
`(57)
`
`ABSTRACT
`
`A biofilm penetrating compos1t10n for coating medical
`devices for substantially preventing the growth or prolifera(cid:173)
`tion of biofilm embedded microorganisms on at least one
`surface of the medical device is disclosed. A biofilm pen(cid:173)
`etrating composition solution for cleaning medical devices
`which is capable of substantially removing all of the biofilm
`embedded microorganisms from at least one surface of
`medical devices is also disclosed. The biofilm penetrating
`composition coating and solution include a biofilm penetrat(cid:173)
`ing agent and may also include a base material. Medical
`devices coated with the biofilm penetrating composition and
`methods for coating medical devices and methods for
`removing biofilm embedded microorganisms from at least
`one surface of the medical devices are also disclosed.
`
`15 Claims, 1 Drawing Sheet
`
`10
`
`11
`
`/
`
`14
`
`15
`
`BAXTER EXHIBIT 1015
`Page 1 of 13
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`

`

`US 6,475,434 Bl
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`11/1997 Hei et al.
`5,683,724 A
`11/1997 Gutierrez et al.
`5,686,402 A
`11/1997 Mason et al.
`5,691,380 A
`12/1997 Sun et al.
`5,696,164 A
`2/1998 Cook
`5,719,110 A
`7/1998 Tang et al.
`5,776,875 A
`5,902,283 A * 5/1999 Darouiche et al. .......... 604/265
`6,162,487 A * 12/2000 Darouiche et al. ......... 427/2.14
`
`Schierholz, et al., Investigation of rifampin, fusidic acid and
`mupirocin releasing silicone catheter, Biomaterials, 1998,
`vol. 19, pp. 2065-2074.
`
`Ditizio, et al., A liposomal hydrogel for the prevention of
`bacterial adhesion to catheters, Biomaterials, 1998, vol. 19,
`pp. 1877-1884.
`
`International Search Report, May 2, 2000.
`
`OIBER PUBLICATIONS
`
`L. F. Prescott, R. N. Illingworth, J.A.J.H. Critchley, M.J.
`Stewart , R. D. Adam and A. T. Proudfoot; Intravenous
`N-acetycysteine: the treatment of choice for paracetamol
`poisoning; British Medical Journal, pp. 1097-1100, vol. 2;
`Nov. 3, 1979.
`A Gillissen, M. Jaworska, M. Orth, M. Coffiner, G.
`Schultze-Werninghaus, P. Maes, E.M. App, and AM. Can(cid:173)
`tin, Nacystelyn, a novel lysine salt of N-acetylcysteine, to
`augment cellular antioxidant defence in vitro; Respiratory
`Medicine(l997) vol. 91, pp. 159-168.
`J. C. Nickel, and I. Ruseska, J.B. Wright, and J. W. Coster(cid:173)
`ton; Tobramycin Resistance of Pseudomonas aeruginosa
`Cells Growing as a Biofilm on Urinary Catheter Material;
`Antimicrobial Agents and Chemotherapy, Apr. 1985, pp.
`619-624.
`International Search Report, Mary 2, 2000.
`Perez-Giraldo, et al., Influence of N-Acetylcysteine on the
`formation of biofilm by Staphylococcus epidermis, Journal
`of Antimicrobial Chemotheraphy, 1997, vol. 39, pp.
`643-646.
`
`Perez-Giraldo, et al., Influence of N-acetlcysteine on the
`formation biofilm by Staphylococcus epidermis, Journal of
`Antimicrobial Chemotherapy, 1997, vol. 39, pp. 643-646.
`
`Schierholz, et al., Investigation of a rifampin, fusidic acid
`and mupirocin releasing silicone catheter, Biomaterials,
`1998, vol. 19, pp. 2065-2074.
`
`L. F. Prescott, R. N. Illingworth, J.A.J.H. Critchley, M.J.
`Stewart, R.D. Adam and A.T. Proudfoot; Intravenous
`N-acetylcysteine: the treatment of choice for paracetamol
`poisoning; British Medical Journal, pp. 1097-1100, vol. 2;
`Nov. 3, 1979.
`
`J. C. Nickel, and I. Ruseska, J. B. Wright, and J. W.
`Costerton; Tobramycin Resistance of Pseudomonas aerugi(cid:173)
`nosa Cells Growing as a Biofilm on Urinary Catheter
`Material; Antimicrobial Agents and Chemotherapy, Apr.
`1985, pp. 619-624.
`
`* cited by examiner
`
`BAXTER EXHIBIT 1015
`Page 2 of 13
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`

`

`U.S. Patent
`US. Patent
`
`Nov. 5, 2002
`Nov. 5, 2002
`
`US 6,475,434 Bl
`US 6,475,434 B1
`
`N ....
`
`
`
`.... •
`~ -LL.
`
`....
`lO
`
`BAXTER EXHIBIT 1015
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`Page 3 of 13
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`BAXTER EXHIBIT 1015
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`

`

`US 6,475,434 Bl
`
`1
`COMPOSITION AND METHODS FOR
`PREVENTING AND REMOVING BIOFILM
`EMBEDDED MICROORGANISMS FROM
`THE SURFACE OF MEDICAL DEVICES
`
`RELATED APPLICATIONS
`This application claims the benefit of U.S. Provisional
`Application No. 60/111,209, filed Dec. 7, 1998.
`
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to a composition for coating
`or cleaning medical devices that are likely to become
`contaminated or have become contaminated with microor(cid:173)
`ganisms and methods for preventing biofilm embedded
`microorganisms from growing, or proliferating, on the sur(cid:173)
`face of medical devices, and for removing biofilm embedded
`microorganisms growing, or proliferating, on the surface of
`medical devices.
`2. Description of Related Art
`As a defense to antimicrobial agents and other environ(cid:173)
`mental hazards which may affect the survival and prolifera(cid:173)
`tion of microorganisms, microorganisms form a defense
`layer called biofilm. Formation of biofilm on the surface of
`various medical devices can be detrimental to the integrity 25
`of the medical device, present health risks, and prevent
`sufficient flow through the lumens of medical devices.
`Although coating or cleaning medical devices with anti(cid:173)
`microbial agents, e.g., antibiotics or antiseptics, can be
`effective in killing or inhibiting growth of planktonic organ- 30
`isms on the surfaces of such items, the antimicrobial agents
`are generally much less active against the microorganisms
`that are deeply embedded within the biofilm. The failure of
`the antimicrobial agents to sufficiently remove the microor(cid:173)
`ganisms is in part due to the shielding effect of the biofilm. 35
`The biofilm prevents penetration of the antimicrobial agents
`deep into the biofilm to kill the microorganisms residing
`therein.
`Accordingly, prior to the development of the present
`invention, there has been no biofilm penetrating
`composition, method for coating medical devices, method
`for removing biofilm embedded microorganisms from at
`least one surface of medical devices, or coated medical
`device, which: provides disruption of the biofilm thereby
`allowing antimicrobial agents and/or antifungal agents to
`penetrate the biofilm and remove biofilm embedded micro(cid:173)
`organisms from the surface of medical devices; and prevents
`the growth or proliferation of biofilm embedded microor(cid:173)
`ganisms on the surface of medical devices. Therefore, the art
`has sought a biofilm penetrating composition, method for
`coating medical devices, method for removing biofilm
`embedded microorganisms from at least one surface of
`medical devices, or coated medical device, which: provides
`disruption of the biofilm thereby allowing antimicrobial
`agents and/or antifungal agents to penetrate the biofilm and
`remove biofilm embedded microorganisms from the surface
`of medical devices; and prevents the growth or proliferation
`of biofilm embedded microorganisms on the surface of
`medical devices. It is believed that the present invention will
`achieve these objectives and overcome the disadvantages of
`other medical devices and techniques in the field of the
`invention, but its results or effects are still dependent upon
`the skill and training of the operator.
`SUMMARY OF INVENTION
`In accordance with the invention the foregoing advan(cid:173)
`tages have been achieved through the present composition
`
`5
`
`2
`for substantially preventing the growth or proliferation of
`biofilm embedded microorganisms on at least one surface of
`a medical device comprising at least one biofilm penetrating
`agent.
`A further feature of the composition is that the composi(cid:173)
`tion may further comprise a base material. Another feature
`of the composition is that the at least one biofilm penetrating
`agent may be selected from the group consisting of cysteine
`and derivatives thereof. An additional feature of the com-
`10 position is that the at least one biofilm penetrating agent may
`be selected from the group consisting of N-acetylcysteine
`and derivatives thereof. A further feature of the composition
`is that the base material may be selected from the group
`consisting of rubbers, thermoplastics, and elastomers.
`15 Another feature of the composition is that the base material
`may be selected from the group consisting of water and
`buffer solutions.
`In accordance with the invention the foregoing advan(cid:173)
`tages have also been achieved through the present compo-
`20 sition for removing substantially all of the biofilm embedded
`microorganisms from at least one surface of a medical
`device comprising at least one biofilm penetrating agent.
`A further feature of the composition is that the composi(cid:173)
`tion may further comprise a base material. Another feature
`of the composition is that the at least one biofilm penetrating
`agent may be selected from the group consisting of cysteine
`and derivatives thereof. An additional feature of the com(cid:173)
`position is that the at least one biofilm penetrating agent may
`be selected from the group consisting of N-acetylcysteine
`and derivatives thereof. A further feature of the composition
`is that the base material may be a buffer solution. Another
`feature of the composition is that the buffer solution may be
`phosphate buffered saline.
`In accordance with the invention the foregoing advan-
`tages have also been achieved through the present method
`for substantially preventing the growth or proliferation of
`biofilm embedded microorganisms on at least one surface of
`a medical device comprising the steps of: providing a
`40 medical device having at least one surface; providing a
`biofilm penetrating composition; and contacting the biofilm
`penetrating composition to the medical device in an amount
`sufficient to substantially prevent the growth or proliferation
`of biofilm embedded microorganisms on the at least one
`45 surface of the medical device.
`A further feature of the method for substantially prevent(cid:173)
`ing the growth or proliferation of biofilm embedded micro(cid:173)
`organisms on at least one surface of a medical device is that
`the biofilm penetrating composition may be formed by
`50 mixing cysteine or derivatives thereof and a base material.
`An additional feature of the method for substantially pre(cid:173)
`venting the growth or proliferation of biofilm embedded
`microorganisms on at least one surface of a medical device
`is that the biofilm penetrating composition may be contacted
`55 to the medical device for a period of time sufficient to form
`a coating of the biofilm penetrating composition on the at
`least one surface of the medical device. Another feature of
`the method for substantially preventing the growth or pro(cid:173)
`liferation of biofilm embedded microorganisms on at least
`60 one surface of a medical device is that the biofilm penetrat(cid:173)
`ing composition may be contacted to the medical device by
`integrating the biofilm penetrating composition with the
`material forming the medical device during formation of the
`medical device. A further feature of the method for substan-
`65 tially preventing the growth or proliferation of biofilm
`embedded microorganisms on at least one surface of a
`medical device is that the biofilm penetrating composition
`
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`

`US 6,475,434 Bl
`
`4
`biofilm embedded microorganisms on the at least one sur(cid:173)
`face of the medical device.
`The biofilm penetrating composition, method for coating
`medical devices, method for removing substantially all
`5 biofilm embedded microorganisms from at least one surface
`of medical devices, and coated medical device of the present
`invention, when compared with previously proposed biofilm
`penetrating compositions, methods of coating medical
`devices, methods of removing substantially all biofilm
`10 embedded microorganisms from at least one surface of
`medical devices, or coated medical devices have the advan(cid:173)
`tages of: providing disruption of the biofilm thereby allow(cid:173)
`ing antimicrobial agents and/or antifungal agents to pen-
`etrate the biofilm and remove biofilm embedded
`microorganisms from the surface of medical devices; and
`preventing the growth or proliferation of biofilm embedded
`microorganisms from the surface of medical devices. It is
`believed that the present invention will achieve these objec(cid:173)
`tives and overcome the disadvantages of other medical
`20 devices and techniques in the field of the invention, but its
`results or effects are still dependent upon the skill and
`training of the operator.
`
`BRIEF DESCRIPTION OF DRAWINGS
`FIG. 1 is a specific embodiment of a catheter insertion
`seal having a biofilm penetrating composition incorporated
`into an adhesive layer located on the catheter insertion seal.
`While the invention will be described in connection with
`30 the preferred embodiments, it will be understood that it is
`not intended to limit the invention to these embodiments. On
`the contrary, it is intended to cover all alternatives,
`modifications, and equivalents, as may be included within
`the spirit and scope of the invention as defined by the
`appended claims and equivalents thereof.
`
`3
`may be contacted to the medical device by flushing the
`medical device in the biofilm penetrating composition for a
`period of time sufficient for preventing the growth or pro(cid:173)
`liferation of biofilm embedded microorganisms on at least
`one surface of the medical device.
`In accordance with the invention the foregoing advan(cid:173)
`tages also have been achieved through the present coated
`medical device having at least one surface which may
`substantially prevent the growth or proliferation of biofilm
`embedded microorganisms on the at least one surface of the
`coated medical device, comprising: (a) a medical device;
`and (b) a biofilm penetrating composition coating for sub(cid:173)
`stantially preventing the growth or proliferation of biofilm
`embedded microorganisms on the at least one surface of the
`coated medical device, the biofilm penetrating composition 15
`coating being disposed upon the at least one surface.
`A further feature of the coated medical device is that the
`biofilm penetrating composition coating may include at least
`one biofilm penetrating agent. An additional feature of the
`coated medical device is that the biofilm penetrating com(cid:173)
`position coating may further include a base A material.
`Another feature of the coated medical device is that the at
`least one biofilm penetrating agent may be selected from the
`group consisting of cysteine and derivatives thereof. A
`further feature of the coated medical device is that the at 25
`least one biofilm penetrating agent may be selected from the
`group consisting of N-acetylcysteine and derivatives
`thereof. An additional feature of the coated medical device
`is that the base material may be a buffer solution.
`In accordance with the invention the foregoing advan(cid:173)
`tages have also been achieved through the present method
`for removing substantially all of the biofilm embedded
`microorganisms from a medical device having at least one
`surface, the at least one surface of the medical device having
`biofilm embedded microorganisms attached thereto, com- 35
`prising the steps of: providing a medical device having at
`least one surface, the at least one surface of the medical
`device having biofilm embedded microorganisms attached
`thereto; providing a biofilm penetrating composition; and
`contacting the biofilm penetrating composition to the medi- 40
`cal device in an amount sufficient to remove substantially all
`of the biofilm embedded microorganisms from the at least
`one surface of the medical device.
`A further feature of the method for removing substantially
`all of the biofilm embedded microorganisms from a medical 45
`device having at least one surface is that the biofilm pen(cid:173)
`etrating composition may be formed by mixing a biofilm
`penetrating agent and a base material. An additional feature
`of the method for removing substantially all of the biofilm
`embedded microorganisms from a medical device having at 50
`least one surface is that the biofilm penetrating agent may be
`selected from the group consisting cysteine and derivatives
`thereof. Another feature of the method for removing sub(cid:173)
`stantially all of the biofilm embedded microorganisms from
`a medical device having at least one surface is that the 55
`biofilm penetrating agent is selected from the group con(cid:173)
`sisting of N-acetylcysteine and derivatives thereof. An addi(cid:173)
`tional feature of the method for removing substantially all of
`the biofilm embedded microorganisms from a medical
`device having at least one surface is that the base material is 60
`a buffer solution. A further feature of the method for
`removing substantially all of the biofilm embedded micro(cid:173)
`organisms from a medical device having at least one surface
`is that the biofilm penetrating composition may be contacted
`to the medical device by flushing the medical device in the
`biofilm penetrating composition for a period of time suffi(cid:173)
`cient to substantially prevent the growth or proliferation of
`
`DETAILED DESCRIPTION AND SPECIFIC
`EMBODIMENTS
`
`In one aspect, the present invention is directed to a biofilm
`penetrating composition which may be in the form of a
`coating which is applied to medical devices and which
`substantially prevents biofilm embedded microorganisms
`from growing and proliferating on at least one surface of the
`medical devices and/or substantially facilitates access of
`antimicrobial agents to the biofilm embedded microorgan(cid:173)
`isms to assist in the prevention of the biofilm embedded
`microorganisms from growing or proliferating on the at least
`one surface of the medical device. The biofilm penetrating
`composition may also be in the form of a liquid, or solution,
`which is used to clean medical devices which include
`biofilm embedded microorganisms living and proliferating
`on at least one surface of the medical devices by flushing,
`rinsing, soaking, and/or any other cleaning method known to
`persons skilled in the art, the medical device in the biofilm
`penetrating composition solution, and thus, remove the
`biofilm embedded microorganisms from at least one surface
`of the medical device.
`Broadly, the biofilm penetrating composition includes a
`biofilm penetrating agent which, in its activated state, dis(cid:173)
`rupts the biofilm of microorganisms and attacks the micro(cid:173)
`organisms and/or allows other antimicrobial agents, e.g.,
`antiseptics or antibiotics, or antifungal agents present in the
`biofilm penetrating composition to remove the biofilm
`embedded microorganisms from at least one surface of the
`65 medical devices; and/or prevents the growth or proliferation
`of biofilm embedded microorganisms on at least one surface
`of the medical device. Specifically, the biofilm penetrating
`
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`US 6,475,434 Bl
`
`6
`plastic or polymeric materials such as rubber, plastic,
`polyesters, polyethylene, polyurethane, silicone, Gortex
`(polytetrafluoroethylene), Dacron® (polyethylene
`tetraphthalate ), Teflon (polytetrafluoroethylene ), latex, elas-
`tamers and Dacron® sealed with gelatin, collagen or
`albumin, and derivatives or combinations thereof. The medi(cid:173)
`cal devices include at least one surface for applying the
`biofilm penetrating composition. Preferably, the biofilm
`penetrating composition is applied to the entire medical
`10 device.
`The biofilm penetrating composition may include any
`number of biofilm penetrating agents and base materials
`known to persons skilled in the art. Preferably, the biofilm
`penetrating agents have mucolytic capabilities, i.e., the
`15 ability to break-up and penetrate mucous, and/or the capa(cid:173)
`bility of penetrating and breaking-up microorganism bio(cid:173)
`film.
`Suitable biofilm penetrating agents include the amino acid
`cysteine and cysteine derivatives. Examples of suitable
`20 biofilm penetrating agents include cysteine (L-cysteine,
`D-cysteine, DL-cysteine), DL-Homocysteine, L-cysteine
`methyl ester, L-cysteine ethyl ester, N-carbamoyl cysteine,
`cysteamine, N-(2-mercaptoisobutyry 1)-L-cysteine, N-(2-
`m ere ap top ropio n yl)-L-cys te ine -A,
`N -(2-
`25 mercaptopropionyl)-L-cysteine-B,
`N-(3-
`mercaptopropionyl)-L-cysteine, L-cysteine ethyl ester
`hydrochloride, L-cysteine methyl ester hydrochloride,
`nacystelyn (a lysine salt of N-acetylcysteine),
`N-acetylcysteine, and derivatives thereof. Preferably, the
`30 biofilm penetrating agent is N-acetylcysteine and derivatives
`thereof.
`N-acetylcysteine corresponds to the chemical formula C5
`H 9 N03 S and the following chemical structure:
`
`5
`
`5
`composition coating for medical devices may be formulated
`to substantially prevent the proliferation of biofilm embed(cid:173)
`ded microorganisms, and/or remove substantially all of the
`microorganisms, on the surface of medical devices. "Bio film
`embedded microorganisms" is herein defined as any micro(cid:173)
`organism which forms a biofilm during colonization and
`proliferation on the surface of medical devices, including,
`but not limited to, gram-positive bacteria (such as Staphy(cid:173)
`lococcus epidermidis), gram-negative bacteria (such as
`Pseudomonas aeruginosa), and/or fungi (such as Candida
`albicans). While the biofilm penetrating coating may
`include a biofilm penetrating agent alone, preferably, the
`biofilm penetrating composition coating includes a base
`material and a biofilm penetrating agent. The biofilm pen(cid:173)
`etrating composition may also include more than one biofilm
`penetrating agent as desired or necessary to prevent or
`remove microorganisms from at least one surface of a
`medical device.
`"Medical devices" are herein defined as disposable or
`permanent catheters, ( e.g., central venous catheters, dialysis
`catheters, long-term tunneled central venous catheters,
`short-term central venous catheters, peripherally inserted
`central catheters, peripheral venous catheters, pulmonary
`artery Swan-Ganz catheters, urinary catheters, and perito(cid:173)
`neal catheters), long-term urinary devices, tissue bonding
`urinary devices, vascular grafts, vascular catheter ports,
`wound drain tubes, ventricular catheters, hydrocephalus
`shunts heart valves, heart assist devices ( e.g., left ventricular
`assist devices), pacemaker capsules, incontinence devices,
`penile implants, small or temporary joint replacements,
`urinary dilator, cannulas, elastomers, hydrogels, surgical
`instruments, dental instruments, tubings, such as intravenous
`tubes, breathing tubes, dental water lines, dental drain tubes,
`and feeding tubes, fabrics, paper, indicator strips ( e.g., paper
`indicator strips or plastic indicator strips), adhesives ( e.g., 35
`hydrogel adhesives, hot-melt adhesives, or solvent-based
`adhesives), bandages, orthopedic implants, and any other
`device used in the medical field. "Medical devices" also
`include any device which may be inserted or implanted into
`a human being or other animal, or placed at the insertion or 40
`implantation site such as the skin near the insertion or
`implantation site, and which include at least one surface
`which is susceptible to colonization by biofilm embedded
`microorganisms. Medical devices also include any other
`surface which may be desired or necessary to prevent 45
`biofilm embedded microorganisms from growing or prolif(cid:173)
`erating on at least one surface of the medical device, or to
`remove or clean biofilm embedded microorganisms from the
`at least one surface of the medical device, such as the
`surfaces of equipment in operating rooms, emergency 50
`rooms, hospital rooms, clinics, and bathrooms. In one spe(cid:173)
`cific embodiment, the biofilm penetrating composition is
`integrated into an adhesive, such as tape, thereby providing
`an adhesive which may prevent growth or proliferation of
`biofilm embedded microorganisms on at least one surface of 55
`the adhesive.
`Implantable medical devices include orthopedic implants
`which may be inspected for contamination or infection by
`biofilm embedded microorganisms using endoscopy. Insert(cid:173)
`able medical devices include catheters and shunts which can
`be inspected without invasive techniques such as endoscopy.
`The medical devices may be formed of any suitable metallic
`materials or non-metallic materials known to persons skilled
`in the art. Examples of metallic materials include, but are not
`limited to, tivanium, titanium, and stainless steel, and
`derivatives or combinations thereof. Examples of non(cid:173)
`metallic materials include, but are not limited to, thermo-
`
`OH
`I
`c=o
`0
`I
`II
`CH3-C-NH-CH-CH2-SH
`
`N-acetylcysteine is an "acetylated" derivative of the amino
`acid cysteine. Cysteine, and all amino acids more complex
`than glycine, exists as two enantiomeric forms, the naturally
`occurring "L" form and its non-naturally occurring "D"
`form. The "L" form of N-acetylcysteine, which is designated
`N-acetyl-L-cysteine, is preferred for use herein, because it is
`more readily available, although the "D" form can be used.
`It is also recognized that cysteine and its N-acetylated
`derivative can exist as an oxidized dimer, however, the
`monomeric form of N-acetylcysteine is preferred for use
`herein.
`While N-acetyl-L-cysteine is preferred, it is contemplated
`that derivatives of N-acetylcysteine may also be used as
`biofilm penetrating agent. These derivatives include esters,
`amides, anhydrides, and thio-esters and thio-ethers of the
`sulfhydryl moiety. Examples of suitable N-acetylcysteine
`derivatives include, but are not limited to, methyl-N(cid:173)
`acetylcysteine, ethyl N-acetylcysteine, stearyl
`N-acetylcysteine, N-acetylcysteine methylthioether, N,S-
`60 d i a c e t y 1 c y s t e i n e , N - a c e t y le y st e i n e am id e ,
`N-mercaptoacetyl-L-cysteine, and the mixed anhydride of
`N-acetylcysteine and acetic acid.
`It is also contemplated that pharmaceutically acceptable
`salts of N-acetylcysteine and derivatives of N-acetylcysteine
`65 may also be used as biofilm penetrating agents. Non-limiting
`examples of these salts include sodium salts, e.g., N-acetyl(cid:173)
`L-cysteine sodium salt and N-acetyl-L-cysteine sodium zinc
`
`BAXTER EXHIBIT 1015
`Page 6 of 13
`
`

`

`US 6,475,434 Bl
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`25
`
`7
`monohydrate, potassium salts, magnesium salts, e.g.,
`N-acetyl-L-cysteine magnesium zinc salts, calcium salts,
`e.g., N-acetyl-L-cysteine calcium zinc monohydrate, zinc
`salts, e.g., N-acetyl-L-cysteine zinc salt, zinc mercaptide
`salts, ammonium slats, e.g., N-acetyl-L-cysteine ammonium
`zinc salt, calcium zinc N-acetyl-L-cysteinate acetate, zinc
`mercaptide N-acetylcysteine carboxylates, and alkyl ammo(cid:173)
`nium and alkanol ammonium salts, i.e., wherein the ammo(cid:173)
`nium ion is substituted with one or more alkyl or alkanol
`moieties.
`The biofilm penetrating agent is included in the biofilm
`penetrating composition in amounts sufficient to penetrate,
`or break-up the biofilm and provide the biofilm penetrating
`agent, antimicrobial agent, and/or antifungal agent access to
`the biofilm embedded microorganisms thereby facilitating 15
`the removal of substantially all of the biofilm embedded
`microorganisms from at least one surface of the medical
`device. While the biofilm penetrating agent may be 100% of
`the biofilm penetrating composition, preferably, the biofilm
`penetrating composition contains from at least about 0.01 % 20
`to about 60% biofilm penetrating agent by weight based
`upon the total weight of the biofilm penetrating composition
`being employed. In the preferred embodiment, the biofilm
`penetrating composition includes from at least about 0.5% to
`about 30% (by weight) biofilm penetrating agent.
`The term "base material" is defined herein as any of a
`group of materials which effectively disperses the biofilm
`penetrating agent at an effective concentration to penetrate,
`or break-up, the biofilm thereby facilitating access of the
`biofilm penetrating agent, antimicrobial agents, and/or anti- 30
`fungal agents to the microorganisms embedded in the
`biofilm, and thus, removal of substantially all of the micro(cid:173)
`organisms from at least one surface of the medical device.
`The term "base material" also includes any group of solu(cid:173)
`tions which effectively disperse the biofilm penetrating 35
`agent at an effective concentration to form a biofilm pen(cid:173)
`etrating composition coating for medical devices which
`substantially prevents the growth or proliferation of biofilm
`embedded microorganisms on at least one surface of the
`medical device. In the case of the biofilm penetrating 40
`composition coating, preferably, the base material also
`facilitates the adhesion of the biofilm penetrating composi(cid:173)
`tion to at least one surface of the medical device and
`prevents the biofilm penetrating composition coating from
`being easily removed from the surface of the medical device,
`thereby facilitating the utilization of the biofilm penetrating
`composition to coat at least one surface of a medical device.
`Examples of suitable base materials include, but are not
`limited to, buffer solutions, phosphate buffered saline,
`saline, water, polyvinyl, polyethylene, polyurethane,
`polypropylene, silicone (e.g., silicone elastomers and sili(cid:173)
`cone adhesives), polycarboxylic acids, ( e.g., polyacrylic
`acid, polymethacrylic acid, polymaleic acid, poly-(maleic
`acid monoester), polyaspartic acid, polyglutamic acid,
`aginic acid or pectimic acid), polycarboxylic acid anhy- 55
`drides (e.g., polymaleic anhydride, polymethacrylic anhy(cid:173)
`dride or polyacrylic acid anhydride), poly amines, poly amine
`ions ( e.g., polyethylene imine, polyvinylarnine, poly lysine,
`poly-(dialkylamineoethyl methacrylate), poly-
`( dialkylaminomethyl styrene) or poly-(vinylpyridine )), 60
`polyammonium ions (e.g., poly-(2-methacryloxyethyl tri(cid:173)
`alkyl ammonium ion), poly-(vinylbenzyl trialkyl ammo(cid:173)
`nium ions), poly-(N.N.-alkylypyridinium ion) or poly(cid:173)
`(dialkyloctamethylene ammonium ion) and polysulfonates
`(e.g. poly-(vinyl sulfonate) or poly-(styrene sulfonate)), 65
`collodion, nylon, rubber, plastic, polyesters, Gortex
`(polytetrafluoroethylene), Dacron® (polyethylene
`
`8
`tetraphthalate ), Teflon polytetrafluoroethylene ), latex, and
`derivatives thereof, elastomers and Dacron(® sealed with
`gelatin, collagen or albumin, cyanoacrylates, methacrylates,
`papers with porous barrier films, adhesives, e.g., hot melt
`5 adhesives,