U.S. patent application number 14/334326 was filed with the patent office on 2014-11-06 for compositions and methods for coating medical implants.
The applicant listed for this patent is Angiotech International AG. Invention is credited to David M. Gravett, William L. Hunter, Richard T. Liggins, Troy A.E. Loss, Philip M. Toleikis.
Application Number | 20140328891 14/334326 |
Document ID | / |
Family ID | 40407889 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140328891 |
Kind Code |
A1 |
Hunter; William L. ; et
al. |
November 6, 2014 |
COMPOSITIONS AND METHODS FOR COATING MEDICAL IMPLANTS
Abstract
Medical implants are provided which release a fluoropyrimidine
or an analog thereof, thereby inhibiting or reducing the incidence
of infection associated with the implant.
Inventors: |
Hunter; William L.;
(Vancouver, CA) ; Gravett; David M.; (Mountain
View, CA) ; Toleikis; Philip M.; (Vancouver, CA)
; Liggins; Richard T.; (Coquitlam, CA) ; Loss;
Troy A.E.; (North Vancouver, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Angiotech International AG |
Vancouver |
|
CA |
|
|
Family ID: |
40407889 |
Appl. No.: |
14/334326 |
Filed: |
July 17, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13663254 |
Oct 29, 2012 |
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14334326 |
|
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|
12107629 |
Apr 22, 2008 |
8313760 |
|
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13663254 |
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10447309 |
May 27, 2003 |
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12107629 |
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60383419 |
May 24, 2002 |
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Current U.S.
Class: |
424/411 ;
514/274 |
Current CPC
Class: |
A61L 2300/204 20130101;
A01N 43/54 20130101; A61L 27/54 20130101; A61L 29/08 20130101; A61L
29/16 20130101; A61L 2300/404 20130101 |
Class at
Publication: |
424/411 ;
514/274 |
International
Class: |
A61L 29/08 20060101
A61L029/08; A61L 29/16 20060101 A61L029/16 |
Claims
1-17. (canceled)
18. A medical device having a reduced likelihood of infection, the
device comprising a medical implant which has been covered or
coated with an antimicrobially effective amount of a
fluoropyrimidine or an analog thereof.
19. The device of claim 18, where the implant is coated or covered
with an antimicrobially effective amount of a fluoropyrimidine.
20. The device of claim 19, wherein said fluoropyrimidine is
5-fluorouracil.
21. The device of claim 18, comprising 0.1 .mu.g to 1 mg
fluoropyrimidine per cm.sup.2 of surface area of the portion of the
medical implant to which the fluoropyrimidine has been applied.
22. The device of claim 21, wherein the implant releases the
fluoropyrimidine in an amount effective to reduce or inhibit the
likelihood of infection associated with the implantation of the
device in a subject.
23. The device of claim 22, wherein the implant does not release
the fluoropyrimidine in an amount effective for the treatment of
cancer in the subject that receives the implant.
24. The device of claim 18, further comprising a polymer coating in
combination with the fluoropyrimidine or analog thereof.
25. The device of claim 24, wherein the polymer coating comprises
polyurethane.
26. The device of claim 18, wherein the implant is a catheter.
27. The device of claim 26, wherein the catheter is a dialysis
catheter.
28. The device of claim 18, which is not useful for treating
cancer.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/663,254, filed Oct. 29, 2012, now pending,
which is a continuation of U.S. patent application Ser. No.
12/107,629, filed Apr. 22, 2008, now U.S. Pat. No. 8,313,760, which
is a continuation-in-part of U.S. patent application Ser. No.
10/447,309, filed May 27, 2003, now abandoned, which claims the
benefit under 35 U.S.C. .sctn.119(e) of U.S. Provisional Patent
Application No. 60/383,419, filed May 24, 2002, where these
applications are incorporated herein by reference in their
entireties.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates generally to pharmaceutical
compositions, methods, and devices, and more specifically, to
compositions and methods which reduce the likelihood of an
infection associated with a medical implant.
[0004] 2. Description of the Related Art
[0005] Infections associated with medical implants represent a
major healthcare problem. For example, 5% of patients admitted to
an acute care facility develop a hospital acquired infection.
Hospital acquired infections (nosocomial infections) are the
11.sup.th leading cause of death in the US and cost over $2 billion
annually. Nosocomial infections directly cause 19,000 deaths per
year in the US and contribute to over 58,000 others.
[0006] The four most common causes of nosocomial infections are:
urinary tract infection (28%); surgical site infection (19%);
respiratory tract infection (17%); and bloodstream infection (16%
and rising). A significant percentage of these infections are
related to bacterial colonization of implanted medical implants
such as Foley catheters (urinary tract infections); surgical
drains, meshes, sutures, artificial joints, vascular grafts (wound
infections); endotracheal and tracheostomy tubes (respiratory tract
infection); and vascular infusion catheters (bloodstream
infections). Although any infectious agent can infect medical
implant, Staphylococci (S. aureus, S. epidermidis, S. pyogenes),
Enterococci (E. coli), Gram Negative Aerobic Bacilli, and
Pseudomonas aeruginosa are common causes. Once a medical implant
becomes colonized by bacteria, it must frequently be replaced
resulting in increased morbidity for the patient and increased cost
to the healthcare system. Often the infected device serves as a
source for a disseminated infection which can lead to significant
morbidity or even death.
[0007] In an attempt to combat this important clinical problem,
devices have been coated with antimicrobial drugs. Representative
examples include U.S. Pat. No. 5,520,664 ("Catheter Having a
Long-Lasting Antimicrobial Surface Treatment"), U.S. Pat. No.
5,709,672 ("Silastic and Polymer-Based Catheters with Improved
Antimicrobial/Antifungal Properties"), U.S. Pat. No. 6,361,526
("Antimicrobial Tympanostomy Tubes"), U.S. Pat. No. 6,261,271
("Anti-infective and antithrombogenic medical articles and method
for their preparation"), U.S. Pat. No. 5,902,283 ("Antimicrobial
impregnated catheters and other medical implants") U.S. Pat. No.
5,624,704 ("Antimicrobial impregnated catheters and other medical
implants and method for impregnating catheters and other medical
implants with an antimicrobial agent") and U.S. Pat. No. 5,709,672
("Silastic and Polymer-Based Catheters with Improved
Antimicrobial/Antifungal Properties").
[0008] One difficulty with these devices, however, is that they can
become colonized by bacteria resistant to the antibiotic coating.
This can result in at least two distinct clinical problems. First,
the device serves as a source of infection in the body with the
resulting development of a local or disseminated infection.
Secondly, if an infection develops, it cannot be treated with the
antibiotic(s) used in the device coating. The development of
antibiotic-resistant strains of microbes remains a significant
healthcare problem, not just for the infected patient, but also for
the healthcare institution in which it develops.
[0009] Thus, there is a need in the art for medical implants which
have a reduced likelihood of an associated infection. The present
invention discloses such devices (as well as compositions and
methods for making such devices) which reduce the likelihood of
infections in medical implants, and further, provides other,
related advantages.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] FIG. 1 shows the effect of palmitic acid on the release
profile of 5-fluorouracil from a polyurethane sample.
[0011] FIG. 2A is a microscopic picture of an uncoated CVC.
[0012] FIG. 2B is a microscopic picture of a CVC coated with a
composition comprising 5-FU according to the method of Example
26.
BRIEF SUMMARY OF THE INVENTION
[0013] Briefly stated, the present invention provides compositions
and methods for preventing, reducing or inhibiting the likelihood
of infections associated with medical implants. More specifically,
within one aspect of the invention medical implants or devices are
provided which release a chemotherapeutic agent, wherein the
chemotherapeutic agent reduces, inhibits, or prevents the growth or
transmission of foreign organisms (e.g., bacteria, fungi, or
viruses) which are on or are associated with the medical device or
implant. For example, within one aspect of the invention medical
implant or devices are provided which release a fluoropyrimidine or
an analog thereof. Within various embodiments, the implant is
coated in whole or in part with a composition comprising a
fluoropyrimidine or an analog thereof.
[0014] Other aspects of the present invention provide methods for
making medical implants, comprising adapting a medical implant
(e.g., coating the implant) with a fluoropyrimidine or an analog
thereof. Within certain embodiments, the fluoropyrimidine or an
analog thereof is coated on and/or released from the medical
implant at a dosage and/or concentration which is less than the
typical dosage and/or concentration of the fluoropyrimidine or
analog thereof when used in the treatment of cancer.
[0015] A wide variety of medical implants can be generated using
the methods provided herein, including, for example, catheters
(e.g., vascular and dialysis catheters), heart valves, cardiac
pacemakers, implantable cardioverter defibrillators, grafts (e.g.,
vascular grafts), ear, nose, or throat implants, urological
implants, endotracheal or tracheostomy tubes, CNS shunts,
orthopedic implants, and ocular implants. Within certain
embodiments, the catheter (e.g., vascular and dialysis catheters),
heart valve, cardiac pacemaker, implantable cardioverter
defibrillator, graft (e.g., vascular grafts), ear, nose, or throat
implant, urological implant, endotracheal or tracheostomy tube, CNS
shunt, orthopedic implant, or ocular implant releases a
fluoropyrimide (e.g., 5-FU) or an analog thereof at a dosage and/or
concentration which is less than a typical dosage and/or
concentration which is used for the treatment of cancer.
[0016] Within further aspects of the invention, there is provided a
catheter which releases a fluoropyrimidine or an analog thereof. In
one embodiment, the catheter releases 5-FU. In other embodiments,
the catheter further comprises a polymer wherein the agent is
released from a polymer on the catheter. In certain embodiments,
the catheter has a polymer that is a polyurethane, cellulose or a
cellulose-derived polymer (e.g., nitrocellulose), or a combination
of polyurethane and cellulose or a cellulose-derived polymer. In
related embodiments, the catheter is a vascular catheter (e.g., a
central venous catheter, a peripheral intravenous catheter, an
arterial line or transducer, or a port-catheter) or a dialysis
catheter (e.g., a hemodialysis catheter or peritoneal dialysis
catheter). In still other embodiments, the catheter releases a
fluoropyrimidine or its analog that is present on the catheter at a
concentration which is less than the typical dosage and/or
concentration that is used in the treatment of cancer.
[0017] Within further aspects of the invention, there is provided a
tube which releases a fluoropyrimidine or an analog thereof. In one
embodiment, the tube releases 5-FU. In other embodiments, the tube
further comprises a polymer wherein the agent is released from a
polymer on the tube. In certain embodiments, the tube has a polymer
that is a polyurethane, cellulose or a cellulose-derived polymer
(e.g., nitrocellulose), or a combination of polyurethane and
cellulose or a cellulose-derived polymer. In related embodiments,
the tube is a drainage tube or nasogastric tube. In still other
embodiments, the tube releases a fluoropyrimidine or an analog
thereof that is present on the catheter at a concentration which is
less than the typical dosage and/or concentration that is used in
the treatment of cancer.
[0018] Within other aspects of the invention, a composition is
provided that comprises one or more polymers and a fluoropyrimidine
or an analog thereof, wherein the composition is in the form of a
coating on a medical implant, and wherein the coated medical
implant releases the fluoropyrimidine or analog thereof in an
amount effective in reducing or inhibiting bacterial infection in
an in vitro radial diffusion assay. In certain embodiments, the
composition further comprises one or more polymers, such as a
polyurethane, cellulose or a cellulose-derived polymer, a
combination of a polyurethane and cellulose or a cellulose-derived
polymer. In certain embodiments, the fluoropyrimidine is
5-fluorouracil.
[0019] Also provided methods for reducing or inhibiting infection
associated with a medical implant, comprising the step of
introducing a medical implant into a patient which has been coated
with a fluoropyrimidine or an analog thereof. In certain
embodiments, the fluoropyrimidine is 5-fluorouracil. Within further
embodiments, the medical implant further comprises a polymer, such
as a polyurethane, cellulose or a cellulose-derived polymer, or a
combination of a polyurethane and cellulose or a cellulose-derived
polymer.
[0020] These and other aspects of the present invention will become
evident upon reference to the following detailed description and
attached drawings. In addition, various references are set forth
herein which describe in more detail certain procedures or
compositions (e.g., compounds or agents and methods for making such
compounds or agents, etc.), and are therefore incorporated by
reference in their entirety. When PCT applications are referred to
it is also understood that the underlying or cited U.S.
applications are also incorporated by reference herein in their
entirety.
DETAILED DESCRIPTION OF THE INVENTION
[0021] Prior to setting forth the invention, it may be helpful to
an understanding thereof to set forth definitions of certain terms
that will be used hereinafter.
[0022] "Medical implant" refers to devices or objects that are
implanted or inserted into a body. Representative examples include
vascular catheters, dialysis catheters, drainage tubes, nasogastric
tubes, prosthetic heart valves, cardiac pacemakers, implantable
cardioverter defibrillators, vascular grafts, ear, nose, or throat
implants, urological implants, endotracheal or tracheostomy tubes,
dialysis catheters, CNS shunts, orthopedic implants, and ocular
implants.
[0023] As used herein, the term "about" or "consists essentially
of" refers to .+-.15% of any indicated structure, value, or range.
Any numerical ranges recited herein are to be understood to include
any integer within the range and, where applicable (e.g.,
concentrations), fractions thereof, such as one tenth and one
hundredth of an integer (unless otherwise indicated).
[0024] Briefly, as noted above, the present invention discloses
medical implants (as well as compositions and methods for making
medical implants) which reduce the likelihood of infections in
medical implants. More specifically, as noted above, infection is a
common complication of the implantation of foreign bodies such as
medical devices. Foreign materials provide an ideal site for
micro-organisms to attach and colonize. It is also hypothesized
that there is an impairment of host defenses to infection in the
microenvironment surrounding a foreign material. These factors make
medical implants particularly susceptible to infection and make
eradication of such an infection difficult, if not impossible, in
most cases.
[0025] Medical implant failure as a result of infection, with or
without the need to replace the implant, results in significant
morbidity, mortality and cost to the healthcare system. Since there
is a wide array of infectious agents capable of causing medical
implant infections, there exists a significant unmet need for
therapies capable of inhibiting the growth of a diverse spectrum of
bacteria and fungi on implantable devices. The present invention
meets this need by providing drugs that can be released from an
implantable device, and which have potent antimicrobial activity at
extremely low doses. Further, these agents have the added advantage
that should resistance develop to the chemotherapeutic agent, the
drug utilized in the coating would not be one which would be used
to combat the subsequent infection (i.e., if bacterial resistance
developed it would be to an agent that is not used as an
antibiotic).
[0026] Discussed in more detail below are (I) Agents; (II)
Compositions and Formulations; (III) Devices, and (IV) Clinical
Applications.
I. Agents
[0027] Briefly, a wide variety of agents (also referred to herein
as `therapeutic agents` or `drugs`) can be utilized within the
context of the present invention, either with or without a carrier
(e.g., a polymer; see section II below). Discussed in more detail
below are fluoropyrimidines (e.g., 5-FU) and their analogs.
[0028] Fluoropyrimidines and Analogs Thereof
[0029] In one aspect, the therapeutic agent is a fluoropyrimidine,
such as 5-fluorouracil, or an analog or derivative thereof,
including Carmofur, Doxifluridine, Emitefur, Tegafur, and
Floxuridine. Exemplary compounds have the structures:
##STR00001##
TABLE-US-00001 R.sub.1 R.sub.2 5-Fluorouracil H H Carmofur
C(O)NH(CH.sub.2).sub.5CH.sub.3 H Doxifluridine A.sub.1 H
Floxuridine A.sub.2 H Emitefur CH.sub.2OCH.sub.2CH.sub.3 B Tegafur
C H A.sub.1 ##STR00002## A.sub.2 ##STR00003## B ##STR00004## C
##STR00005##
[0030] "Fluoropyrimidine," as used herein, refers to a pyrimidine
analog that contains at least one F substituent at a carbon of its
pyrimidine ring struction. A "primidine analog" refers to a
compound with a pyrimidine ring structure (1,3-diazine) substituted
with one or more atoms or chemical groups or oxidized at one or
more carbons in the pyrimidine ring structure.
[0031] Other suitable fluoropyrimidines and analogs thereof include
5-FudR (5-fluoro-deoxyuridine), or an analog or derivative thereof,
including 5-iododeoxyuridine (5-IudR), 5-bromodeoxyuridine
(5-BudR), Fluorouridine triphosphate (5-FUTP), and
Fluorodeoxyuridine monophosphate (5-dFUMP). Exemplary compounds
have the structures:
##STR00006##
[0032] Other representative examples of fluoropyrimidines or their
analogs include N3-alkylated analogues of 5-fluorouracil (Kozai et
al., J. Chem. Soc., Perkin Trans. 1(19):3145-3146, 1998),
5-fluorouracil derivatives with 1,4-oxaheteroepane moieties (Gomez
et al., Tetrahedron 54(43):13295-13312, 1998), 5-fluorouracil and
nucleoside analogues (Li, Anticancer Res. 17(1A):21-27, 1997), cis-
and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van der Wilt et al.,
Br. J. Cancer 68(4):702-7, 1993), cyclopentane 5-fluorouracil
analogues (Hronowski & Szarek, Can. J. Chem. 70(4):1162-9,
1992), A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi
20(11):513-15, 1989),
N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and
5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull.
38(4):998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et
al., J. Pharmacobio-Dun. 3(9):478-81, 1980; Maehara et al.,
Chemotherapy (Basel) 34(6):484-9, 1988), B-3839 (Prajda et al., In
Vivo 2(2):151-4, 1988), uracil-1-(2-tetrahydrofuryl)-5-fluorouracil
(Anai et al., Oncology 45(3):144-7, 1988),
1-(2'-deoxy-2'-fluoro-.beta.-D-arabinofuranosyl)-5-fluorouracil
(Suzuko et al., Mol. Pharmacol. 31(3):301-6, 1987), doxifluridine
(Matuura et al., Oyo Yakuri 29(5):803-31, 1985),
5'-deoxy-5-fluorouridine (Bollag & Hartmann, Eur. J. Cancer
16(4):427-32, 1980), 1-acetyl-3-O-toluyl-5-fluorouracil (Okada,
Hiroshima J. Med. Sci. 28(1):49-66, 1979),
5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173),
N'-(2-furanidyl)-5-fluorouracil (JP 53149985) and
1-(2-tetrahydrofuryl)-5-fluorouracil (JP 52089680).
[0033] These compounds are believed to function as therapeutic
agents by serving as antimetabolites of pyrimidine.
[0034] In certain embodiment, the fluoropyrimidine is
5-fluorouracil, a compound approved for the treatment of carcinoma
and actinic or solar keratoses of the face. It is currently
approved for use as an intravenous injection, a topical solution,
and a topical cream. 5-FU is metabolized intracellularly to its
active form, fluorodeoxyuridine monophosphate (FdUMP). The active
form inhibits fungal and bacterial DNA synthesis by inhibiting the
normal production of thymidine. The mode of action of 5-FU is to
create a thymine deficiency that influences reproduction of
bacterial cells and ultimately leads to bacterial cell death.
[0035] The effects are most marked on those bacteria that replicate
more rapidly and take up 5-FU at a more rapid rate. 5-FU is cell
cycle phase-specific, affecting cells in S-phase.
[0036] As indicated in the examples below, 5-FU was shown to have
antimicrobial activity against bacterial strains commonly found
associated with catheter infections using the minimum inhibitory
concentration (MIC) test.
[0037] In certain embodiments, a fluoropyrimidine or its analog has
an MIC of less than or equal to any one of 10.sup.-4M, 10.sup.-5M,
10.sup.-6M, or, 10.sup.-7M against at least one of the following
common infecting organisms associated with medical implants, such
as catheters: Staphylococci (S. aureus, S. epidermidis, and S.
pyogenes), Enterococci (E. coli), gram negative aerobic Bacilli and
Pseudomonas aeruginosa as measured by, for example, the microtiter
broth assay described herein. Furthermore, the fluoropyrimidine or
its analog is suitable for use when coated on or otherwise
associated with a medical implant at a daily dosage less than that
10%, 5%, 1%, 0.5%, or 0.1% of a daily dosage typically used in
chemotherapeutic applications (Goodman and Gilman's The
Pharmacological Basis of Therapeutics. Editors J. G. Hardman, L. L.
Limbird. Consulting editor A. Goodman Gilman Tenth Edition.
McGraw-Hill Medical publishing division. 10th edition, 2001, 2148
pp.).
[0038] In certain embodiments, the fluoropyrimidine or its analog
is sparingly soluble in water. In certain other embodiments, the
fluoropyrimidine or its analog is soluble, slightly soluble, or
very slightly soluble in water. Water solubility is expressed in
terms of the volume of solvent (e.g., water) required to dissolve 1
gram of a drug (e.g., a fluoropyrimidine or its analog) at a
specified temperature (e.g., at 25.degree. C.) and is classified
according to the following table from Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa., 21.sup.st edition,
2006.
TABLE-US-00002 Parts of solvent needed for Descriptive terms 1 part
solute Very soluble <1 Freely soluble 1-10 Soluble 10-30
Sparingly soluble 30-100 Slightly soluble 100-1000 Very slightly
soluble 1000-10,000 Practically insoluble or insoluble
>10,000
[0039] Secondary Agents
[0040] In certain embodiments, the medical implants provided herein
may comprise more than one fluoropyrimidine or its analog. For
example, it may contain 5-fluorouracil and another fluoroprimidine
or an analog thereof. In certain embodiments, the anti-infective
medical implant may comprise, in addition to a fluoropyrimidine or
its analog (e.g., 5-fluorouracil), one or more other
chemotherapeutic agents that have anti-infective activities when
used at concentrations lower than those for chemotherapy. In
certain embodiments, the anti-infective medical implant may
comprise, in addition to a fluoropyrimidine or its analog, one or
more anti-infective agents (e.g., antibiotics) that are not
chemotherapeutic agents. In certain embodiments, the anti-infective
medical implant may comprise, in addition to a fluoropyrimidine or
its analog, one or more active agents other than anti-infective
agents (e.g., anti-thromobotic agents and anti-platelet agents) to
help minimize additional complications (e.g., venous thrombosis)
associated with medical implants.
Chemotherapeutics as Secondary Anti-Infective Agents
[0041] Chemotherapeutic agents other than fluoropyrimidines or
their analogs may be used as anti-infective agents in combination
with fluoropyrimidines or their analogs to provide anti-infective
medical implants. Exemplary classes of chemotherapeutics useful in
combination with fluoropyrimidines or their analogs are
anthracyclins, folic acid antagonists, podophyllotoxins,
camptothecins, hydroxyureas, and platinum complexes.
[0042] In certain embodiments, the secondary anti-infective agent
is an anthracyclin. Exemplary anthracylins include, but are not
limited to, doxorubicin, daunorubicin, idarubicin, epirubicin,
pirarubicin, zorubicin, carubicin, anthramycin, mitoxantrone,
menogaril, nogalamycin, aclacinomycin A, olivomycin A, chromomycin
A.sub.3, and plicamycin.
[0043] In certain embodiments, the second anti-infective agent is a
folic acid antagonist. Exemplary folic acid antagonists include,
but are not limited to, methotrexate or derivatives or analogs
thereof, such as edatrexate, trimetrexate, raltitrexed, piritrexim,
denopterin, tomudex, and pteropterin.
[0044] In certain embodiments, the second anti-infective agent is a
podophyllotoxin. Exemplary podophyllotoxin include, but are not
limited to, etoposide or teniposide.
[0045] In certain embodiments, the second anti-infective agent is a
camptothecin or an analog or derivative thereof. Exemplary
camptothecin compounds include, but are not limited to, topotecan,
irinotecan (CPT-11), 9-aminocamptothecin,
21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin,
SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin.
[0046] In certain embodiments, the second anti-infective agent is a
hydroxyurea. Hydroxyureas have the following general structure:
##STR00007##
[0047] Suitable hydroxyureas are disclosed in, for example, U.S.
Pat. No. 6,080,874, wherein R.sub.1 is:
##STR00008##
and R.sub.2 is an alkyl group having 1-4 carbons and R.sub.3 is one
of H, acyl, methyl, ethyl, and mixtures thereof, such as a
methylether.
[0048] Other suitable hydroxyureas are disclosed in, e.g., U.S.
Pat. No. 5,665,768, wherein R.sub.1 is a cycloalkenyl group, for
example
N-[3-[5-(4-fluorophenylthio)-furyl]-2-cyclopenten-1-yl]N-hydroxyurea;
R.sub.2 is H or an alkyl group having 1 to 4 carbons and R.sub.3 is
H; X is H or a cation.
[0049] Other suitable hydroxyureas are disclosed in, e.g., U.S.
Pat. No. 4,299,778, wherein R.sub.1 is a phenyl group substituted
with one or more fluorine atoms; R.sub.2 is a cyclopropyl group;
and R.sub.3 and X is H.
[0050] Other suitable hydroxyureas are disclosed in, e.g., U.S.
Pat. No. 5,066,658, wherein R.sub.2 and R.sub.3 together with the
adjacent nitrogen form:
##STR00009##
wherein m is 1 or 2, n is 0-2 and Y is an alkyl group.
[0051] In certain embodiments, the hydroxyurea has the
structure:
##STR00010##
[0052] In certain embodiments, the second anti-infective agent is a
platinum compound. Exemplary platinum compounds include, but are
not limited to, cisplatin, carboplatin, oxaliplatin, and
miboplatin.
[0053] Other Secondary Anti-Infective Agents
[0054] In addition to the above-described chemotherapeutics as
secondary anti-infective agents, other anti-infective agents may
also be used in combination with a fluoropyrimidine or its analog
to provide anti-infective medical implants. Such anti-infective
agents may be antibacterial or antifungal agents. Exemplary
antibacterial agents include antibiotics (i.e., agents that destroy
microorganisms internally), agents effective against gram positive
bacteria, and agents effective against gram negative bacteria,
disinfectants (i.e., agents that destroy microorganism found on
nonliving objects), and antiseptics (i.e., agents that kill or
inhibit the growth of microorganisms on the external surfaces of
the body). Antiseptics include germicides (i.e., agents capable of
destroying microbes) and bacteriostatics (i.e., agents capable of
preventing or inhibiting bacterial growth).
[0055] Anti-infective agents that may be used in combination with a
fluoropyrimidine or its analog include, but are not limited to,
silver compounds (e.g., silver chloride, silver nitrate, silver
oxide), silver ions, silver particles, iodine, povidone/iodine,
chlorhexidine, 2-p-sulfanilyanilinoethanol, 4,4'-sulfinyldianiline,
4-sulfanilamidosalicylic acid, acediasulfone, acetosulfone,
amikacin, amoxicillin, amphotericin B, ampicillin, apalcillin,
apicycline, apramycin, arbekacin, aspoxicillin, azidamfenicol,
azithromycin, aztreonam, bacitracin, bambermycin(s), biapenem,
brodimoprim, butirosin, capreomycin, carbenicillin, carbomycin,
carumonam, cefadroxil, cefamandole, cefatrizine, cefbuperazone,
cefclidin, cefdinir, cefditoren, cefepime, cefetamet, cefixime,
cefinenoxime, cefminox, cefodizime, cefonicid, cefoperazone,
ceforanide, cefotaxime, cefotetan, cefotiam, cefozopran,
cefpimizole, cefpiramide, cefpirome, cefprozil, cefroxadine,
ceftazidime, cefteram, ceftibuten, ceftriaxone, cefuzonam,
cephalexin, cephaloglycin, cephalosporin C, cephradine,
chloramphenicol, chlortetracycline, ciprofloxacin, clarithromycin,
clinafloxacin, clindamycin, clomocycline, colistin, cyclacillin,
dapsone, demeclocycline, diathymosulfone, dibekacin,
dihydrostreptomycin, dirithromycin, doxycycline, enoxacin,
enviomycin, epicillin, erythromycin, flomoxef, fortimicin(s),
gentamicin(s), glucosulfone solasulfone, gramicidin S,
gramicidin(s), grepafloxacin, guamecycline, hetacillin, imipenem,
isepamicin, josamycin, kanamycin(s), leucomycin(s), lincomycin,
lomefloxacin, lucensomycin, lymecycline, meclocycline, meropenem,
methacycline, micronomicin, midecamycin(s), minocycline,
moxalactam, mupirocin, nadifloxacin, natamycin, neomycin,
netilmicin, norfloxacin, oleandomycin, oxytetracycline,
p-sulfanilylbenzylamine, panipenem, paromomycin, pazufloxacin,
penicillin N, pipacycline, pipemidic acid, polymyxin, primycin,
quinacillin, ribostamycin, rifamide, rifampin, rifamycin SV,
rifapentine, rifaximin, ristocetin, ritipenem, rokitamycin,
rolitetracycline, rosaramycin, roxithromycin, salazosulfadimidine,
sancycline, sisomicin, sparfloxacin, spectinomycin, spiramycin,
streptomycin, succisulfone, sulfachrysoidine, sulfaloxic acid,
sulfamidochrysoidine, sulfanilic acid, sulfoxone, teicoplanin,
temafloxacin, temocillin, tetracycline, tetroxoprim, thiamphenicol,
thiazolsulfone, thiostrepton, ticarcillin, tigemonam, tobramycin,
tosufloxacin, trimethoprim, trospectomycin, trovafloxacin,
tuberactinomycin, vancomycin, azaserine, candicidin(s),
chlorphenesin, dermostatin(s), filipin, fungichromin, mepartricin,
nystatin, oligomycin(s), ciproflaxacin, norfloxacin, ofloxacin,
pefloxacin, enoxacin, rosoxacin, amifloxacin, fleroxacin,
temafloaxcin, lomefloxacin, perimycin A or tubercidin, and the
like.
[0056] The fluoropyrimidine or its analog may be further combined
with one or more of the antibiotics known to combat growth of gram
negative bacteria. Antibiotics that are useful against gram
negative bacteria include amoxicillin, ampicillin, azithromycin,
aztreonam, cefepime, cefixime, ceftriaxone, cephalosporin C,
chloramphenicol, ciprofloxacin, clindamycin, doxycycline,
erythromycin, imipenem, meropenem, rifampin, spectinomycin,
streptomycin, tetracycline, tobramycin, and trimethoprim.
[0057] In certain embodiments, the fluoropyrimdine or its analog
may be combined with one or more disinfecting agents, including but
are not limited to, AgNO.sub.3 (silver nitrate), BAKCl
(benzalkonium chloride), BenthonCl (benzethonium chloride),
BenzChlPheno (benzyl-p-chlorophenol), Bronopol
(2-bromo-2-nitro-1,3-propanediol), CetPyrCl (cetylpyridinium
chloride), Chlorhexidine
(1,1'-hexamethylenebis[-(p-chlorophenyl)biguanide]), Proxel
(1,2-Benzisothiazolin-3-one), Triclosan
(5-Chloro-2-(2,4-dichlorophenoxy)phenol), and Vantocil
(poly(hexamethylene biguanide) hydrochloride).
[0058] In certain embodiments, the fluoropyrimidine or its analog
may be combined with one or more antibiotic agents, including but
are not limited to, bacitracin, Cephalasporin C, Miconizole
Nitrate, Neomycin Sulfate, Norfloxacin, Phosphomycin, Polymyxin B
Sufate, and Rifampin.
[0059] In certain embodiments, the fluoropyrimidine or its analog
may be combined with a combination of two disinfecting agents, a
combination of two antibiotic agents, or a combination of a
disinfecting agent and an antibiotic agent. Such a combination
includes but is not limited to, the combination of AgNO.sub.3 and
Triclosan, Bronopol and BAKCl, Bronopol and HBAK (heparin
benzalkonium complex), Bronopol and Triclosan, Bronopol and
Vantocil, and Triclosan and Phosphomycin.
[0060] In certain embodiments, the fluoropyrimidine or its analog
may be combined with an antiseptic agent. Useful antiseptic agents
include but are not limited to alcohols, such as ethanol,
1-propanol, and isopropanol; aldehydes, such as glutaraldehyde,
formaldehyde, formaldehyde-releasing agents, o-phthalaldehyde;
anilides, such as Triclocarban (TCC; 3,4,4'-triclorocarbanilide);
biguanides, such as chlorhexidine, poly(hexamethylene
biguanide)hydrochloride; bronopol, such as
2-bromo-2-nitro-1,3-propanediol, diamidines, such as propamidine
(4,4-diaminodiphenoxypropane), dibromopropamidine,
(2,2-dobromo-4,4-diamidinodiphenoxypropane); halogen-releasing
agents, such as Sodium hypochlorite, chlorine dioxide, sodium
dichloroisocyanurate; silver compounds, such as silver nitrate,
silver sulfadiazine; peroxygens, such as hydrogen peroxide,
peracetic acid; phenols, such as phenol, o-phenylphenol,
benzyl-p-chlorophenol, chlorocresol; bis-phenols, such as
triclosan, hexachlorophene, and quaternary compounds, such as
benzalkonium chloride, benzethonium chloride, cetylpyridinium
chloride, cetyltrimethylammonium bromide, cetylpyridinium
chloride.
[0061] In certain embodiments, the fluoropyrimidine or its analog
may be combined with an antifungal agent. Useful antifungal agents
include but are not limited to Amphoteracin B, Micafungin,
Caspofungin (Cancidas, MK-0991), Miconazole, V-echinocandin,
Nystatin, Fluconazole (Diflucan), Posaconazole, Flucytosine
(Ancobon), Ravuconazole, Griseofulvin, Terbinafine, Hamycin,
Voriconazole (Vfend), Itraconazole (Sporanox), Ketoconazole.
Further examples of anti-infective agents that may be used in
combination with a fluoropyrimidine or its analog include
quaternary amines and other biocides.
[0062] Other Secondary Agents
[0063] The anti-infective medical implants may comprise active
agents other than anti-infective agents. Depending on the intended
use of the medical implants, additional active agents may be
desirable. For example, thrombosis and thrombophlebitis are common
complications associated with implantation of vascular implants
such as vascular catheters. Therefore, vascular implants may
include, in addition to a fluoropyrimidine or its analog (with or
without a secondary anti-infective agent), an antithrombotic agent
(i.e., agents used to treat or prevent thrombosis). Exemplary
classes of antithrombotics include antithrombogenics,
antiaggregants, thrombolytics, anticoagulants, antiplatelet agents,
and other antithrombotics. These agents may be administered alone
or in combination.
[0064] In exemplary embodiments, the antithrombotic is a
thrombolytic, i.e., an agent which dissolves blood clots.
Thrombolytics include, for example, enzymes such as brinase;
plasminogen activators; e.g., t-PA (alteplase, activase), reteplase
(retavase), tenecteplase (TNKase), anistreplase (eminase), plamin,
streptokinase (kabikinase, streptase), single chain urokinase,
urokinase (abbokinase), and saruplase; and serine endopeptidases,
e.g., ancrod, drotrecogin alfa/protein C, and fibrinolysin.
[0065] In other exemplary embodiments, the antithrombotic is an
anticoagulant, i.e., an agent which prevents coagulation.
Anticoagulants include, for example, Vitamin K antagonists,
heparin, derivatives, heparin related compounds and direct thrombin
inhibitors.
[0066] Examples of Vitamin K antagonists include acenocoumarol,
clorindione, coumatetralyl, dicumarol (dicoumarol), diphenadione,
ethyl biscoumacetate, phenprocoumon, phenindione, tioclomarol and
warfarin (coumadin).
[0067] Heparin, derivative substances and related compounds of
heparin, may be referenced to as the heparin group. Examples of the
heparin group agents include antithrombin III, danaparoid, heparin,
sulodexide, and low molecular weight heparin (LMWHs), e.g.,
bemiparin, dalteparin, enoxaparin, nadroparin, parnaparin,
reviparin, and tinzaparin. A related agent is fondaparinux, a
synthetic sugar composed of the five sugars (pentasaccharide) in
heparin that bind to antithrombin.
[0068] Other heparin related compounds include heparin reacted with
quaternary ammonium compounds, e.g., benzalkonium chloride,
tridodecylmethylammonium chloride, cetylpyridinium chloride,
benzyldimethylstearylammonium chloride, benzylcetyldimethylammonium
chloride. See, for example, U.S. Pat. Nos. 5,525,348 and 5,069,899,
issued to Whitbourne, et al., which are hereby incorporated by
reference in their entirety.
[0069] Examples of direct thrombin inhibitors include argatroban,
bivalirudin, dabigatran, desirudin, hirudin, recombinant hirudin,
lepirudin, melagatran and ximelagatran (EXANTA.RTM.).
[0070] In other exemplary embodiments, the antithrombotic is an
antiplatelet agent, i.e., an agent which decreases platelet
aggregation and inhibit thrombus formation. Examples of
antiplatelet agents include cyclooxygenase inhibitors,
acetylsalicylic acid (aspirin), adenosine diphosphate (ADP)
receptor inhibitors, clopidogrel (Plavix), ticlopidine (Ticlid),
phosphodiesterase inhibitors, cilostazol (Pletal), adenosine
reuptake inhibitors, prostacyclins such as epoprostenol, and
analogues, and dipyridamole (Persantine), dextrans, sulfinpyrazone
(Anturane), and glycoprotein IIb/IIIa inhibitors including,
monoclonal antibodies and murine-human chimeric antibodies such as
abciximab (ReoPro), synthetic peptides such as eptifibatide
(Integrilin), and synthetic non-peptides such as tirofiban
(Aggrastat). Other examples include aloxiprin, ditazole,
carbasalate calcium, cloricromen, indobufen, picotamide, prasugrel,
triflusal and prostaglandin analogues, e.g., beraprost,
prostacyclin, iloprost, and treprostinil.
[0071] Examples of other antithrombotics include defibrotide,
dermatan sulfate, rivaroxaban, aminocaproic acid, cilastagel,
vapiprost, angiopeptin, thromboxane inhibitors anti-thrombin and
synthetic antithrombins.
[0072] In certain embodiments, anti-inflammatory agents may be
included in anti-infective medical implants provided herein.
Exemplary anti-inflammatory agents include dexamethasone,
cortisone, fludrocortisone, prednisone, prednisolone,
6.alpha.-methylprednisolone, triamcinolone, betamethasone, and
aspirin.
[0073] In certain embodiments, immunomodulatory agents may be
included in anti-infective medical implants provided herein.
Exemplary immunomodulatory agents include rapamycin, everolimus,
ABT-578, azathioprine azithromycin, analogues of rapamycin,
including tacrolimus and derivatives thereof (e.g., EP 0184162B1
and those described in U.S. Pat. No. 6,258,823) and everolimus and
derivatives thereof (e.g., U.S. Pat. No. 5,665,772).
[0074] In certain embodiments, ant-fibrotic agents may be included
in anti-infective medical implants provided herein. Exemplary
anti-fibrotic agents include paclitaxel, docetaxol, rapamycin,
everorlimus, tacrolimus, epothilone A or B, discodermolide,
deuterium oxide (D.sub.2O), hexylene glycol, tubercidin, LY290181,
aluminum fluoride, ethylene glycol bis-(succinimidylsuccinate),
glycine ethyl ester, campothecin, or combinations thereof.
Additional examples of anti-fibrotic agents may be found in U.S.
Patent Application Publication No. 20050208095 and PCT Application
Publication No. WO 2006/135479. The sections related to
anti-fibrotic agents in these publications are incorporated herein
by reference.
II. Compositions and Formulations
[0075] As noted above, therapeutic agents described herein may be
formulated in a variety of manners, and thus may additionally
comprise a carrier. In this regard, a wide variety of carriers may
be selected of either polymeric or non-polymeric origin. The
polymers and non-polymer based carriers and formulations which are
discussed in more detail below are provided merely by way of
example, not by way of limitation.
[0076] Within one embodiment of the invention a wide variety of
polymers can be utilized to contain and/or deliver one or more of
the agents discussed above, including for example both
biodegradable and non-biodegradable compositions. Representative
examples of biodegradable compositions include albumin, collagen,
gelatin, chitosan, hyaluronic acid, starch, cellulose and
derivatives thereof (e.g., methylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose
acetate phthalate, cellulose acetate succinate,
hydroxypropylmethylcellulose phthalate), alginates, casein,
dextrans, polysaccharides, fibrinogen, poly(L-lactide),
poly(D,L-lactide), poly(L-lactide-co-glycolide),
poly(D,L-lactide-co-glycolide), poly(glycolide), poly(trimethylene
carbonate), poly(hydroxyvalerate), poly(hydroxybutyrate),
poly(caprolactone), poly(alkylcarbonate) and poly(orthoesters),
polyesters, poly(hydroxyvaleric acid), polydioxanone, poly(malic
acid), poly(tartronic acid), polyanhydrides, polyphosphazenes,
poly(amino acids), copolymers of such polymers and blends of such
polymers (see generally, Ilium, L., Davids, S. S. (eds.) "Polymers
in Controlled Drug Delivery" Wright, Bristol, 1987; Arshady, J.
Controlled Release 17:1-22, 1991; Pitt, Int. J. Phar. 59:173-196,
1990; Holland et al., J. Controlled Release 4:155-0180, 1986).
Representative examples of nondegradable polymers include
poly(ethylene-co-vinyl acetate) ("EVA") copolymers, silicone
rubber, acrylic polymers (e.g., polyacrylic acid, polymethylacrylic
acid, poly(hydroxyethylmethacrylate), polymethylmethacrylate,
polyalkylcyanoacrylate), polyethylene, polyproplene, polyamides
(e.g., nylon 6,6), polyurethane (e.g., poly(ester urethanes),
poly(ether urethanes), poly(ester-urea), poly(carbonate
urethanes)), polyethers (e.g., poly(ethylene oxide), poly(propylene
oxide), Pluronics and poly(tetramethylene glycol)) and vinyl
polymers [e.g., polyvinylpyrrolidone, poly(vinyl alcohol),
poly(vinyl acetate phthalate)]. Polymers may also be developed
which are either anionic (e.g., alginate, carrageenin,
carboxymethyl cellulose and poly(acrylic acid), or cationic (e.g.,
chitosan, poly-L-lysine, polyethylenimine, and poly (allyl amine))
(see generally, Dunn et al., J. Applied Polymer Sci. 50:353-365,
1993; Cascone et al., J. Materials Sci.: Materials in Medicine
5:770-774, 1994; Shiraishi et al., Biol. Pharm. Bull.
16(11):1164-1168, 1993; Thacharodi and Rao, Int'l J. Pharm.
120:115-118, 1995; Miyazaki et al., Int'l J. Pharm. 118:257-263,
1995). Particularly preferred polymeric carriers include
poly(ethylene-co-vinyl acetate), polyurethane, acid,
poly(caprolactone), poly(valerolactone), polyanhydrides, copolymers
of poly(caprolactone) or poly(lactic acid) with a polyethylene
glycol (e.g., MePEG), and blends thereof.
[0077] Other representative polymers include carboxylic polymers,
polyacetates, polyacrylamides, polycarbonates, polyethers,
polyesters, polyethylenes, polyvinylbutyrals, polysilanes,
polyureas, polyurethanes, polyoxides, polystyrenes, polysulfides,
polysulfones, polysulfonides, polyvinylhalides, pyrrolidones,
rubbers, thermal-setting polymers, cross-linkable acrylic and
methacrylic polymers, ethylene acrylic acid copolymers, styrene
acrylic copolymers, vinyl acetate polymers and copolymers, vinyl
acetal polymers and copolymers, epoxy, melamine, other amino
resins, phenolic polymers, and copolymers thereof, water-insoluble
cellulose ester polymers (including cellulose acetate propionate,
cellulose acetate, cellulose acetate butyrate, cellulose nitrate,
cellulose acetate phthalate, and mixtures thereof),
polyvinylpyrrolidone, polyethylene glycols, polyethylene oxide,
polyvinyl alcohol, polyethers, polysaccharides, hydrophilic
polyurethane, polyhydroxyacrylate, dextran, xanthan, hydroxypropyl
cellulose, methyl cellulose, and homopolymers and copolymers of
N-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinyl
caprolactam, other vinyl compounds having polar pendant groups,
acrylate and methacrylate having hydrophilic esterifying groups,
hydroxyacrylate, and acrylic acid, and combinations thereof;
cellulose esters and ethers, ethyl cellulose, hydroxyethyl
cellulose, cellulose nitrate, cellulose acetate, cellulose acetate
butyrate, cellulose acetate propionate, polyurethane, polyacrylate,
natural and synthetic elastomers, rubber, acetal, nylon, polyester,
styrene polybutadiene, acrylic resin, polyvinylidene chloride,
polycarbonate, homopolymers and copolymers of vinyl compounds,
polyvinylchloride, polyvinylchloride acetate.
[0078] Representative examples of patents relating to polymers and
their preparation include PCT Publication Nos. WO72827, 98/12243,
98/19713, 98/41154, 99/07417, 00/33764, 00/21842, 00/09190,
00/09088, 00/09087, 2001/17575 and 2001/15526 (as well as their
corresponding U.S. applications), and U.S. Pat. Nos. 4,500,676,
4,582,865, 4,629,623, 4,636,524, 4,713,448, 4,795,741, 4,913,743,
5,069,899, 5,099,013, 5,128,326, 5,143,724, 5,153,174, 5,246,698,
5,266,563, 5,399,351, 5,525,348, 5,800,412, 5,837,226, 5,942,555,
5,997,517, 6,007,833, 6,071,447, 6,090,995, 6,099,563, 6,106,473,
6,110,483, 6,121,027, 6,156,345, 6,179,817, 6,197,051, 6,214,901,
6,335,029, 6,344,035, which, as noted above, are all incorporated
by reference in their entirety.
[0079] Polymers can be fashioned in a variety of forms, with
desired release characteristics and/or with specific desired
properties. For example, polymers can be fashioned to release a
therapeutic agent upon exposure to a specific triggering event such
as pH (see, e.g., Heller et al., "Chemically Self-Regulated Drug
Delivery Systems," in Polymers in Medicine III, Elsevier Science
Publishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J.
Applied Polymer Sci. 48:343-354, 1993; Dong et al., J. Controlled
Release 19:171-178, 1992; Dong and Hoffman, J. Controlled Release
15:141-152, 1991; Kim et al., J. Controlled Release 28:143-152,
1994; Cornejo-Bravo et al., J. Controlled Release 33:223-229, 1995;
Wu and Lee, Pharm. Res. 10(10):1544-1547, 1993; Serres et al.,
Pharm. Res. 13(2):196-201, 1996; Peppas, "Fundamentals of pH- and
Temperature-Sensitive Delivery Systems," in Gurny et al. (eds.),
Pulsatile Drug Delivery, Wissenschaftliche Verlagsgesellschaft mbH,
Stuttgart, 1993, pp. 41-55; Doelker, "Cellulose Derivatives," 1993,
in Peppas and Langer (eds.), Biopolymers I, Springer-Verlag,
Berlin). Representative examples of pH-sensitive polymers include
poly(acrylic acid)-based polymers and derivatives (including, for
example, homopolymers such as poly(aminocarboxylic acid),
poly(acrylic acid), poly(methyl acrylic acid), copolymers of such
homopolymers, and copolymers of poly(acrylic acid) and
acrylmonomers such as those discussed above). Other pH sensitive
polymers include polysaccharides such as carboxymethyl cellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropyl-methylcellulose acetate succinate, cellulose acetate
trimellilate, chitosan and alginates. Yet other pH sensitive
polymers include any mixture of a pH sensitive polymer and a water
soluble polymer.
[0080] Likewise, polymers can be fashioned which are temperature
sensitive (see, e.g., Chen et al., "Novel Hydrogels of a
Temperature-Sensitive Pluronic Grafted to a Bioadhesive Polyacrylic
Acid Backbone for Vaginal Drug Delivery," in Proceed. Intern. Symp.
Control. Rel. Bioact. Mater. 22:167-168, Controlled Release
Society, Inc., 1995; Okano, "Molecular Design of Stimuli-Responsive
Hydrogels for Temporal Controlled Drug Delivery," in Proceed.
Intern. Symp. Control. Rel. Bioact. Mater. 22:111-112, Controlled
Release Society, Inc., 1995; Johnston et al., Pharm. Res.
9(3):425-433, 1992; Tung, Int'l J. Pharm. 107:85-90, 1994; Harsh
and Gehrke, J. Controlled Release 17:175-186, 1991; Bae et al.,
Pharm. Res. 8(4):531-537, 1991; Dinarvand and D'Emanuele, J.
Controlled Release 36:221-227, 1995; Yu and Grainger, "Novel
Thermo-sensitive Amphiphilic Gels: Poly
N-isopropylacrylamide-co-sodium acrylate-co-n-N-alkylacrylamide
Network Synthesis and Physicochemical Characterization," Dept. of
Chemical & Biological Sci., Oregon Graduate Institute of
Science & Technology, Beaverton, Oreg., pp. 820-821; Zhou and
Smid, "Physical Hydrogels of Associative Star Polymers," Polymer
Research Institute, Dept. of Chemistry, College of Environmental
Science and Forestry, State Univ. of New York, Syracuse, N.Y., pp.
822-823; Hoffman et al., "Characterizing Pore Sizes and Water
`Structure` in Stimuli-Responsive Hydrogels," Center for
Bioengineering, Univ. of Washington, Seattle, Wash., p. 828; Yu and
Grainger, "Thermo-sensitive Swelling Behavior in Crosslinked
N-isopropylacrylamide Networks: Cationic, Anionic and Ampholytic
Hydrogels," Dept. of Chemical & Biological Sci., Oregon
Graduate Institute of Science & Technology, Beaverton, Oreg.,
pp. 829-830; Kim et al., Pharm. Res. 9(3):283-290, 1992; Bae et
al., Pharm. Res. 8(5):624-628, 1991; Kono et al., J. Controlled
Release 30:69-75, 1994; Yoshida et al., J. Controlled Release
32:97-102, 1994; Okano et al., J. Controlled Release 36:125-133,
1995; Chun and Kim, J. Controlled Release 38:39-47, 1996;
D'Emanuele and Dinarvand, Int'l J. Pharm. 118:237-242, 1995; Katono
et al., J. Controlled Release 16:215-228, 1991; Hoffman, "Thermally
Reversible Hydrogels Containing Biologically Active Species," in
Migliaresi et al. (eds.), Polymers in Medicine III, Elsevier
Science Publishers B.V., Amsterdam, 1988, pp. 161-167; Hoffman,
"Applications of Thermally Reversible Polymers and Hydrogels in
Therapeutics and Diagnostics," in Third International Symposium on
Recent Advances in Drug Delivery Systems, Salt Lake City, Utah,
Feb. 24-27, 1987, pp. 297-305; Gutowska et al., J. Controlled
Release 22:95-104, 1992; Palasis and Gehrke, J. Controlled Release
18:1-12, 1992; Paavola et al., Pharm. Res. 12(12):1997-2002,
1995).
[0081] Representative examples of thermogelling polymers include
homopolymers such as poly(N-methyl-N-n-propylacrylamide),
poly(N-n-propylacrylamide), poly(N-methyl-N-isopropylacrylamide),
poly(N-n-propylmethacrylamide), poly(N-isopropylacrylamide),
poly(N,n-diethylacrylamide), poly(N-isopropylmethacrylamide),
poly(N-cyclopropylacrylamide), poly(N-ethylmethyacrylamide),
poly(N-methyl-N-ethylacrylamide), poly(N-cyclopropylmethacrylamide)
and poly(N-ethylacrylamide). Moreover thermogelling polymers may be
made by preparing copolymers between (among) monomers of the above,
or by combining such homopolymers with other water soluble polymers
such as acrylmonomers (e.g., acrylic acid and derivatives thereof
such as methylacrylic acid, acrylate and derivatives thereof such
as butyl methacrylate, acrylamide, and N-n-butyl acrylamide).
[0082] Other representative examples of thermogelling cellulose
ether derivatives such as hydroxypropyl cellulose, methyl
cellulose, hydroxypropylmethyl cellulose, ethylhydroxyethyl
cellulose, and Pluronics, such as F-127.
[0083] A wide variety of forms may be fashioned by the polymers of
the present invention, including for example, rod-shaped devices,
pellets, slabs, particulates, micelles, films, molds, sutures,
threads, gels, creams, ointments, sprays or capsules (see, e.g.,
Goodell et al., Am. J. Hosp. Pharm. 43:1454-1461, 1986; Langer et
al., "Controlled release of macromolecules from polymers", in
Biomedical Polymers, Polymeric Materials and Pharmaceuticals for
Biomedical Use, Goldberg, E. P., Nakagim, A. (eds.) Academic Press,
pp. 113-137, 1980; Rhine et al., J. Pharm. Sci. 69:265-270, 1980;
Brown et al., J. Pharm. Sci. 72:1181-1185, 1983; and Bawa et al.,
J. Controlled Release 1:259-267, 1985). Agents may be incorporated
by dissolution in the polymer, occlusion in the matrices of the
polymer, bound by covalent linkages, or encapsulated in
microcapsules. Within certain preferred embodiments of the
invention, therapeutic compositions are provided in non-capsular
formulations, such as coatings microspheres (ranging from
nanometers to micrometers in size), pastes, threads or sutures of
various size, films and sprays.
[0084] Other compounds which can be utilized to carry and/or
deliver the agents provided herein include vitamin-based
compositions (e.g., based on vitamins A, D, E and/or K, see, e.g.,
PCT publication Nos. WO 98/30205 and WO 00/71163) and liposomes
(see, U.S. Pat. Nos. 5,534,499, 5,683,715, 5,776,485, 5,882,679,
6,143,321, 6,146,659, 6,200,598, and PCT Publication Nos. WO
98/34597, WO 99/65466, WO 00/01366, WO 00/53231, WO 99/35162, WO
00/117508, WO 00/125223, WO 00/149,268, WO 00/1565438, and WO
00/158455).
[0085] Preferably, therapeutic compositions of the present
invention are fashioned in a manner appropriate to the intended
use. Within certain aspects of the present invention, the
therapeutic composition should be biocompatible, and release one or
more agents over a period of several days to months, such as for at
least 2, 3, 4, 5, 6 or 7 days; 2, 3 or 4 weeks; or 2, 3, 4, 5, 6,
7, 8, 9, 10, 11, or 12 months. Further, therapeutic compositions of
the present invention should preferably be stable for several
months and capable of being produced, and maintained under sterile
conditions.
[0086] Within certain aspects of the present invention, therapeutic
compositions may be fashioned in any size ranging from 50 nm to 500
.mu.m, depending upon the particular use. Alternatively, such
compositions may also be readily applied as a "spray" which
solidifies into a film or coating. Such sprays may be prepared from
microspheres of a wide array of sizes, including for example, from
0.1 .mu.m to 9 .mu.m, from 10 .mu.m to 30 .mu.m and from 30 .mu.m
to 100 .mu.m.
[0087] Therapeutic compositions of the present invention may also
be prepared in a variety of "paste" or gel forms. For example,
within one embodiment of the invention, therapeutic compositions
are provided which are liquid at one temperature (e.g., temperature
greater than 37.degree. C.) and solid or semi-solid at another
temperature (e.g., ambient body temperature, or any temperature
lower than 37.degree. C.). Also included are polymers, such as
Pluronic F-127, which are liquid at a low temperature (e.g.,
4.degree. C.) and a gel at body temperature. Such "thermopastes"
may be readily made given the disclosure provided herein.
[0088] Within yet other aspects of the invention, the therapeutic
compositions of the present invention may be formed as a film.
Preferably, such films are generally less than 5, 4, 3, 2 or 1 mm
thick, more preferably less than 0.75 mm or 0.5 mm thick, and most
preferably less than 500 .mu.m. Such films are preferably flexible
with a good tensile strength (e.g., greater than 50, preferably
greater than 100, and more preferably greater than 150 or 200
N/cm.sup.2), good adhesive properties (i.e., readily adheres to
moist or wet surfaces), and have controlled permeability.
[0089] Within certain embodiments of the invention, the therapeutic
compositions can also comprise additional ingredients such as
surfactants (e.g., Pluronics such as F-127, L-122, L-92, L-81, and
L-61).
[0090] Within further aspects of the present invention, polymers
are provided which are adapted to contain and release a hydrophobic
compound, the carrier containing the hydrophobic compound in
combination with a carbohydrate, protein or polypeptide. Within
certain embodiments, the polymeric carrier contains or comprises
regions, pockets or granules of one or more hydrophobic compounds.
For example, within one embodiment of the invention, hydrophobic
compounds may be incorporated within a matrix which contains the
hydrophobic compound, followed by incorporation of the matrix
within the polymeric carrier. A variety of matrices can be utilized
in this regard, including for example, carbohydrates and
polysaccharides, such as starch, cellulose, dextran,
methylcellulose, and hyaluronic acid, proteins or polypeptides such
as albumin, collagen and gelatin. Within alternative embodiments,
hydrophobic compounds may be contained within a hydrophobic core,
and this core contained within a hydrophilic shell.
[0091] Other carriers that may likewise be utilized to contain and
deliver the agents described herein include: hydroxypropyl
.beta.-cyclodextrin (Cserhati and Hollo, Int. J. Pharm. 108:69-75,
1994), liposomes (see, e.g., Sharma et al., Cancer Res.
53:5877-5881, 1993; Sharma and Straubinger, Pharm. Res.
11(60):889-896, 1994; WO 93/18751; U.S. Pat. No. 5,242,073),
liposome/gel (WO 94/26254), nanocapsules (Bartoli et al., J.
Microencapsulation 7(2):191-197, 1990), micelles (Alkan-Onyuksel et
al., Pharm. Res. 11(2):206-212, 1994), implants (Jampel et al.,
Invest. Ophthalm. Vis. Science 34(11): 3076-3083, 1993; Walter et
al., Cancer Res. 54:22017-2212, 1994), nanoparticles (Violante and
Lanzafame PAACR), nanoparticles--modified (U.S. Pat. No.
5,145,684), nanoparticles (surface modified) (U.S. Pat. No.
5,399,363), taxol emulsion/solution (U.S. Pat. No. 5,407,683),
micelle (surfactant) (U.S. Pat. No. 5,403,858), synthetic
phospholipid compounds (U.S. Pat. No. 4,534,899), gas borne
dispersion (U.S. Pat. No. 5,301,664), foam, spray, gel, lotion,
cream, ointment, dispersed vesicles, particles or droplets solid-
or liquid-aerosols, microemulsions (U.S. Pat. No. 5,330,756),
polymeric shell (nano- and micro-capsule) (U.S. Pat. No.
5,439,686), taxoid-based compositions in a surface-active agent
(U.S. Pat. No. 5,438,072), liquid emulsions (Tarr et al., Pharm
Res. 4:62-165, 1987), nanospheres (Hagan et al., Proc. Intern.
Symp. Control Rel. Bioact. Mater. 22, 1995; Kwon et al., Pharm Res.
12(2):192-195; Kwon et al., Pharm Res. 10(7):970-974; Yokoyama et
al., J. Contr. Rel. 32:269-277, 1994; Gref et al., Science
263:1600-1603, 1994; Bazile et al., J. Pharm. Sci. 84:493-498,
1994) and implants (U.S. Pat. No. 4,882,168).
[0092] The agents provided herein can also be formulated as a
sterile composition (e.g., by treating the composition with
ethylene oxide or by irradiation), packaged with preservatives or
other suitable excipients suitable for administration to humans.
Similarly, the devices provided herein (e.g., coated catheter) may
be sterilized and prepared suitable for implantation into
humans.
[0093] In another aspect, the present invention provides an
anti-infective composition for applying to or incorporated into
(e.g., coating) a medical implant such as a catheter or a tube that
comprises a polyurethane, a cellulose or cellulose-derived polymer,
and a fluoropyrimidine or its analog, wherein the fluoropyrimidine
or its analog is present in the composition (e.g., in the form of a
coating) at a concentration effective in reducing or inhibiting
infection associated with the medical implant.
[0094] The composition (e.g., a coating composition) provided
herein allows for an effective amount of a fluoropyrimidine or its
analog, such as 5-FU, to be applied to or incorporated onto (e.g.,
coated on) a medical implant (e.g., a catheter or a tube). In
addition, the polymers in the composition enable release of the
fluoropyrimidine or its analog from the composition (e.g., in form
of a coating) on the implant at effective concentrations over a
sustained period of time. Furthermore, the composition (e.g., a
coating composition) provided herein may be applied to or
incorporated onto, such as form a coating on, a medical implant
(e.g., a catether or a tube) with one or more of the following
desirable features: (1) strong adhesion to the implant when it is
in use (e.g., after insertion in patients); (2) good flexibility
and elasticity to remain intact following sterilization and
implantation of the implant in the patient; (3) excellent
uniformity; (4) not significantly bioerodable, which allows for
sustained release of the fluoropyrimidine or its analog over a
period of days, weeks, or months and minimizes patient's response
to breakdown products of the coating; and (5) easy control of drug
elution rate by using various ratios of the polyurethane to the
cellulose or cellulose-derived polymer in the composition, which in
turn allows for better control of the concentration and duration of
anti-infective activity of the fluoropyrimidine or its analog.
[0095] In certain embodiments, the compositions (e.g., coating
compositions) provided herein were developed and optimized for
total drug loading, drug elution kinetics and anti-microbial
efficacy. They were modified to balance coating thickness, physical
properties (e.g., flexibility), coating quality (e.g., adhesion and
coating uniformity), and drug release kinetics. Parameters of the
coating composition affecting these attributes include the ratios
of the coating polymers to each other, the ratio of drug to total
polymer, percent solids in the coating, choice and relative amounts
of solvents, and the viscosity of the coating solution. In general,
changes to the drug/polymer ratio can affect the rate and amount of
drug eluted from the medical implant. Increasing the drug to
polymer ratio in the coating composition typically increases the
rate of drug elution. However, if drug loading is too high, release
of the drug from the coating can create voids and destroy the
coating integrity. In certain embodiments, the total solids (and
viscosity and coating thickness) were increased to achieve a higher
dose of drug (e.g., 5-FU) while keeping the drug to polymer ratio
below a certain level (e.g., about 40%, 30%, 25%, 20%, 15% or
10%).
[0096] "Polyurethane" refers to a linear polymer that has a
molecular backbone containing carbamate groups (--NHCO.sub.2).
These groups are produced through a chemical reaction between a
diisocyanate (a compound that comprises two --NCO groups) or
polyisocyanate (a compound that comprises more than two --NCO
groups) and a diol (a compound with two --OH groups) or polyol (a
compound that comprises more than two --OH groups).
[0097] Diisocyanates and polyisocyanates that may be used to form
polyurethanes useful in the present application can be aromatic,
such as diphenylmethane diisocyaanate (MDI) or toluene diisocyanate
(TDI), or aliphatic, such as hexamethylene diisocyanate (HDI) or
isophorone diisocyanate (IPDI). Polyurethanes made of aromatic
diisocyanates or aromatic polyisocyanates are referred to as
"aromatic polyurethanes." Similarly, polyurethanes made of
aliphatic diisocynates or aliphatic polyisocyanates are referred to
as "aliphatic polyurethanes."
[0098] Additional exemplary diisocyanates and polyisocyanates that
may be used to make polyurethanes useful in the present application
include, but are not limited to, polymeric isocyanate (PMDI),
1,5-naphthalene diisocyanate, biotolylene diisocyanate,
2,4-tolylene diisocyanate and position isomers thereof,
4,4'-diphenylmethane diisocyanate and position isomer thereof,
polymethylenepolyphenyl isocyanate, 1,5-naphylene diisocyanate,
olymeric diphenylmethane diisocyanate, which is a blend of
molecules with two-, three-, and four or more isocyanate groups.
Further examples of polyisocyanates may be found in Encyclopedia of
Polymer Science and Technology, Mark et al., 1969, incorporated
herein by reference.
[0099] Polyols that may be used to make polyurethanes in the
coating compositions provided herein may be polyester polyols. They
are formed by polyesterification of a di-acid, such as adipic acid,
with glycols, such as ethylene glycol or dipropylenen glycol.
Polyurethane formed with polyester polyols are referred to as
"poly(ester urethanes)."
[0100] Polyether polyols may also be used to make polyurethanes in
the coating compositions provided herein. Polyether polyols are
formed by free radical additions of propylene oxide or ethylene
oxide onto a hydroxyl or amine containing initiator. Exemplary
polyether polyols that may be used to form polyurethanes include
polyethylene glycol, polypropylene glycol, and polytetramethylene
glycol. Polyurethanes formed with polyether polyols are referred to
as "poly(ether urethanes)."
[0101] Polyols that may be used to make polyurethanes in the
coating compositions provided herein may also be a polycarbonate
terminated with hydroxyl groups. The resulting polyurethanes are
referred to as "poly(carbonate urethanes)." Exemplary
poly(carbonate urethanes) that may be included in the coating
compositions provided herein include CHRONOFLEX.RTM. AL
(aliphatic), CHRONOFLEX.RTM. AR (aromatic), CHRONOFLEX.RTM. C
(aromatic), and BIONATE.RTM. (aromatic) 80A, 90A, 55D, and 75D.
[0102] Polyurethanes present in the compositions (e.g., coating
compositions) provide flexibility and adhesion to the medical
implant (e.g., a catheter or a tube). In addition, polyurethanes
may be more or less hydrophilic depending on the number of
hydrophilic groups contained in the polymer structures. The
polyurethanes included in the coating compositions provided herein
are water-insoluble, flexible, and compatible with cellulose or
cellulose-derived polymers and fluoropyrimidines or their analogs
also present in the coating compositions.
[0103] As indicated above, the compositions (e.g., coating
compositions) provided herein also comprise cellulose or
cellulose-derived polymers. "Cellulose" refers to a carbohydrate,
(C.sub.6H.sub.10O.sub.5).sub.n, that is composed of glucose units.
"Cellulose-derived polymers" refers to chemically altered forms of
cellulose, such as cellulose esters, that are water insoluble.
Various types of cellulose esters, such as cellulose acetate,
cellulose acetate propionate, cellulose acetate butyrate, cellulose
acetate phthalate, cellulose xanthate, and cellulose nitrate (also
referred to as "nitrocellulose") may be used in the coating
compositions provided herein.
[0104] Certain cellulose esters (e.g., cellulose nitrates) are
particularly compatible with fluoropyrimidines (e.g., 5-FU) or
their analogs. Cellulose esters can impart non-tackiness and
cohesiveness to the coatings, and as hydrophobic, water-insoluble
polymers, cellulose esters can be highly water resistant.
Furthermore, the structure contributes to high degree of
stabilization provided to active agents entrapped in cellulose
esters. The structure of nitrocellulose is given below:
[0105] In certain embodiments, the cellulose ester may be a
nitrocellulose. The amount of nitrogen content in cellulose
nitrates can vary. Cellulose nitrate (nitrogen content=11.8-12.2%)
preferably is used in this invention, although grades of the
polymer having lower nitrate concentrations (e.g., 11.3-11.8% or
10.8-11.3%) could be used. Cellulose nitrates are available in
viscosities ranging from high viscosity (e.g., 600-1000''; 60-80'';
15-20''; 5-6''), medium viscosity (e.g., 1/2''; 3/8''; 1/4''; 30-35
cps), to low viscosity (e.g., 18-25 cps or 10-15 cps). Lower
viscosity grades, such as 3.5, 0.5 or 0.25 seconds, can be used in
order to provide favorable rheological properties when combined
with the coating solids used in these compositions. Alternatively,
higher or lower viscosity grades could be used. At the solids
concentrations preferred for use in the practice of the invention,
higher viscosity grades can produce coating solutions of such high
viscosity, which may cause coating of medical implants to become
technically challenging. Physical properties such as tensile
strength, elongation, flexibility, and softening point are related
to viscosity. Viscosity, in turn, depends on the molecular weight
of the polymer and can decrease with the lower molecular weight
species, especially below the 0.25 second grades.
[0106] Representative examples of nitrocellulose polymers include
grades A, AM and E nitrocellulose from Dow Wolff Cellulosics,
NCC-H130, NCC-H60, NCC-H3040, NCC-H1520, NCC-H0506, NCC-HM005,
NCC-H0025, NCC-M0025, and NCC-H0062L nitrocellulose from Darwin
Chemical, the ester-soluble types, such as H4, H7, H9, H12, H15,
H22.5, H24, H27, H28, H30, and H33 and alcohol soluble types, such
as AH15, AH22, AH25, AH27, and AH 28 from Hagedorn, L, H, and M
types of nitrocellulose from Shandong Zhiqiang Group Co., and
various types of nitrocellulose from Sherman Chemicals Ltd.
Nitrocellulose polymers are also available from many other
manufacturers and providers.
[0107] Additional examples of cellulose esters that may be combined
with a fluoropyrimidine or its analog include cellulose acetate,
cellulose acetate propionate, cellulose acetate butyrate, cellulose
acetate phthalate, and cellulose xanthate.
[0108] As described above, the composition (e.g., a coating
composition) comprises, in addition to cellulose or a
cellulose-derived polymer, a polyurethane. The presence of both a
polyurethane and a cellulose or cellulose-derived polymer
facilitates the loading or elution control of a fluoropyrimidine
and its analog in the composition. Cellulose or cellulose-derived
polymers in the compositions provided herein are typically
hydrophobic, whereas as discussed above, polyurethane in the
compositions may be more or less hydrophilic depending on its
structure. The ratio of hydrophilic to hydrophobic components in
the coating compositions is an important parameter that affects the
final properties and release characteristics of the composition
(e.g., in form of a coating) on medical implants.
[0109] For instance, to deliver a sparingly water soluble
fluoropyrimidine or its analog, such as 5-FU, a higher percentage
of hydrophobic cellulose or cellulose-derived polymer (i.e., a
lower ratio of polyurethane to cellulose or cellulose-derived
polymer) may be needed comparing with delivering a water insoluble
drug. The higher percentage of hydrophobic cellulose or
cellulose-derived polymer prevents the sparingly water soluble
fluoropyrimidine or its analog (i.e., 5-FU) from being released
from the composition (e.g., in form of a coating) too quickly if
the medical implant with such coating is intended to maintain its
anti-infective activity for a sustained period of time. Thus, the
weight ratio of polyurethane to cellulose or cellulose-derived
polymer may be optimized by taking into consideration various
factors such as the hydrophobicity of the polyurethane, the
hydrophilicity of the fluoropyrimidine or its analog, the amount of
the fluoropyrimidine and its analog present in the coating
composition (e.g., the ratio of the fluoropyrimidine or its analog
to total polymers), and the period during which a medical implant
that comprises the composition intended to have its anti-infective
activity.
[0110] In certain embodiments, the weight ratio of the polyurethane
(e.g., a poly(carbonate urethane)) to the cellulose or
cellulose-derived polymer (e.g., nitrocellulose) in the composition
(e.g., a coating composition) ranges from about 1:10 to about 2:1,
such as from 1:9 to 1:1, 1:8 to 1:1, 1:7 to 1:1, 1:6 to 1:1, 1:5 to
1:1, 1:4 to 1:1, 1:3 to 1:1, 1:2 to 1:1, 1:9 to 1:2, 1:8 to 1:2,
1:7 to 1:2, 1:6 to 1:2, 1:5 to 1:2, 1:4 to 1:2, 1:3 to 1:2, 1:9 to
1:3, 1:8 to 1:3, 1:7 to 1:3, 1:6 to 1:3, 1:5 to 1:3, 1:4 to 1:3,
1:9 to 1:4, 1:8 to 1:4, 1:7 to 1:4, 1:6 to 1:4, 1:5 to 1:4, 1:9 to
1:5, 1:8 to 1:5, 1:7 to 1:5, 1:6 to 1:5, 1:9 to 1:6, 1:8 to 1:6,
1:7 to 1:6, 1:9 to 1:7, 1:8 to 1:7, or 1:9 to 1:8. In certain
embodiments, the weight ratio of the polyurethane (e.g., a
poly(carbonate urethane)) to the cellulose or cellulose-derived
polymer (e.g., nitrocellulose) in the composition (e.g., a coating
composition) is about 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8,
1:9, or 1:10.
[0111] In certain embodiments, the compositions (e.g., coating
compositions) may include other polymers to impart certain
desirable physical properties, such as to modify hydrophobicity,
control elution, and improve flexibility. Exemplary additional
polymers include, but are not limited to, hydroxyethyl
methacrylate, acrylic HEMA (polyhydroxyethyl
methacylate/methylmethacrylate) copolymers, polyvinyl pyrrolidone,
polyethylene glycols, and polyethylene oxides.
[0112] The composition (e.g., a coating composition) provided
herein comprises fluoropyrimidines or their analogs at a
concentration effective in reducing or inhibiting infection
associated with the medical implant that comprises the composition.
Any fluoropyrimidine or its analog with an anti-infective activity
may be used in the coating composition, including those (e.g.,
5-FU) described above.
[0113] A "concentration effective in reducing or inhibiting
infection" refers to a concentration of a fluoropyrimidine or its
analog in a coating composition at which when the composition is
applied or incorporated (e.g., coated) onto a medical implant, the
fluoropyrimidine or its analog is present on or released at an
amount sufficient to statistically significantly reduce or inhibit
infection associated with the medical implant when inserted into a
patient compared with infection associated with the same medical
implant but without the fluoropyrimidine or its analog in its
coating. Effective concentrations can be maintained from the time
of insertion of the medical implant (e.g., a catheter) to up to a
month or more. In certain embodiments, the present medical implants
can offer a concentration effective in reducing or inhibiting
infection for at least 30 days, thus significantly extending or
even eliminating the change interval for the medical implant.
[0114] "Infection associated with a medical implant" or "medical
implant-related infection" (CRI) refers to infection directly or
indirectly caused by the insertion of a medical implant into a
patient. It includes local infection on the medical implant and
systemic infection resulted from the infection on the medical
implant. Reduction in colonization by bacteria also may reduce
biofilm formation on the implanted medical implant (e.g., a
catheter), making it less likely to serve as a reservoir for
additional infection.
[0115] The amount of a fluoropyrimidine or its analog to be
included in the composition (e.g., a coating composition) provided
herein may depend on various factors such as the anti-infective
activity of the analog, the polymer components in the composition
(e.g., a particular polyurethane and cellulose or a particular
cellulose-derived polymer), the weight ratio of the polyurethane to
the cellulose or cellulose-derived polymer, and the intended use of
a medical implant that comprises (e.g., coated with) the
composition. The amount should be sufficient for the
fluoropyrimidine or its analog to be released from the medical
implant at concentrations effective in reducing or inhibiting
medical implant-related infections for the intended period of time,
such as for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days or at least
2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks.
[0116] In certain embodiments, the weight ratio of the
fluoropyrimidine or its analog (e.g., 5-FU) to the sum of the
polyurethane (e.g., poly(carbonate urethane)) and the cellulose or
cellulose-derived polymer (e.g., nitrocellulose) in the composition
(e.g., a coating composition) ranges from 2% to 40%, such as 3% to
30%, 4% to 20%, 5% to 25%, 10% to 20%, 15% to 19%, or 10% to 19%,
or about 10%, 15%, or 20%. In certain embodiments, the weight ratio
of the fluoropyrimidine (e.g., 5-FU) or its analog to the sum of
the polyurethane and the cellulose or cellulose-derived polymer in
the coating is below 20%.
[0117] In certain embodiments, the composition (e.g., a coating
composition) comprises poly(carbonate urethane), nitrocellulose,
and 5-FU in which the weight ratio of the poly(carbonate urethane)
to the nitrocellulose ranges from 1:2 to 1:4 (e.g., about 1:3), and
the weight ratio of 5-FU to the sum of poly(carbonate urethane) and
nitrocellulose is below 20% (e.g., about 15%).
[0118] In certain embodiments, the composition (e.g., a coating
composition) further comprises one or more of the following
components: a solvent for the cellulose or cellulose-derived
polymer, a solvent for the polyurethane, and a swelling agent.
Exemplary solvents for cellulose or cellulose-derived polymers are
known in the art, including ketones such as methyl ethyl ketone
(MEK). Exemplary solvents for polyurethanes are also known in the
art, including amides, such as dimethylacetamide (DMAC), N-methyl
pyrrolidone (NMP), dimethylsulfoxide (DMSO), tetrahydrofuran (THF),
toluene, cyclohexanone, and 2-methyl pentanone (MIEK). Small
amounts of a cosolvent, such as isopropyl alcohol, ethanol, n-butyl
alcohol also may be used to improve solubility of the
fluoropyrimidine or its analog in the coating solution.
[0119] A "swelling agent" is an agent having the ability to swell
the substrate of a medical implant, thereby enabling some of the
composition (e.g., a coating composition) to penetrate
superficially into the substrate surface and improve adhesion. The
choice of swelling agent depends on the composition of the
substrate and should generally be chosen to avoid dissolution of
the medical implant substrate. Such agents are well known in the
art and include, for example, ethers such as tetrahydrofuran (THF),
DMAC, NMP, toluene, and alcohols. Swelling of polyurethane
substrates may be achieved using any of these solvents.
[0120] In certain embodiments, the composition (e.g., a coating
composition) comprises poly(carbonate urethane), nitrocellulose,
5-FU, and a solvent or mixture of solvents (e.g., DMAC, MEK, and
THF). The solvent or solvent mixture is capable of dissolving both
the fluoropyrimidine or its analog and the polymeric components of
the formulation and yields a coating that has adequate adhesion to
the substrate. In certain embodiments, a mixture of solvents
comprises, or is composed of, about 2% to about 25% DMAC, about 15%
to about 58% MEK, and about 40% to about 60% THF. The above
percentages of DMAC, MEK and THF in the mixture of solvents are
weight percentages of each component in the solvent mixture.
[0121] In certain exemplary compositions of such embodiments, the
weight ratio of the poly(carbonate urethane) to the nitrocellulose
ranges from 1:2 to 1:4 (e.g., about 1:3), and the weight ratio of
5-FU to the sum of poly(carbonate urethane) and nitrocellulose
ranges from 5% to 25% (e.g., about 15% to about 20%). In the same
or different exemplary compositions of the above-noted embodiments,
the total weight percentage of the poly(carbonate urethane), the
nitrocellulose, and 5-FU in the coating compositions may be from 2%
to 20%, such as from 4% to 10%, about 5%, about 6%, about 7%, or
about 8%.
[0122] In certain embodiments, the composition (e.g., a coating
composition) provided herein may further comprise one or more
additional anti-infective agents or other active agents. The
anti-infective agents include additional fluoropyrimidines or their
analogs, other chemotherapeutics with anti-infective activities,
antibiotics, and anti-fungal agents. Other active agents include
antithrombotic agents such as antiplatelet agents,
anti-inflammatory agents, immunomodulatory agents and anti-fibrotic
agents. Examples of additional anti-infective agents and other
active agents are described above.
[0123] In certain embodiments, the compositions (e.g., coating
compositions) provided herein may further comprise various agents
that can impart certain desirable attributes, such as plasticizers
(e.g., glycerol and triethyl citrate) to increase the flexibility,
colorants such as dyes, hyaluronic acid or PVP to improve
lubricity, heparin to enhance biocompatibility or hemocompatability
of the coating.
III. Medical Implants
[0124] A. Representative Medical Implants
[0125] A wide variety of implants or devices can be coated with or
otherwise constructed to contain and/or release the therapeutic
agents provided herein. Representative examples include
cardiovascular devices (e.g., implantable central venous catheters,
peripheral intravenous catheters, arterial lines and transducers,
port-catheters, venous ports, tunneled venous catheters, chronic
infusion lines or ports, including hepatic artery infusion
catheters, pacemakers and pacesmaker leads (see, e.g., U.S. Pat.
Nos. 4,662,382, 4,782,836, 4,856,521, 4,860,751, 5,101,824,
5,261,419, 5,284,491, 6,055,454, 6,370,434, and 6,370,434),
implantable defibrillators (see, e.g., U.S. Pat. Nos. 3,614,954,
3,614,955, 4,375,817, 5,314,430, 5,405,363, 5,607,385, 5,697,953,
5,776,165, 6,067,471, 6,169,923, and 6,152,955));
neurologic/neurosurgical devices (e.g., ventricular peritoneal
shunts, ventricular atrial shunts, nerve stimulator devices, dural
patches and implants to prevent epidural fibrosis post-laminectomy,
devices for continuous subarachnoid infusions); dialysis catheters
(e.g., hemodialysis catheters and peritoneal dialysis catheters);
gastrointestinal devices (e.g., chronic indwelling catheters,
feeding tubes, portosystemic shunts, shunts for ascites, peritoneal
implants for drug delivery, peritoneal dialysis catheters, and
suspensions or solid implants to prevent surgical adhesions);
genitourinary devices (e.g., uterine implants, including
intrauterine devices (IUDs) and devices to prevent endometrial
hyperplasia, fallopian tubal implants, including reversible
sterilization devices, fallopian tubal stents, artificial
sphincters and periurethral implants for incontinence, ureteric
stents, chronic indwelling catheters, bladder augmentations, or
wraps or splints for vasovasostomy, central venous catheters (see,
e.g., U.S. Pat. Nos. 3,995,623, 4,072,146 4,096,860, 4,099,528,
4,134,402, 4,180,068, 4,385,631, 4,406,656, 4,568,329, 4,960,409,
5,176,661, 5,916,208), urinary catheters (see, e.g. U.S. Pat. Nos.
2,819,718, 4,227,533, 4,284,459, 4,335,723, 4,701,162, 4,571,241,
4,710,169, and 5,300,022)); prosthetic heart valves (see, e.g.,
U.S. Pat. Nos. 3,656,185, 4,106,129, 4,892,540, 5,528,023,
5,772,694, 6,096,075, 6,176,877, 6,358,278, and 6,371,983),
vascular grafts (see, e.g. U.S. Pat. Nos. 3,096,560, 3,805,301,
3,945,052, 4,140,126, 4,323,525, 4,355,426, 4,475,972, 4,530,113,
4,550,447, 4,562,596, 4,601,718, 4,647,416, 4,878,908, 5,024,671,
5,104,399, 5,116,360, 5,151,105, 5,197,977, 5,282,824, 5,405,379,
5,609,624, 5,693,088, and 5,910,168), ophthalmologic implants
(e.g., multino implants and other implants for neovascular
glaucoma, drug eluting contact lenses for pterygiums, splints for
failed dacrocystalrhinostomy, drug eluting contact lenses for
corneal neovascularity, implants for diabetic retinopathy, drug
eluting contact lenses for high risk corneal transplants);
otolaryngology devices (e.g., ossicular implants, Eustachian tube
splints or stents for glue ear or chronic otitis as an alternative
to transtempanic drains); plastic surgery implants (e.g., breast
implants or chin implants), catheter cuffs and orthopedic implants
(e.g., cemented orthopedic prostheses), drainage tubes, and
nasogastric tubes. Further exemplary medical implants that may be
coated with or otherwise comprise a composition that comprises a
fluoropyrimidine or its analog according to the present invention
include those discussed in the Clinical Applications section
below.
[0126] In certain embodiments, the medical implants are catheters,
including but not limited to: acorn-tipped catheters, angiography
catheters, balloon catheters, balloon-tip catheters, bicoudate
catheters, Bozeman-Fritsch catheters, Braasch catheters, Broviac
catheters, brush catheters, cardiac catheters, central venous
catheters, conical catheters, catheters coude, catheters a demeure,
de Pezzer catheters, double-channel catheters, elbowed catheters,
Eustachian catheters, female catheters, Fogarty embolectomy
catheters, Foley catheters, Gouley catheters, Hickman catheters,
indwelling catheters, intracardiac catheters, Malecot catheters,
Nelaton catheters, olive-tipped catheters, pacing catheters, Pezzer
catheters, Phillips catheters, pigtail catheters, prostatic
catheters, pulmonary artery catheters, Robinson catheters,
self-retaining catheters, spiral tip catheters, Swan-Ganz
catheters, two-way catheters, vertebrated catheters, whistle-tip
catheters, and winged catheters. The above types of catheters are
well known in the art and defined in Stedman's Medical Dictionary,
27.sup.th Edition, Lippincott Williams & Wilkins, 2000.
[0127] Additional representative examples of catheters that may be
coated with or otherwise comprise a composition that comprises a
pyrimidine analog according to the present invention on the
catheters include implantable venous catheters, tunneled venous
catheters, coronary catheters useful for angiography, angioplasty,
or ultrasound procedures in the heart or in peripheral veins and
arteries, chronic infusion lines, hepatic artery infusion
catheters, central venous catheters (see, e.g., U.S. Pat. Nos.
3,995,623, 4,072,146 4,096,860, 4,099,528, 4,134,402, 4,180,068,
4,385,631, 4,406,656, 4,568,329, 4,960,409, 5,176,661, 5,916,208),
peripheral intravenous catheters, peripherally inserted central
venous catheters (PIC lines), flow-directed balloon-tipped
pulmonary artery catheters, arterial lines, total parenteral
nutrition catheters, devices for continuous subarachnoid infusions,
chronic dwelling catheters (e.g., chronic dwelling gastrointestinal
catheters and chronic dwelling genitourinary catheters), peritoneal
dialysis catheters, hemodialysis catheters, and urinary catheters
(see, e.g. U.S. Pat. Nos. 2,819,718, 4,227,533, 4,284,459,
4,335,723, 4,701,162, 4,571,241, 4,710,169, and 5,300,022).
[0128] Additional exemplary catheters that may be coated with or
otherwise comprise a composition that comprises a pyrimidine analog
according to the present invention on the catheters include
SKATER.RTM. drainage catheters for percutaneous fluid collection
drainage procedures, such as SKATER.RTM. biliary catheters,
SKATER.RTM. nephrostomy catheter, SKATER.RTM. single step
catheters; GOLDEN-RULE.TM. scaling catheters for delivering
radiopaque media to selected sites in the vascular system and
anatomical measurements in conjunction with routine diagnostic
procedures, and HSG catheters for use in the injection of contrast
material in the examination of the uterus and fallopian tubes.
These exemplary catheters are available from Angiotech.
[0129] The catheters may have one lumen or multiple lumens,
depending on the application. In certain embodiments, the catheters
may be double catheters (e.g., hemodialysis catheters) or
triple-lumen catheters (e.g., central venous catheters). In other
embodiments, the catheters may have 4 or 5 lumens.
[0130] In certain embodiments, the catheter does not include an
expandable portion such as a balloon. In other embodiments, the
catheter is not a transient delivery vehicle that is intended to be
removed shortly after to delivery of a drug or balloon or the like
(e.g., within an hour or less after insertion).
[0131] In certain embodiments, the catheter further comprises a
cuff that locates at the junction where the catheter exits the
skin. In certain embodiments, the catheter further comprises a
catheter hub. In certain embodiments, the catheter may be
positioned in the body via a trocar. In certain embodiments, the
catheter is to be placed under the skin and referred to as a
"tunneled catheter."
[0132] In certain embodiments, an anti-infective hemodialysis
catheter is provided. In an embodiment, the anti-infective
hemodialysis catheter is a two lumen catheter. It may or may not
further comprise a cuff, and may or may not be delivered using a
trocar.
[0133] In certain embodiments, the medical implant is a chronic
indwelling medical implant intended to be inserted and stay inside
a patient for an extended period of time, such as at least for 1,
2, 3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks, or 1, 2, 3, 4, 5, 6, 7,
8, 9, 10, 11, or 12 months.
[0134] A "coating," as used herein, refers to a composition that
(1) adheres to the surface of at least a portion of a medical
implant, and (2) comprises at least one component different from
the material(s) that form the medical implant.
[0135] In certain embodiments, the coating is a layer on a medical
implant that is of substantially uniform thickness. A layer is "of
substantially uniform thickness" if the thickness at any position
of the layer is between 70% and 130% of the average thickness of
the layer. In certain embodiments, the thickness at any position of
the layer is between 80% and 120%, such as between 90% and 100%
[0136] In certain other embodiments, the coating adheres to
multiple non-continuous areas of the surface of a medical implant.
Such a coating is referred to as "spot coating."
[0137] In certain other embodiments, the medical implant contains a
plurality of reservoirs, and the composition that comprises at
least one component different from the material(s) that form the
medical implant adheres to the surface of the plurality of
reservoirs. Such a coating is referred to as "well coating" or "pit
coating." The reservoirs may be formed from divets or voids in the
medical implant surface or from micropores or channels in the
medical implant body.
[0138] Any of the compositions (e.g., coating compositions)
described herein may be used in combination with any of the medical
implants described herein to provide the anti-infective medical
implants according to the present invention.
[0139] In certain embodiments, the polyurethane in the composition
(e.g., in form of a coating) on the medical implant is a
poly(carbonate urethane), poly(ester urethane), or poly(ether
urethane).
[0140] In certain embodiments, the cellulose-derived polymer is
nitrocellulose, cellulose acetate butyrate, or cellulose acetate
propionate.
[0141] The anti-infective medical implant provided herein comprises
a fluoropyrimidine or its analog (e.g., 5-FU) in an amount
effective in reducing or inhibiting infection associated with the
medical implant.
[0142] An "amount effective in reducing or inhibiting infection"
refers to an amount of an anti-infective agent when used in
combination with a medical implant (e.g., as a coating of the
medical implant) that is sufficient in statistically significantly
reducing infection associated with the medical implant when
inserted into a patient with the same implant but without the
anti-infective agent. Such an amount may be determined using
methods known in the relevant art.
[0143] In certain embodiments, the fluoropyrimidine or its analog
is released from the composition (e.g., in form of a coating) on
the anti-infective medical implant at an amount effective in
reducing or inhibiting infection associated with the medical
implant for an extended period of time, such as at least for 1, 2,
3, 4, 5, or 6 days, 1, 2, 3, or 4 weeks, or 1, 2, 3, 4, 5, 6, 7, 8,
9, 10, 11, or 12 months. In certain embodiments, the release of the
fluoropyrimidine or its analog starts upon the implantation of the
anti-infective medical implant into a patient. In certain other
embodiments, there is a delay before the fluoropyrimidine or its
analog starts to release from the anti-infective medical
implant.
[0144] In certain embodiments, the fluoropyrimidine or its analog
is released from the composition (e.g., in form of a coating)
during the entire residence time of the implant within the patient.
For example, for a central venous catheter that may remain
implanted for up to about 30 days and for a hemodialysis catheter
that may remain implanted for 6 to 12 months, the fluoropyrimidine
or its analog releases from the catheter beginning after
implantation up until removal of the catheter from the patient. In
other embodiments, the fluoropyrimidine or its analog is not
released (e.g., does not dissociate) from the medical implant but
is present on the surface of the medical implant in an amount
effective in reducing or inhibiting infection for an extended
period of time, such as at least for 1, 2, 3, 4, 5, or 6 days, 1,
2, 3, or 4 weeks, or 1, 2, 3, 4, 5, or 6 months.
[0145] In certain embodiments, the average thickness of the coating
ranges form 0.5 .mu.m to 10 .mu.m. In certain embodiments, the
average thickness of the coating is about 3-6 .mu.m. In certain
embodiments, the average thickness of the coating is about 5
.mu.m.
[0146] In certain embodiments, the weight ratio (i.e., w/w) of the
polyurethane to the cellulose or cellulose-derived polymer in the
composition (e.g., in form of a coating) ranges from 1:2 to 1:4. In
certain embodiments, the weight ratio of the polyurethane to the
cellulose or cellulose-derived polymer in the composition is about
1:3.
[0147] In certain embodiments, the weight ratio of the
fluoropyrimidine or its analog (e.g., 5-FU) to the sum of the
polyurethane (e.g., poly(carbonate urethane)) and the cellulose or
cellulose-derived polymer (e.g., nitrocellulose) in the composition
(e.g., in form of a coating) may range from 2% to 40%, such as 5%
to 25%, 10% to 20%, or 15% to 19%. In certain embodiments, the
weight ratio of the fluoropyrimidine or its analog to the sum of
the polyurethane and the cellulose or cellulose-derived polymer in
the composition is about 15% or about 20%. In certain embodiments,
the weight ratio of the fluoropyrimidine or its analog to the sum
of the polyurethane and the cellulose or cellulose-derived polymer
in the composition is below 20%.
[0148] The amount of fluoropyrimidine or its analog is chosen to
achieve the desired level of infection control with negligible
systemic exposure and/or negligible damages to surrounding host
tissues. In other words, the amount of fluoropyrimidine or its
analog must be high enough to prevent bacterial infection, such as
bacterial growth, in, on or around the medical implant, but low
enough not to damage cells in the vicinity or in contact with the
medical implant, or cause systemic adverse effects on the host. For
example, in certain embodiments, when a medical implant (e.g., a
vascular catheter) that comprises a fluoropyrimidine or its analog
is implanted into a blood vessel, the plasma concentration of the
fluoropyrimidine or its analog is less than 500 ng/ml, 100 ng/ml,
50 ng/ml, 10 ng/ml, 5 ng/ml, or 1 ng/ml. In certain embodiments,
when a vascular implant that comprises a fluoropyrimidine or its
analog is implanted into a blood vessel, fluoropyrimidine or its
analog does not across the blood vessel wall and infiltrate to the
surrounding tissue at a detectable concentration (e.g., 1 ng/ml or
higher).
[0149] In certain embodiments, the total dose of 5-fluorouracil
applied to the medical implant, such as a central venous catheter,
should not exceed 250 mg (range of 1.0 .mu.g to 250 mg). In a
particularly preferred embodiment, the total amount of drug applied
to the medical implant should be in the range of 10 .mu.g to 25 mg.
The dose per unit area of the implant (i.e. the amount of drug as a
function of the surface area of the portion of the implant to which
drug is applied and/or incorporated) should fall within the range
of 0.1 .mu.g-1 mg per mm.sup.2 of surface area. In a particularly
preferred embodiment, 5-fluorouracil should be applied to the
implant surface at a dose of 1.0 .mu.g/mm.sup.2-50 .mu.g/mm.sup.2.
As different polymer and non-polymer coatings will release
5-fluorouracil at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the implant surface such that a minimum concentration of
10.sup.-4-10.sup.-7M of 5-fluorouracil is maintained on the implant
surface. It is necessary to insure that drug concentrations on the
device surface exceed concentrations of 5-fluorouracil known to be
lethal to numerous species of bacteria and fungi (i.e., are in
excess of 10.sup.-4M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the surface of the implant such
that anti-infective activity is maintained for a period ranging
from several hours to several months. In a particularly preferred
embodiment the drug is released in effective concentrations for a
period ranging from 1-30 days. It should be readily evident given
the discussions provided herein that analogues and derivatives of
5-fluorouracil (as described previously) with similar functional
activity can be utilized for the purposes of this invention; the
above dosing parameters are then adjusted according to the relative
potency of the analogue or derivative as compared to the parent
compound (e.g. a compound twice as potent as 5-fluorouracil is
administered at half the above parameters, a compound half as
potent as 5-fluorouracil is administered at twice the above
parameters, etc.).
[0150] In certain embodiments, the fluoropyrimidine (e.g., 5-FU) or
its analog is present at 0.1 .mu.g to 1 mg per cm.sup.2, such as at
0.1 .mu.g to 1 .mu.g per cm.sup.2, 1 .mu.g to 10 .mu.g per
cm.sup.2, at 10 .mu.g to 100 .mu.g per cm.sup.2 (e.g., at about 20,
30, 40, 50, 60, 70, 80, or 90 .mu.g per cm.sup.2), at 100 .mu.g to
1 mg per cm.sup.2, 0.1 .mu.g to 10 .mu.g per cm.sup.2, 10 .mu.g to
1 mg per cm.sup.2, 1 .mu.g to 100 .mu.g per cm.sup.2 of the surface
area of the anti-infective medical implant to which a composition
that comprises the fluoropyrimidine or its analog is applied or
incorporated (e.g., the surface area of the anti-infective medical
implant coated with the composition). In certain embodiments,
inhibition of infection (e.g., bacterial colonization) of certain
types of medical implants (e.g., vascular access catheters) may be
achieved by incorporation of a fluoropyrimidine or its analog
(e.g., 5-FU) in the amount of about 40-100 .mu.g per cm.sup.2 of
coated surface area of the anti-infective medical implant (e.g.,
vascular access catheters).
[0151] In certain embodiments, the fluoropyrimidine (e.g., 5-FU) or
its analog is present, in terms of weight per linear cm of medical
implant (e.g., a catheter or a tube), at 0.1 .mu.g to 1 mg per
linear cm of catheter or tube length to which a composition that
comprises the fluoropyrimidine or its analog, a polyurethane, and
cellulose or a cellulose-derived polymer is applied or incorporated
(e.g., the surface area of the anti-infective coated with the
composition), such as at 0.1 .mu.g to 1 .mu.g per cm, 1 .mu.g to 10
.mu.g per cm, 10 .mu.g to 100 .mu.g per cm (e.g., at about 20, 30,
40, 50, 60, 70, 80, or 90 .mu.g per cm), 100 .mu.g to 1 mg per cm,
0.1 .mu.g to 10 .mu.g per cm, 10 .mu.g to 1 mg per cm, 1 .mu.g to
100 .mu.g per cm, of catheter or tube length of the anti-infective
catheter or tube to which the fluoropyrimidine or its
analog-containing polymeric composition is applied or incorporated.
In certain embodiments, inhibition of infection (e.g., bacterial
colonization) of certain types of medical implants (e.g., vascular
access catheters or tubes) may be achieved by incorporation of a
fluoropyrimidine or its analog (e.g., 5-FU) in an amount of about
10 .mu.g to 25 .mu.g, about 25 .mu.g to about 75 .mu.g, about 75
.mu.g to about 100 .mu.g, about 10 .mu.g to about 40 .mu.g, about
40 .mu.g to about 60 .mu.g, about 60 .mu.g to about 100 .mu.g,
about 10 .mu.g to 45 .mu.g, about 45 .mu.g to about 55 .mu.g, or
about 55 .mu.g to about 100 .mu.g, per linear cm of catheter or
tube length to which the fluoropyrimidine or its analog-containing
polymeric composition is applied or incorporated.
[0152] In certain embodiments, the anti-infective medical implant
comprises 1 .mu.g to 250 mg, such as 1 .mu.g to 10 .mu.g, 10 .mu.g
to 100 .mu.g, 100 .mu.g to 1 mg, 1 mg to 10 mg, 10 mg to 100 mg,
100 mg to 250 mg, 1 .mu.g to 100 .mu.g, 100 .mu.g to 10 mg, or 10
mg to 250 mg of a fluoropyrimidine (e.g., 5-FU) or its analog. In
certain embodiments, the anti-infective medical implant (e.g., a
catheter or a tube) comprises about 0.2, 0.4, 0.6, 0.8, 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10 mg of a fluoropyrimidine or its analog (e.g.,
5-FU). In certain embodiments, anti-infective medical implants
(e.g., a vascular access catheter such as a CVC) are provided that
comprise a total dose of about 0.1 mg to about 0.5 mg, about 0.5 mg
to about 1.5 mg, about 1.5 mg to about 10 mg, about 0.1 mg to about
0.75 mg, or about 0.75 mg to about 1.5 mg, about 0.1 mg to about 10
mg, about 0.2 mg to 4 mg of a fluoropyrimidine (e.g., 5-FU) or its
analog.
[0153] Any fluoropyrimidine or its analog described above may be
used (e.g., for coating on a medical implant) to provide the
anti-infective medical implant according to the present invention.
In certain embodiments, the fluoropyrimidine or its analog is
5-fluorouracil.
[0154] In certain embodiments, the composition (e.g., in form of a
coating) may further comprise one or more secondary anti-infective
agents, one or more other active agents (e.g., antithrombotic
agents), or combinations thereof. Any of the secondary
anti-infective agents or other active agents described above may be
used in combination of a fluoropyrimidine or its analog in a
coating on a medical implant according to the present
invention.
[0155] In certain embodiments, a medical implant (e.g., a catheter
or a tube) may have a composition that comprises a fluoropyrimidine
or its analog on a portion of its surface (e.g., in form of a
coating), and have a composition that comprises another active
agent (e.g. an antithromobotic agent) on a different portion of its
surface (e.g., in form of a coating).
[0156] In certain embodiments, the anti-infective medical implant
of the present invention is a medical implant that is composed at
least partially of polyurethane. A "medical implant that is
composed at least partially of polyurethane," as used herein,
refers to a medical implant at least a section of which is made of
a composition that comprises polyurethane, and (b) in which
polyurethane is not present only in a composition that further
comprises a fluoropyrimidine or its analog (e.g., in the form of a
coating) on the medical implant. In other words, such a medical
implant has at least a section formed form a polyurethane material
or a blend or copolymer of polyurethane and another polymer. In
certain embodiments, polyurethane contributes to at least 60%, 70%,
80%, 90%, 95%, 98% or 99% of the weight of at least a section of
the medical implant. In certain embodiments, polyurethane
contributes to at least 60%, 70%, 80%, 90%, 95%, 98% or 99% of the
total weight of the medical implant.
[0157] In certain embodiments, the medical implant is composed of
polyurethane that is different from the polyurethane in the coating
of the medical implant. In certain embodiments, the medical implant
is composed of polyurethane that is the same as the polyurethane in
the coating of the medical implant.
[0158] Polyurethanes useful in the production of medical implants
(e.g., catheters and tubes) are well known in the art. They may be
aliphatic or aromatic. In certain embodiments, polyurethanes that
form catheter shafts or tubes are thermoplastic. For example, in
certain embodiments, a catheter or tube can be composed of an
aliphatic, thermoplastic polyurethane including poly(ester
urethane) such as TECOFLEX, TECOTHANE, TECOLAST, AND TECHOPHILIC
available from Lubrizol Advanced Materials, Inc., aliphatic,
thermoplastic polyurethane elastomer such as PELLETHANE available
from Dow, or thermoplastic poly(carbonate urethane) such as
CARBOTHANE available from Lubrizol. Additional exemplary
polyurethanes useful in producing catheters or tubes may be
MICRO-RENATHANE.RTM. and RENAPULSE.TM. from Braintree Scientific.
Typically, polyurethanes that form catheter shaft may range in
hardness measured in terms of durometer ranging from 72A to
84D.
[0159] In certain embodiments, a medical implant, such as a
catheter or tube composed at least partially of polyurethane may
include up to about 20% barium sulfate, bismuth salts, and/or
tungsten to make them radiopaque.
[0160] In certain embodiments where the medical implant is composed
of at least partially of a polyurethane, the fluoropyrimidine or
its analog is also incorporated (e.g., penetrated) into the
polyurethane of which the medical implant is composed. The
incorporation may occur during the process of applying or
incorporating a composition that comprises a fluoropyrimidine or
its analog onto a medical implant or a portion thereof, such as
during the process of coating a medical implant or a portion
thereof with the composition. For example, when a catheter or a
tube is coated with a composition that comprises a swelling agent,
the swelling agent induces swelling of the polyurethane from which
the catheter or tube is made, which in turn may cause the
fluoropyrimidine or its analog also present in the composition to
penetrate or embed into the polyurethane from which the medical
implant is made. In certain embodiments, such penetration or
embedment of the fluoropyrimidine or its analog in the polyurethane
that forms the implant allows sustained release of the
fluoropyrimidine or its analog for a relatively long period of time
(e.g., for at least 6, 7, 8, 9, 10, 11, or 12 months). In certain
embodiments, such penetration of the fluoropyrimidine or its analog
in the polyurethane that forms the medical implant allows the
fluoropyrimidine analog if applied to the exterior surface of the
medical implant (e.g., a catheter or a tube) to be eluted inside
the lumen of the implant.
[0161] In certain embodiments, the anti-infective device of the
present invention comprises a medical implant that has a surface
that is made from a polyurethane or a blend or copolymer of
polyurethane and another polymer, whereas the underlying substrate
is made from material that does not comprise polyurethane. Such a
medical implant is referred to as "polyurethane-clad medical
implant."
[0162] In certain embodiments, the medical implant may be made of
polymers other than polyurethane. Exemplary polymers include
silicone such as RENASIL.TM. from Briantree Scientific.
[0163] In certain embodiments, an anti-infective medical implant is
provided that comprises a medical implant (e.g., a catheter or a
tube), and a composition (e.g., in the form of coating) on the
implant, wherein (1) the coating comprises poly(carbonate
urethane), nitrocellulose, and 5-fluorouracil, (2) the weight ratio
of poly(carbonate urethane) to nitrocellulose in the coating ranges
from 1:2 to 1:4 (e.g., about 1:3), and (3) 5-fluorouracil is
present at 10 .mu.g to 100 .mu.g per linear cm (e.g., at about 50,
60, or 70 .mu.g per linear cm) of the implant surface area to which
the composition is applied or incorporated (e.g., coated implant
surface area). In certain embodiments, the implant is only coated
on its non-luminal surface or a portion thereof. In certain
embodiments, the coating on the non-luminal surface or a potion
thereof is about 3-7 .mu.m (e.g., about 5 .mu.m) thick. In certain
embodiments, the total amount of 5-FU in the implant is from about
0.2 mg to about 2 mg, such as from 0.5 mg to about 1.5 mg, or about
1 mg. In certain embodiments, the weight ratio of 5-FU to the sum
of poly(carbonate urethane) and nitrocellulose is below 20%.
[0164] In certain embodiments, inhibition of infection (e.g.,
bacterial colonization) of certain types of medical implants (e.g.,
vascular access catheters) may be achieved by incorporation of a
fluoropyrimidine (e.g., 5-FU) in an amount of about 25 .mu.g to
about 75 .mu.g per linear cm of the implant length to which a
fluoropyrimidine or its analog-containing polymeric composition is
applied or incorporated (e.g., coated implant length). The
anti-infective surface of the implant (e.g., CVC's) may contain
fluoropyrimidine (e.g., 5-FU) in an amount of about 40 .mu.g to
about 60 .mu.g per linear cm or about 45 .mu.g/linear cm to about
55 .mu.g/linear cm.
[0165] 5-FU is given intravenously (IV) for cancer therapy due to
its inefficient absorption by ingestion. The doses used vary but a
typical regimen is a dose of 500 mg/m.sup.2 administered daily for
5 days, which is repeated in monthly cycles (Calabresi and Chabner,
Chemotheapy of neoplastic disease. In: Gilman et al. (Eds), The
Pharmacologic Basis of Therapeutics, 8.sup.th Ed. New York:
Pergamon Press, p. 1227-30, 1990). Another regimen delivers as much
as 5 grams over a 12-day period (Physician's Desk Reference (PDR),
Fluorouracil for Injection, 1998). When the dose is given IV,
plasma concentrations reach 0.1-1.0 mM (13-130 .mu.g/ml) with a
rapid infusion and levels of about 10 .mu.M with a continuous
infusion.
[0166] Published literature is available reporting the genotoxicity
and carcinogenicity potential of 5-FU; the LD.sub.50 in mammalian
species is between 94-880 mg/kg (PDR 1998). In contrast, in certain
embodiments, central venous catheters are provided herein that
contain only about 1 mg of 5-FU, which is released gradually over
several weeks. The total 5-FU content of such catheters is
approximately 800-fold less than a maximum daily intravenous dosage
or 5000-fold less than a typical 12-day treatment (PDR 1998).
Non-clinical blood analysis has shown no systemically detectable
levels of 5-FU (assay sensitivity of 1 ng/ml) at any time point
after implantation of the (up to 21 days) in goats as shown in the
example section.
[0167] B. Methods of Making Medical Implants Having Therapeutic
Agents
[0168] Implants and other surgical or medical devices may be
covered, coated, contacted, combined, loaded, filled, associated
with, or otherwise adapted to release therapeutic agents
compositions of the present invention in a variety of manners,
including for example: (a) by directly affixing to the implant or
device a therapeutic agent or composition (e.g., by either spraying
the implant or device with a polymer/drug film, or by dipping the
implant or device into a polymer/drug solution, or by other
covalent or noncovalent means); (b) by coating the implant or
device with a substance, such as a hydrogel, which will in turn
absorb the therapeutic composition (or therapeutic factor above);
(c) by interweaving therapeutic composition coated thread (or the
polymer itself formed into a thread) into the implant or device;
(d) by inserting the implant or device into a sleeve or mesh which
is comprised of or coated with a therapeutic composition; (e)
constructing the implant or device itself with a therapeutic agent
or composition; or (f) by otherwise adapting the implant or device
to release the therapeutic agent. Within preferred embodiments of
the invention, the composition should firmly adhere to the implant
or device during storage and at the time of insertion. The
therapeutic agent or composition should also preferably not degrade
during storage, prior to insertion, or when warmed to body
temperature after insertion inside the body (if this is required).
In addition, it should preferably coat or cover the desired areas
of the implant or device smoothly and evenly, with a uniform
distribution of therapeutic agent. Within preferred embodiments of
the invention, the therapeutic agent or composition should provide
a uniform, predictable, prolonged release of the therapeutic factor
into the tissue surrounding the implant or device once it has been
deployed. For vascular implants, in addition to the above
properties, the composition should not render the implant
thrombogenic (causing blood clots to form), or cause significant
turbulence in blood flow (more than the implant itself would be
expected to cause if it was uncoated).
[0169] Within certain embodiments of the invention, a therapeutic
agent can be deposited directly onto all or a portion of the device
(see, e.g., U.S. Pat. Nos. 6,096,070 and 6,299,604), or admixed
with a delivery system or carrier (e.g., a polymer, liposome, or
vitamin as discussed above) which is applied to all or a portion of
the device (see the patents, patent applications, and references
listed above under "Compositions and Formulations").
[0170] Within certain aspects of the invention, therapeutic agents
can be attached to a medical implant using non-covalent
attachments. For example, for compounds that are relatively
sparingly water soluble or water insoluble, the compound can be
dissolved in an organic solvent a specified concentration. The
solvent chosen for this application would not result in dissolution
or swelling of the polymeric device surface. The medical implant
can then be dipped into the solution, withdrawn and then dried (air
dry and/or vacuum dry). Alternatively, this drug solution can be
sprayed onto the surface of the implant. This can be accomplished
using current spray coating technology. The release duration for
this method of coating would be relatively short and would be a
function of the solubility of the drug in the body fluid in which
it was placed.
[0171] In another aspect, a therapeutic agent can be dissolved in a
solvent that has the ability to swell or partially dissolve the
surface of a polymeric implant. Depending on the solvent/implant
polymer combination, the implant could be dipped into the drug
solution for a period of time such that the drug can diffuse into
the surface layer of the polymeric device. Alternatively the drug
solution can be sprayed onto all or a part of the surface of the
implant. The release profile of the drug depends upon the
solubility of the drug in the surface polymeric layer. Using this
approach, one would ensure that the solvent does not result in a
significant distortion or dimensional change of the medical
implant.
[0172] If the implant is composed of materials that do not allow
incorporation of a therapeutic agent into the surface layer using
the above solvent method, one can treat the surface of the device
with a plasma polymerization method such that a thin polymeric
layer is deposited onto the device surface. Examples of such
methods include parylene coating of devices, and the use of various
monomers such hydrocyclosiloxane monomers, acrylic acid, acrylate
monomers, methacrylic acid or methacrylate monomers. One can then
use the dip coating or spray coating methods described above to
incorporate the therapeutic agent into the coated surface of the
implant.
[0173] For therapeutic agents (e.g., fluoropyrimidine or its
analogs or secondary agents as described above) that have some
degree of water solubility, the retention of these compounds on a
device are relatively short-term. For therapeutic agents that
contain ionic groups, it is possible to ionically complex these
agents to oppositely charged compounds that have a hydrophobic
component. For example, therapeutic agents containing amine groups
can be complexed with compounds such as sodium dodecyl sulfate
(SDS). Compounds containing carboxylic groups can be complexed with
tridodecymethyammonium chloride (TDMAC). Mitoxantrone, for example,
has two secondary amine groups and comes as a chloride salt. This
compound can be added to sodium dodecyl sulfate in order to form a
complex. This complex can be dissolved in an organic solvent which
can then be dip coated or spray coated. Doxorubicin has an amine
group and could thus also be complexed with SDS. This complex could
then be applied to the device by dip coating or spray coating
methods. Methotrexate, for example contains 2 carboxylic acid
groups and could thus be complexed with TDMAC and then coated onto
the medical implant.
[0174] For therapeutic agents that have the ability to form ionic
complexes or hydrogen bonds, the release of these agents from the
device can be modified by the use of organic compounds that have
the ability to form ionic or hydrogen bonds with the therapeutic
agent. As described above, a complex between the ionically charged
therapeutic agent and an oppositely charged hydrophobic compound
can be prepared prior to application of this complex to the medical
implant. In another embodiment, a compound that has the ability to
form ionic or hydrogen bond interactions with the therapeutic agent
can be incorporated into the implant during the manufacture
process, or during the coating process. Alternatively, this
compound can be incorporated into a coating polymer that is applied
to the implant or during the process of loading the therapeutic
agent into or onto the implant. These agents can include fatty
acids (e.g., palmitic acid, stearic acid, lauric acid), aliphatic
acids, aromatic acids (e.g., benzoic acid, salicylic acid),
cylcoaliphatic acids, aliphatic (stearyl alcohol, lauryl alcohol,
cetyl alcohol) and aromatic alcohols alco multifunctional alcohols
(e.g., citric acid, tartaric acid, pentaerithratol), lipids (e.g.,
phosphatidyl choline, phosphatidylethanolamine), carbohydrates,
sugars, spermine, spermidine, aliphatic and aromatic amines,
natural and synthetic amino acids, peptides or proteins. For
example, a fatty acid such as palmitic acid can be used to modulate
the release of 5-Fluoruracil from the implant.
[0175] For therapeutic agents that have the ability to form ionic
complexes or hydrogen bonds, the release of these agents from the
implant can be modified by the use of polymers that have the
ability to form ionic or hydrogen bonds with the therapeutic agent.
For example, therapeutic agents containing amine groups can form
ionic complexes with sulfonic or carboxylic pendant groups or
end-groups of a polymer. Examples of polymers that can be used for
this application include, but are not limited to polymers and
copolymers that are prepared using acrylic acid, methacrylic acid,
sodium styrene sulfonate, styrene sulfonic acid, maleic acid or
2-acrylamido-2-methyl propane sulfonic acid. Polymers that have
been modified by sulfonation post-polymerization can also be used
in this application. The medical implant, for example, can be
coated with, or prepared with, a polymer that comprises nafion, a
sulfonated fluoropolymer. This medical device can then be dipped
into a solution that comprises the amine-containing therapeutic
agent. The amine-containing therapeutic agent can also be applied
by a spray coating process. Methotrexate and doxorubicin are
examples of therapeutic agents that can be used in this
application.
[0176] It is known that the presence of bacteria on the implant
surface can result in a localized decrease in pH. For polymers that
comprise ionic exchange groups, for example, carboxylic groups,
these polymers can have a localized increase in release of the
therapeutic agent in response to the localized decrease in pH as a
result of the presence of the bacteria. For therapeutic agents that
contain carboxylic acid groups, polymers with pendant end-groups
comprising primary, secondary, tertiary or quaternary amines can be
used to modulate the release of the therapeutic agent.
[0177] Therapeutic agents with available functional groups can be
covalently attached to the medical implant surface using several
chemical methods. If the polymeric material used to manufacture the
implant has available surface functional groups then these can be
used for covalent attachment of the agent. For example, if the
implant surface contains carboxylic acid groups, these groups can
be converted to activated carboxylic acid groups (e.g., acid
chlorides, succinimidyl derivatives, 4-nitrophenyl ester
derivatives, etc). These activated carboxylic acid groups can then
be reacted with amine functional groups that are present on the
therapeutic agent (e.g., methotrexate, mitoxantrone).
[0178] For surfaces that do not contain appropriate functional
groups, these groups can be introduced to the polymer surface via a
plasma treatment regime. For example, carboxylic acid groups can be
introduced via a plasma treatment process process (e.g., the use of
O.sub.2 and/or CO.sub.2 as a component in the feed gas mixture).
The carboxylic acid groups can also be introduced using acrylic
acid or methacrylic acid in the gas stream. These carboxylic acid
groups can then be converted to activated carboxylic acid groups
(e.g., acid chlorides, succinimidyl derivatives, 4-nitrophenyl
ester derivatives, etc.) that can subsequently be reacted with
amine functional groups that are present on the therapeutic
agent.
[0179] In addition to direct covalent bonding to the implant
surface, the therapeutic agents with available functional groups
can be covalently attached to the medical implant via a linker.
These linkers can be degradable or non-degradable. Linkers that are
hydrolytically or enzymatically cleaved are preferred. These
linkers can comprise azo, ester, amide, thioester, anhydride, or
phosphoester bonds.
[0180] To further modulate the release of the therapeutic agent
from the medical implant, portions of or the entire medical implant
may be further coated with a polymer. The polymer coating can
comprise the polymers described above. The polymer coating can be
applied by a dip coating process, a spray coating process or a
plasma deposition process. This coating can, if desired, be further
crosslinked using thermal, chemical, or radiation (e.g., visible
light, ultraviolet light, e-beam, gamma radiation, x-ray radiation)
techniques in order to further modulate the release of the
therapeutic agent from the medical implant.
[0181] This polymer coating can further contain agents that can
increase the flexibility (e.g., plasticizer--glycerol, triethyl
citrate), lubricity (e.g., hyaluronic acid), biocompatibility or
hemocompatability (e.g., heparin) of the coating.
[0182] In certain embodiments, 30% to 70% of the fluoropyrimidine
or its analog is released during the first 10 days after the
anti-infective medical implant is implanted into a patient, and the
remainder is released gradually over 20 or more days.
[0183] In certain embodiments, 20% to 70% (e.g., about 40% to about
60%) of the fluoropyrimidine or its analog (e.g., 5-FU) is released
from the anti-infective composition at day 7 after implanted into a
patient, 50% to 90% (e.g., about 60% to about 90%) released at day
14, and 70% to 95% (e.g., about 80% to about 95%) at day 21.
[0184] In certain embodiments, the release rate of the
fluoropyrimidine or its analog from the anti-infective medical
implant is substantially constant for at least 5, 10, 15, 20, 25,
or 30 days. The release rate is substantially constant for a period
of time when at a given time point within the period of time, the
release rate is within the range of 75% to 125% of the average
release rate during this period of time.
[0185] The anti-infective medical implants can be packaged and
sterilized. Ethylene oxide may be used to sterilize the medical
implants prepared as described herein.
IV. Clinical Applications
[0186] In order to further the understanding of the invention,
discussed in more detail below are various clinical applications
for the compositions, methods and devices provided herein.
[0187] Briefly, as noted above, within one aspect of the invention
methods are provided for preventing, reducing, and/or inhibiting an
infection associated with a medical device or implant, comprising
the step of introducing into a patient a medical implant which
releases a chemotherapeutic agent, wherein the chemotherapeutic
agent reduces, inhibits, or prevents the growth or transmission of
foreign organisms (e.g., bacteria, fungi, or viruses). As used
herein, agents that reduce, inhibit, or prevent the growth or
transmission of foreign organisms in a patient means that the
growth or transmission of a foreign organism is reduced, inhibited,
or prevented in a statistically significant manner in at least one
clinical outcome, or by any measure routinely used by persons of
ordinary skill in the art as a diagnostic criterion in determining
the same. In a preferred embodiment, the medical implant has been
covered or coated with a fluoropyrimidine (e.g., 5-FU).
[0188] Particularly preferred fluoropyrimidines or analogs thereof
which are utilized within the context of the present invention
should have an MIC of less than or equal to any one of 10.sup.-4M,
10.sup.-5M, 10.sup.-6M, or, 10.sup.-7M. Furthermore, particularly
preferred fluoropyrimidines or analogs thereof are suitable for use
at concentrations less than that 10%, 5%, or even 1% of the
concentration typically used in chemotherapeutic applications
(Goodman and Gilman's The Pharmacological Basis of Therapeutics.
Editors J. G. Hardman, L. L. Limbird. Consulting editor A. Goodman
Gilman Tenth Edition. McGraw-Hill Medical publishing division. 10th
edition, 2001, 2148 pp.). Finally, the devices should preferably be
provided sterile, and suitable for use in humans.
[0189] A. Vascular Catheter--Associated Infections
[0190] More than 30 million patients receive infusion therapy
annually in the United States. In fact, 30% of all hospitalized
patients have at least one vascular catheter in place during their
stay in hospital. A variety of medical devices are used for
infusion therapy including, but not restricted to, peripheral
intravenous catheters, central venous catheters, total parenteral
nutrition catheters, peripherally inserted central venous catheters
(PIC lines), totally implanted intravascular access devices,
flow-directed balloon-tipped pulmonary artery catheters, arterial
lines, and long-term central venous access catheters (Hickman
lines, Broviac catheters).
[0191] Unfortunately, vascular access catheters are prone to
infection by a variety of bacteria and are a common cause of
bloodstream infection. Of the 100,000 bloodstream infections in US
hospitals each year, many are related to the presence of an
intravascular device. For example, 55,000 cases of bloodstream
infections are caused by central venous catheters, while a
significant percentage of the remaining cases are related to
peripheral intravenous catheters and arterial lines.
[0192] Bacteremia related to the presence of intravascular devices
is not a trivial clinical concern: 50% of all patients developing
this type of infection will die as a result (over 23,000 deaths per
year) and in those who survive, their hospitalization will be
prolonged by an average of 24 days. Complications related to
bloodstream infections include cellulites, the formation of
abscesses, septic thrombophlebitis, and infective endocarditis.
Therefore, there is a tremendous clinical need to reduce the
morbidity and mortality associated with intravascular catheter
infections.
[0193] The most common point of entry for the infection-causing
bacteria is tracking along the device from the insertion site in
the skin. Skin flora spread along the outside of the device to
ultimately gain access to the bloodstream. Other possible sources
of infection include a contaminated infusate, contamination of the
catheter hub-infusion tubing junction, and hospital personnel. The
incidence of infection increases the longer the catheter remains in
place and any device remaining in situ for more than 72 hours is
particularly susceptible. The most common infectious agents include
common skin flora such as coagulase-negative staphylococci (S.
epidermidis, S. saprophyticus) and Staphylococcus aureus
(particularly MRSA--methicillin-resistant S. aureus) which account
for 2/3 of all infections. Coagulase-negative staphylococci (CNS)
is the most commonly isolated organism from the blood of
hospitalized patients. CNS infections tend to be indolent; often
occurring after a long latent period between contamination (i.e.
exposure of the medical device to CNS bacteria from the skin during
implantation) and the onset of clinical illness. Unfortunately,
most clinically significant CNS infections are caused by bacterial
strains that are resistant to multiple antibiotics, making them
particularly difficult to treat. Other organisms known to cause
vascular access catheter-related infections include Enterococci
(e.g. E. coli, VRE--vancomycin-resistant enterococcci),
Gram-negative aerobic bacilli, Pseudomonas aeruginosa, Klebsiella
spp., Serratia marcescens, Burkholderia cepacia, Citrobacter
freundii, Corynebacteria spp. and Candida species.
[0194] Most cases of vascular access catheter-related infection
require removal of the catheter and treatment with systemic
antibiotics (although few antibiotics are effective), with
vancomycin being the drug of choice. As mentioned previously,
mortality associated with vascular access catheter-related
infection is high, while the morbidity and cost associated with
treating survivors is also extremely significant.
[0195] It is therefore extremely important to develop vascular
access catheters capable of reducing the incidence of bloodstream
infections. Since it is impossible to predict in advance which
catheters will become infected, any catheter expected to be in
place longer than a couple of days would benefit from a therapeutic
coating capable of reducing the incidence of bacterial colonization
of the device. An ideal therapeutic coating would have one or more
of the following characteristics: (a) the ability to kill, prevent,
or inhibit colonization of a wide array of potential infectious
agents including most or all of the species listed above; (b) the
ability to kill, prevent, or inhibit colonization of bacteria (such
as CNS and VRE) that are resistant to multiple antibiotics; (c)
utilize a therapeutic agent unlikely to be used in the treatment of
a bloodstream infection should one develop (i.e., one would not
want to coat the device with a broad-acting antibiotic, for if a
strain of bacteria resistant to the antibiotic were to develop on
the device it would jeopardize systemic treatment of the patient
since the infecting agent would be resistant to a potentially
useful therapeutic).
[0196] Fluoropyrimidines (e.g., 5-FU) have a high degree of
antibacterial activity against CNS (S. epidermidis) and
Staphylococcus aureus--the most common causes of vascular catheter
infections. It is important to note that not all anticancer agents
are suitable for the practice of the present invention as several
agents, including 2-mercaptopurine, 6-mercaptopurine, hydroxyurea,
cytarabine, cisplatinum, tubercidin, paclitaxel, and camptothecin
did not have antibacterial activity against the organisms known to
cause vascular access catheter-related infections.
[0197] 1. Central Venous Catheters
[0198] For the purposes of this invention, the term "Central Venous
Catheters" should be understood to include any catheter or line
that is used to deliver fluids (e.g., intravenous fluids, blood
products, drugs, and parenteral nutrition solutions) to, as well as
blood withdrawal from, the large (central) veins of the body (e.g.,
jugular, pulmary, femoral, iliac, inferior vena cava, superior vena
cava, axillary etc.).
[0199] There are many types of central venous catheters (CVC) that
vary by insertion technique, size, tip style, catheter material,
and number of lumens.
[0200] There are non-tunneled percutaneously placed catheters as
well as tunneled catheters. Non-tunneled CVCs are placed directly
into one of the large central veins with direct access. For
example, the HOHN CVC (C.R. Bard, Inc.) is a silicone, open-ended,
non-tunneled catheter. The HOHN CVC may have a single or dual
lumen. The dual lumen version is for multi-purpose access when two
separate fluid pathways are required.
[0201] Tunneled CVCs are typically designed for long-term vascular
access and for patients that lack adequate peripheral venous
access. The tunneled catheter is the best choice when access to the
vein is needed for long period of time and when the catheter line
will be used many times each day. They are used to tunnel
subcutaneously from one of the large central veins to the desired
exit site and can have single, dual or triple lumens. Some may be
bifurcated to aid in functionality. Tunneled CVCs are often
composed of processed silicone or polyurethane. Examples of
tunneled CVCs made of silicone with an open-end include, but are
not limited to, the HICKMAN, LEONARD and BROVIAC CVCs (C.R. Bard,
Inc., Murray Hill, N.J.). The GROSHONG CVC (C.R. Bard, Inc.) which
is also a tunneled silicone CVC has a closed rounded tip style.
Unlike, open-ended catheters (such as the HICKMAN, LEONARD and
BROVIAC lines), the closed end has a valve or valves that allow
liquids to flow in or out, but remains closed when not in use to
restrict back flow and air embolisms.
[0202] Another type of tunneled CVC are the polyurethane,
open-ended "power" CVCs made by C.R. Bard, Inc. For example, the
POWERLINE CVC is a kink-resistant, reverse-tapered design which has
an exclusive bifurcated design. The POWERLINE, POWERHOHN and
POWERHICKMAN (C.R. Bard, Inc.) may be used for either long or short
term indications where power injection (e.g., power injection of
contrast media) is needed.
[0203] Some tunneled CVCs are very specialized in their indication
of use. For example, the DU PEN Epidural Catheter (C.R. Bard, Inc.)
which is a silicone based, open-ended catheter is intended for
long-term access to the epidural space for the delivery of morphine
to relieve pain associated with cancer.
[0204] Other types of CVCs include, but are not limited to total
parenteral nutrition catheters, peripherally inserted central
venous catheters, and flow-directed balloon-tipped pulmonary artery
catheters. Representative examples of such CVCs are described in
U.S. Pat. Nos. 3,995,623, 4,072,146 4,096,860, 4,099,528,
4,134,402, 4,180,068, 4,385,631, 4,406,656, 4,568,329, 4,960,409,
5,176,661, 5,916,208.
[0205] CVCs can provide a suitable surface for the colonization of
microorganisms. Bacteria that are present on the skin, around the
catheter hubs, or surrounding the CVC insertion site can become
established on the catheter surface. When bacteria that colonize on
and around the catheter propagate along the catheter surface and
into the intracutaneous tract, they can disseminate away from the
catheter and seed into the bloodstream. This may result in systemic
bloodstream infections, which can lead to significant increases in
morbidity and mortality.
[0206] Although many infectious agents can colonize and infect a
catheter, skin microorganisms are the most common causes of
catheter-related infection. Staphylococci (S. aureus, S.
epidermidis, and S. pyogenes), Enterococci (E. coli), Gram Negative
Aerobic Bacilli, and Pseudomonas aeruginosa are all common causes
of CRI.
[0207] Microorganisms commonly present on the skin and those
associated with catheter-related infection (CRI) produce proteins
that enhance their adherence properties. The production of these
proteins promotes the formation of biofilms, which influences
microbial resistance to host defense mechanisms. Biofilms can be
defined as a highly consolidated structure composed of bacteria
reversibly attached to themselves or a substrate, embedded in a
matrix of polymeric substances.
[0208] Biofilm formation begins with the attachment of bacteria to
a surface of the catheter, followed by cell proliferation and
intracellular adhesion. A CVC first becomes coated with plasma and
connective tissue proteins, such as fibronectin, fibrinogen,
vitronectin, thombospondin, lamin, collagen and von Willebrand
factor. These proteins then act as receptors for colonizing
bacteria. Following adherence to the catheter surface, bacteria
multiply and accumulate in multilayered clusters followed by
differentiation into exopolysaccharide-encased mature biofilms.
Within biofilms, bacteria acquire or develop different
characteristics. Following adherence to the catheter surface,
bacteria multiply and accumulate in multilayered clusters followed
by differentiation into exopolysaccharide-encased muture biofilms.
Thus the biofilm shields bacteria against immune response
mechanisms and systemic antibiotics. Bacteria in biofilms are
protected from host defenses and antibacterial treatments due to a
number of biofilm properties. This decreased susceptibility to
antimicrobial agents requires that novel strategies be developed to
prevent CRIs.
[0209] The most frequent life-threatening complication of CVC use
is septicemia. Other severe complications of central venous
catheter infection include infective endocarditis and suppurative
phlebitis of the great veins. If the device becomes infected, it
must be replaced at a new site (over-the-wire exchange is not
acceptable) which puts the patient at further risk to develop
mechanical complications of insertion such as bleeding,
pneumothorax and hemothorax. In addition, systemic antibiotic
therapy is also required.
[0210] As described previously, 55,000 cases of bloodstream
infections are caused by central venous catheters every year in the
United States resulting in 23,000 deaths. The risk of infection
increases the longer the catheter remains in place, particularly if
it is used beyond 72 hours. Severe complications of central venous
catheter infection also include infective endocarditis and
suppurative phlebitis of the great veins. If the device becomes
infected, it must be replaced at a new site (over-the-wire exchange
is not acceptable) which puts the patient at further risk to
develop mechanical complications of insertion such as bleeding,
pneumothorax and hemothorax. In addition, systemic antibiotic
therapy is also required. An effective therapy would reduce the
incidence of device infection, reduce the incidence of bloodstream
infection, reduce the mortality rate, reduce the incidence of
complications (such as endocarditis or suppurative phlebitis),
prolong the effectiveness of the central venous catheter and/or
reduce the need to replace the catheter. This would result in lower
mortality and morbidity for patients with central venous catheters
in place.
[0211] Antibiotic-coated catheters have been developed to prevent
bacterial infections, but these catheters may become colonized by
bacteria that are resistant to the antibiotic coating. Antibiotic
resistance creates additional complications, as these infections
cannot be treated systemically with the antibiotic(s) used in the
coating. Antibacterial resistance is a concern that has reduced the
utilization of antibiotic-coated CVCs. Widespread acceptance and
usage of antibiotic-coated catheters may be limited because of the
risk of developing antibiotic resistant organisms that would
require newer and/or stronger antibiotics. Additional concerns
regarding the use of antibiotic-coated catheters include the
additional time that must be spent preparing the coated catheter
for insertion and the lack of efficacy against yeasts of the
anti-infective agents that are in common use.
[0212] Some other means of preventing microbial infections have
been implemented including adding cuffs to the ends of the
catheter. For example, Dacron cuffs about 2 cm above the exit site
may act as a barrier to ascending microorganisms and act to prevent
catheter dislodgment. Other examples of catheter cuffs include the
SURECUFF Tissue Ingrowth Cuff (means to fix the catheter in a
subcutaneous tunnel) or VITACUFF Antimicrobial Cuff (designed to
protect against infections related to vascular access catheters).
Cuffs may be used as a means to incorporate an antimicrobial agent
into its materials. For example, the VITACUFF is composed of two
concentric layers of materials (silicone and collagen matrix which
are collectively known as VITAGUARD) to decrease the incidence of
infection at the outer, tissue-interfacing surface of the VITACUFF
device. By adding additional antimicrobial agents to the cuff, more
effective antimicrobial properties may be achieved.
[0213] In a preferred embodiment, a fluoropyrimidine ((e.g.,
5-fluorouracil) or an analog thereof is formulated into a coating
applied to the surface of the vascular catheter. The drug can be
applied to the central venous catheter system in several manners:
(a) as a coating applied to the exterior surface of the
intravascular portion of the catheter and/or the segment of the
catheter that traverses the skin; (b) as a coating applied to the
interior and exterior surface of the intravascular portion of the
catheter and/or the segment of the catheter that traverses the
skin; (c) incorporated into the polymers which comprise the
intravascular portion of the catheter; (d) incorporated into, or
applied to the surface of, a subcutaneous "cuff" around the
catheter; (e) in solution in the infusate; (f) incorporated into,
or applied as a coating to, the catheter hub, junctions and/or
infusion tubing; and (g) any combination of the aforementioned.
[0214] Drug-coating of, or drug incorporation into, the central
venous catheter will allow bacteriocidal drug levels to be achieved
locally on the catheter surface, thus reducing the incidence of
bacterial colonization of the vascular catheter (and subsequent
development of blood borne infection), while producing negligible
systemic exposure to the drugs. Although for some agents polymeric
carriers are not required for attachment of the drug to the
catheter surface, several polymeric carriers are particularly
suitable for use in this embodiment. Of particular interest are
polymeric carriers such as polyurethanes (e.g., ChronoFlex AL 85A
[CT Biomaterials], ChronoFlex AR [CT Biomaterials], HydroMed640.TM.
[CT Biomaterials], HYDROSLIP C.TM. [CT Biomaterials],
HYDROTHANE.TM. [CT Biomaterials]), acrylic or methacrylic
copolymers (e.g., poly(ethylene-co-acrylic acid), cellulose-derived
polymers (e.g. nitrocellulose, Cellulose Acetate Butyrate,
Cellulose acetate propionate), acrylate and methacrylate copolymers
(e.g., poly(ethylene-co-vinyl acetate)) as well as blends thereof.
Detailed description of the compositions that may be used for
coating central intravenous catheters is provided in the above
Composition and Formulation section.
[0215] As central venous catheters are made in a variety of
configurations and sizes, the exact dose administered will vary
with device size, surface area and design. However, certain
principles can be applied in the application of this art. Drug dose
can be calculated as a function of dose per unit area (of the
portion of the device being coated), total drug dose administered
can be measured and appropriate surface concentrations of active
drug can be determined. Regardless of the method of application of
the drug to the central venous catheter, dosing guidelines are
provided in the above Medical Implants section.
[0216] The anti-infective central venous catheters provided herein
may be used to reduce or inhibit infections associated with central
venous catheters, including bacterial colonization, local
infection, and infection in bloodstream associated with catheters.
The anti-infective central venous catheters provided herein also
may inhibit the formation of biofilm on the surface of the
catheter. Such catheters comprise fluoropyrimidines or their
analogs (e.g., 5-fluorouracil) that have anti-infective activities
against a broad spectrum of microorganisms (e.g., gram positive
bacteria). In addition, the polymeric coating on the catheters
allows the fluoropyrimidines or their analogs to be released at
effective concentrations for a sustained period of time.
[0217] 2. Peripheral Intravenous Catheters
[0218] For the purposes of this invention, the term "Peripheral
Venous Catheters" should be understood to include any catheter or
line that is used to deliver fluids to the smaller (peripheral)
superficial veins of the body (e.g., veins in the arm or leg).
Peripheral venous catheters include radial and femoral access
catheters.
[0219] Peripherally inserted central catheter (PICC or PIC line) is
a form of intravenous access whereby they can be used for extended
periods of time (e.g., long chemotherapy regimens, extended
antibiotic therapy or total parenteral nutrition). PICCs typically
provide central intravenous access for several weeks, but may
remain in place for several months. PICCs are usually inserted in a
peripheral vein, such as the cephalic vein, basilica vein, or
brachial vein and then advanced through increasingly larger veins
toward the heart until the tip rests in the distal superior vena
cava.
[0220] Certain types of PICCs have multiple lumens such as the POLY
PER-Q-CATH Triple-Lumen PICC (C.R. Bard) and the TWINCATH Multiple
Lumen Peripheral Catheter made by Arrow International, Inc.
(Reading, Pa.).
[0221] Certain types of PICCs have been approved for use in power
injection, such as the polyurethane PICCs made by C.R. Bard, Inc.
The POWERPICC Catheter and the POWERPICC SOLO Catheter come in
single, dual or triple lumens. They are used for injection of
contrast media into the bloodstream. Other power injection
catheters include the XCELA Power Injectable PICC (Boston
Scientific) and the PRO-PICC CT (Medical Components, Inc.,
Harleysville, Pa.). Arrow International also makes a Pressure
Injectable PICC.
[0222] Some PICCs have greater radiopacity. For example, the POLY
RADPICC Catheters made by C.R. Bard are specifically designed with
greater radiopacity. These polyurethane-based catheters have a
kink-resistant hub enhancing strength and comfort. The RADPICC
catheters also made by C.R. Bard are silicone based which are
available in either single or dual lumens. The VASCU-PICC II which
has greater x-ray and fluoroscopic visibility is made by Medical
Components. Another PICC that has greater imaging capabilities is
the MORPHEUS CT PICC made by Angiodynamics Inc. (Queensbury,
N.Y.).
[0223] PICCs may be open-ended or may be valved. Examples of
open-ended PICCs include, but are not limited to, the polyurethane
ARROW PICC (Arrow International), the polyurethane POLY PER-Q-CATH
PICC and the POWERPICC Catheters (C.R. Bard) as well as the
silicone PER-Q-CATH PICC (C.R. Bard). Smiths Medical (Herts, UK)
makes open-ended PICCs such as the DELTEC CLINICATH and POLYFLOW
PICCs.
[0224] Examples of valved PICCs include, but are not limited to,
the silicone-based GROSHONG PICC lines and the polyurethane-based
POWERPICC SOLO Catheter from C.R. Bard. Boston Scientific (Natick,
Mass.) makes the VAXCEL PICC with PASV Valve technology.
[0225] Other peripherally inserted catheters are midline catheters.
Midline catheters are inserted peripherally but unlike the PICC
that ends at the heart or the largest central vein, the midline
catheter tip does not extend to the heart. Typically, the midline
catheter tip ends at an upstream vein. Midline catheters are also
typically not used as long as PICCs. Examples of midline catheters,
include those made by C.R. Bard such as the silicone open-ended
midlne catheters (e.g., PER-Q-CATH Plus Midline Catheter) and the
silicone valved midline catheters (e.g., GROSHONG Midline
Catheter). Arrow International makes the polyurethane open-ended
ARROW Midline Catheter.
[0226] Peripheral venous catheters have a much lower rate of
infection than do central venous catheters, particularly if they
are in place for less than 72 hours. One exception is peripheral
catheters inserted into the femoral vein (so called "femoral
lines") which have a significantly higher rate of infection. The
organisms that cause infections in a peripheral venous catheter are
identical to those described above (for central venous
catheters).
[0227] In a preferred embodiment, a fluoropyrimidine (e.g.,
5-fluorouracil) or an analog thereof is formulated into a coating
applied to the surface of the peripheral vascular catheter. The
drug can be applied to the peripheral venous catheter system in
several manners: (a) as a coating applied to the exterior and/or
interior surface of the intravascular portion of the catheter
and/or the segment of the catheter that traverses the skin; (b)
incorporated into the polymers which comprise the intravascular
portion of the catheter; (c) incorporated into, or applied to the
surface of, a subcutaneous "cuff" around the catheter; (e) in
solution in the infusate; (f) incorporated into, or applied as a
coating to, the catheter hub, junctions and/or infusion tubing; and
(g) any combination of the aforementioned.
[0228] The formulation and dosing guidelines for this embodiment
are identical to those described for central venous catheters.
[0229] The anti-infective peripheral venous catheters provided
herein may be used to reduce or inhibit infections associated with
peripheral venous catheters, including bacterial colonization,
local infection, and infection in bloodstream associated with
catheters. The anti-infective peripheral venous catheters provided
herein also may inhibit the formation of biofilm on the surface of
the catheter. Such catheters comprise fluoropyrimidines (e.g.,
5-fluorouracil) or their analogs that have anti-infective
activities against a broad spectrum of microorganisms (e.g., gram
positive bacteria). In addition, the polymeric coating on the
catheters allows the fluoropyrimidines or their analogs to be
released at effective concentrations for a sustained period of
time.
[0230] 3. Arterial Lines and Transducers
[0231] Arterial lines are used to draw arterial blood gasses,
obtain accurate blood pressure readings and to deliver fluids. They
are placed in a peripheral artery (typically the radial artery of
the wrist) and often remain in place for several days. Arterial
line catheters are typically those catheters that are used for
peripheral lines. Arterial lines are often composed of a transducer
setup (such as the DELTRAN pressure transducer from Utah Medical
Products, Inc., Midvale, Utah) at the open end of the arterial
catheter. This maintains a pressure to control the forward flow
into the artery to ensure the arterial blood pressure of the
patient does not result in the patient's blood climbing up the
catheter line.
[0232] Arterial lines have a very high rate of infection (12-20% of
arterial lines become infected) and the causative organisms are
identical to those described above (for central venous
catheters).
[0233] In a preferred embodiment, a fluoropyrimidine (e.g.,
5-fluorouracil) or an analog thereof is formulated into a coating
applied to the arterial line and transducer in several manners: (a)
as a coating applied to the exterior and/or interior surface of the
intravascular portion of the arterial line and/or the segment of
the arterial line that traverses the skin; (b) incorporated into
the polymers which comprise the intravascular portion of the
arterial line; (c) incorporated into, or applied to the surface of,
a subcutaneous "cuff" around the arterial line; (e) in solution in
the infusate; (f) incorporated into, or applied as a coating to,
the arterial line hub, junctions and/or infusion tubing; and (g)
any combination of the aforementioned.
[0234] The formulation and dosing guidelines for this embodiment
are identical to those described for central venous catheters.
[0235] The anti-infective arterial lines provided herein may be
used to reduce or inhibit infections associated with arterial
lines, including bacterial colonization, local infection, and
infection in bloodstream associated with arterial lines. The
anti-infective arterial lines provided herein also may inhibit the
formation of biofilm on the surface of the arterial lines. Such
arterial lines comprise fluoropyrimidines (e.g., 5-fluorouracil) or
their analogs that have anti-infective activities against a broad
spectrum of microorganisms (e.g., gram positive bacteria). In
addition, the polymeric coating on the arterial lines allows the
fluoropyrimidines or their analogs to be released at effective
concentrations for a sustained period of time.
[0236] 4. Port-Catheters
[0237] Port-catheters provide implantable accessibility for repeat
access to the vascular system or to the peritoneal cavity. Ports
have two main components consisting of an injection port with a
self-sealing septum and a catheter. The port reservoir is implanted
subcutaneously and is tunneled via central catheter to the large
central vein in the chest. Port access is performed by percutaneous
needle insertion using non-coring needles.
[0238] Arterial ports are implantable vascular access devices that
provide repeated access to the vascular system for the delivery of
medications, intravenous fluids, parenteral nutrition solutions,
blood products, imaging solutions and for the withdrawal of blood
samples.
[0239] Peritoneal ports with peritoneal catheters are a totally
implantable access device designed to provide repeated access to
the peritoneal cavity for the delivery of medications and other
fluids.
[0240] Ports may be used with either open-ended catheters or valved
catheters. For example, implanted ports, such as the BARDPORT,
SLIMPORT and X-PORT (C.R. Bard), may be used with open-ended
radiopaque silicone or CHRONOFLEX polyurethane catheters. When
security against blood reflux and air embolism in the port/catheter
system is required, valved catheters, such as the GROSHONG
catheters, are used. Ports typically used with GROSHONG catheters
are the BARDPORT and X-PORT products. Other valved implantable
ports include the PASV Valved VAXCEL Implantable Port from Boston
Scientific.
[0241] Other ports can be used for power injection of contrast
media. For example, the POWERPORT (C.R. Bard) implanted port may be
used with the POWERLOC Safety Infusion Set to deliver power
injection of contrast media.
[0242] Ports may have either a single lumen or a dual lumen to
facilitate multiple-infusion therapy. Most of the ports have single
lumens, however, some dual lumen ports include the SLIMPORT
Dual-Lumen ROSENBLATT Implanted Port and the M.R.I. Dual-Lumen
Implanted Port made by C.R. Bard.
[0243] Ports may also have low, intermediate or full size profiles.
For example, C.R. Bard makes low profile ports, such as the M.R.I.
ULTRA SLIMPORT and the SLIMPORT Dual-Lumen ROSENBLATT Implanted
Port. Intermediate profile ports made by C.R. Bard include the
X-PORT (duo and inline) Dual-Lumen Implanted Ports, and full
profile ports made by C.R. Bard include the Titanium DOME Implanted
Port and the M.R.I. Implanted Port.
[0244] The formulation and dosing guidelines for this embodiment
are identical to those described for central venous catheters.
[0245] The anti-infective port-catheters provided herein may be
used to reduce or inhibit infections associated with
port-catheters, including bacterial colonization, local infection,
and infection in bloodstream associated with the port-catheters.
The anti-infective port-catheters provided herein also may inhibit
the formation of biofilm on the surface of the catheters. Such
catheters comprise fluoropyrimidines (e.g., 5-fluorouracil) or
their analogs that have anti-infective activities against a broad
spectrum of microorganisms (e.g., gram positive bacteria). In
addition, the polymeric coating on the catheters allows the
fluoropyrimidines or their analogs to be released at effective
concentrations for a sustained period of time.
[0246] B. Infections Associated with Dialysis Catheters
[0247] In 1997, there were over 300,000 patients in the United
States with end-stage renal disease. The typical form of treatment
is dialysis in the form of either hemodialysis (63%) or peritoneal
dialysis (9%). A full renal transplantion occurs in the remaining
cases.
[0248] In the case of hemodialysis, reliable access is required to
the vascular system typically as a surgically created arteriovenous
fistula (AVF; 18%), via a synthetic bridge graft (usually a PTFE
arteriovenous interposition graft in the forearm or leg; 50%) or a
dialysis catheter (32%). In hemodialysis, the patient's blood is
pumped through the blood compartment of a dialyzer machine,
exposing it to a semipermeable membrane. The cleansed blood is then
returned via the circuit back to the body. Ultrafiltration occurs
by increasing the hydrostatic pressure across the dialyzer
membrane.
[0249] In the case of peritoneal dialysis, regular exchange of
dialysate through the peritoneum is required via a double-cuffed
and tunneled peritoneal dialysis catheter. In peritoneal dialysis,
a sterile solution containing minerals and glucose is run through a
tube into the peritoneal cavity, the abdominal body cavity around
the intestine, where the peritoneal membrane acts as a
semipermeable membrane. The dialysate is left there for a period of
time to absorb waste products, and then it is drained out through
the catheter and discarded.
[0250] Regardless of the form of dialysis employed, infection is
the second leading cause of death in renal failure patients (15.5%
of all deaths) after heart disease. A significant number of those
infections are secondary to the dialysis procedure itself.
Hemodialysis Access Grafts
[0251] Kidney failure patients have a dysfunctional immune response
that makes them particularly susceptible to infection. Infections
of hemodialysis access grafts are characterized as either being
early (within month; thought to be a complication of surgery) and
late (after 1 month; thought to be related to access care). Over a
2 year period, approximately 2% of AVF's become infected while
11-16% of PTFE grafts will become infected on at least one
occasion. Although infection can result from extension of an
infection from an adjacent contaminated tissue or hematogenous
seeding, the most common cause of infection is intraoperative
contamination. The most common causes of infection include
Staphylococcus aureus, Enterobacteriaceae, Pseudomonas aerugenosa,
and Coagulase Negative Staphylococci.
[0252] Complications arising from hemodialysis access graft
infection include sepsis, subcutaneous infection, false aneurysm
formation, endocarditis, osteomyelitis, septic arthritis,
haemorrhage, septic or thrombotic emboli, graft thrombosis and
septic dealth (2-4% of all infections). Treatment often requires
removal of part or all of the graft combined with systemic
antibiotics.
[0253] In a preferred embodiment, a fluoropyrimidine (e.g.,
5-fluorouracil) or an analog thereof is formulated into a coating
applied to the surface of the components of the synthetic
hemodialysis access graft. The drug can be applied in several
manners: (a) as a coating applied to the external surface of the
graft; (b) as a coating applied to the internal (luminal) surface
of the graft; and/or (c) as a coating applied to all or parts of
both surfaces. For an AVF, the drug would be formulated into a
surgical implant placed around the outside of the fistula at the
time of surgery.
[0254] Drug-coating of, or drug incorporation into hemodialysis
access grafts will allow bacteriocidal drug levels to be achieved
locally on the graft surface, thus reducing the incidence of
bacterial colonization and subsequent development of infectious
complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required
for attachment of the drug, several polymeric carriers are
particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g.,
ChronoFlex AL 85A [CT Biomaterials], ChronoFlex AR [CT
Biometerials], HydroMed640.TM. [CT Biomaterials], HYDROSLIP C.TM.
[CT Biomaterials], HYDROTHANE.TM. [CT Biomaterials]), acrylic or
methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid),
cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate
Butyrate, Cellulose acetate propionate), acrylate and methacrylate
copolymers (e.g. poly(ethylene-co-vinyl acetate)), collagen, PLG as
well as blends thereof. Detailed description of the compositions
that may be used for coating hemodialysis access graft is provided
in the above Composition and Formulation section.
[0255] An effective hemodialysis access graft coating would reduce
the incidence of complications such as sepsis, haemorrhage,
thrombosis, embolism, endocarditis, osteomyelitis and even death.
An effective coating would also decrease the number of hemodialysis
access grafts requiring replacement, resulting in lower mortality
and morbidity for patients with these implants.
[0256] As hemodialysis access grafts are made in a variety of
configurations and sizes, the exact dose administered will vary
with device size, surface area, design and portions of the graft
coated. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function
of dose per unit area (of the portion of the device being coated),
total drug dose administered can be measured and appropriate
surface concentrations of active drug can be determined. Regardless
of the method of application of the drug to the hemodialysis access
graft, dosing guidelines are provided in the above Medical Implants
section.
Hemodialysis Catheters
[0257] A hemodialysis catheter is a venous catheter used for
hemodialysis (i.e., dialysis of the blood). It is a type of central
venous catheter and may be inserted into the subclavian, internal
jugular, or femoral veins. It contains two lumens: one for
withdrawing blood from the patient and carries it to dialysis
machine, the other for returns blood to the patient from the
dialysis machine. They typically are tunneled catheters and may be
cuffed or non-cuffed. Hemodialysis catheters may be used for a
short period (e.g., up to 30 days), an intermediate period (e.g., 1
to 3 months), or a long period (e.g., 6-12 months). An exemplary
hemodialysis catheter that may be used for a long period is
HEMOSTREAM chronic dialysis catheter from Angiotech.
[0258] A variety of dialysis catheters are available for use in
hemodialysis including, but not restricted to, CVCs which are
totally implanted such as the Lifesite (Vasca Inc., Tewksbury,
Mass.) and the Dialock (Biolink Corp., Middleboro, Mass.).
[0259] Longterm vascular access catheters, such as the HICKMAN
Hemodialysis/Apheresis CVC made by C.R. Bard are designed for
hemodialysis, hemoperfusion and apheresis as well as the
administration of intravenous fluids, blood products, drugs,
parenteral nutrition solutions and blood withdrawal. Other
catheters used for long-term hemodialysis made by C.R. Bard include
the HEMOSTAR Catheter lines and the HEMOSPLIT Catheter lines made
of CARBOTHANE radiopaque polyurethane. The SOFT-CELL Dual Lumen
Catheter (C.R. Bard) is made from polyurethane in both straight and
pre-curved designs which can be used in both long-term and
short-term vascular access for hemodialysis, hemoperfusion or
apheresis therapy.
[0260] Short-term hemodialysis catheters, such as the NIAGARA
Catheter lines and BREVIA Short-Term Dialysis Catheter by C.R.
Bard, are made of thermosensitive BODYSOFT polyurethane and are
used for attaining temporary vascular access for less than 30
days.
[0261] Common problems associated with hemodialysis catheters are
infection and clotting. The anti-infective hemodialysis catheters
provided herein may be used to reduce or inhibit infections
associated with hemodialysis catheters. In addition, as described
above, in certain embodiments, the hemodialysis catheter may
further comprise an antithromotic agent in an amount effective in
reducing or inhibiting clotting associate with the catheter. For
example, the antithromotic agent may be in the composition that
comprises a polyurethane, cellulose or a cellulose-derived polymer,
and a fluoropyrimidine or its analog, such as in form of a coating.
In other embodiments, the antithromotic agent may be present on the
surface (e.g., exterior surface) of a distal section of the
catheter shaft while the anti-infective composition may be present
on the surface (e.g., exterior surface) of a proximal section of
the catheter shaft.
Peritoneal Dialysis Catheters
[0262] Peritoneal dialysis catheters are typically double-cuffed
and tunneled catheters that provide access to the peritoneum. The
most common peritoneal dialysis catheter designs are the TENCKHOFF
Catheter, the SWAN NECK Missouri and SWAN NECK CURL CATH Missouri
Peritoneal Catheters and the Toronto Western Catheter. In
peritoneal dialysis, the peritoneum acts as a semipermeable
membrane across which solutes can be exchanged down a concentration
gradient.
[0263] Peritoneal dialysis infections are typically classified as
either peritonitis or exit-site/tunnel infections (i.e. catheter
infections). Exit-site/tunnel infections are characterized by
redness, induration or purulent discharge from the exit site or
subcutaneous portions of the catheter. Peritonitis is more a severe
infection that causes abdominal pain, nausea, fever and systemic
evidence of infection. Unfortunately, the peritoneal dialysis
catheter likely plays a role in both types of infection. In
exit-site/tunnel infections, the catheter itself becomes infected.
In peritonitis, the infection is frequently the result of bacteria
tracking from the skin through the catheter lumen or migrating on
the outer surface (pericatheter route) of the catheter into the
peritoneum. Peritoneal catheter-related infections are typically
caused by Staphylococcus aureus, Coagulase Negative Staphylococci,
Escherichia coli, Viridans group streptococci, Enterobacteriacae,
Corynebacterium, Branhamella, Actinobacter, Serratia, Proteus,
Pseudomonas aeruginosa and Fungi.
[0264] Treatment of peritonitis involves rapid in-and-out exchanges
of dialysate, systemic antibiotics (intravenous and/or
intraperitoneal administration) and often requires removal of the
catheter. Complications include hospitalization, the need to switch
to another form of dialysis (30%) and mortality (2%; higher if the
infection is due to Enterococci, S. aureus or polymicrobial).
[0265] In a preferred embodiment, a fluoropyrimidine (e.g.,
5-fluorouracil) or an analog thereof is formulated into a coating
applied to the surface of the components of the synthetic
peritoneal dialysis catheter. The drug can be applied in several
manners: (a) as a coating applied to the external surface of the
catheter; (b) as a coating applied to the internal (luminal)
surface of the catheter; (c) as a coating applied to the
superficial cuff; (d) as a coating applied to the deep cuff; (e)
incorporated into the polymers that comprise the catheter; and/or
(f) as a coating applied to a combination of these surfaces.
[0266] Drug-coating of, or drug incorporation into, peritoneal
dialysis grafts will allow bacteriocidal drug levels to be achieved
locally on the graft surface, thus reducing the incidence of
bacterial colonization and subsequent development of infectious
complications, while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required
for attachment of the drug, several polymeric carriers are
particularly suitable for use in this embodiment. Of particular
interest are polymeric carriers such as polyurethanes (e.g.,
ChronoFlex AL 85A [CT Biomaterials], ChronoFlex AR [CT
Biomaterials], HydroMed640.TM. [CT Biomaterials], HYDROSLIP C.TM.
[CT Biomaterials], HYDROTHANE.TM. [CT Biomaterials]), acrylic or
methacrylic copolymers (e.g. poly(ethylene-co-acrylic acid),
cellulose-derived polymers (e.g. nitrocellulose, Cellulose Acetate
Butyrate, Cellulose acetate propionate), acrylate and methacrylate
copolymers (e.g. poly(ethylene-co-vinyl acetate)) as well as blends
thereof. Detailed description of the compositions that may be used
for coating central intravenous catheters is provided in the above
Composition and Formulation section.
[0267] An effective peritoneal dialysis catheter coating would
reduce the incidence of complications such as hospitalization,
peritonoitis, sepsis, and even death. An effective coating would
also decrease the number of peritoneal dialysis catheters requiring
replacement, resulting in lower mortality and morbidity for
patients with these implants.
[0268] As peritoneal dialysis catheters are made in a variety of
configurations and sizes, the exact dose administered will vary
with device size, surface area, design and portions of the graft
coated. However, certain principles can be applied in the
application of this art. Drug dose can be calculated as a function
of dose per unit area (of the portion of the device being coated),
total drug dose administered can be measured and appropriate
surface concentrations of active drug can be determined. Regardless
of the method of application of the drug to the peritoneal dialysis
graft, the dosing guidelines are provided in the above Medical
Implants section. The anti-infective peritoneal dialysis catheters
provided herein may be used to reduce or inhibit infections
associated with peritoneal dialysis catheters.
[0269] C. Infections Associated with Other Medical Devices and
Implants
[0270] Implants are commonly used in the practice of medicine and
surgery for a wide variety of purposes. These include implants such
as drainage tubes (such as the ASPIRA Pleural Drainage Catheter
from C.R. Bard), biliary T-tubes, clips, sutures, meshes, barriers
(for the prevention of adhesions), anastomotic devices, conduits,
irrigation fluids, packing agents, stents, staples, inferior vena
cava filters, embolization agents, pumps (for the delivery of
therapeutics), hemostatic implants (sponges), tissue fillers,
cosmetic implants (breast implants, facial implants, prostheses),
bone grafts, skin grafts, intrauterine devices (IUD), ligatures,
titanium implants (particularly in dentistry), chest tubes,
nasogastric tubes (such as the BARD Jejunal Feeding/Gastric
Decompression Tube from C.R. Bard), percutaneous feeding tubes
(such as the BARD Button Replacement Gastrostomy Devices, the BARD
PEG Feeding Devices, the DUAL PORT WIZARD Low-Profile Gastrostomy
Device, FASTRAC Gastric Access Port, the GAUDERER GENIE System, the
PONSKY Non-Balloon Replacement Gastrostomy Tubes, and the BARD
Tri-Funnel Replacement Gastrostomy Tube from C.R. Bard), colostomy
devices, bone wax, and Penrose drains, hair plugs, ear rings, nose
rings, and other piercing-associated implants, as well as
anaesthetic solutions to name a few. Any foreign body when placed
into the body is at risk for developing an infection--particularly
in the period immediately following implantation.
[0271] The drug-coating, dosing, surface concentrations and release
kinetics of these implants is as described in the above Composition
and Formulation section and the Medical Implants section. In
addition, 5-fluorouracil can be added to solutions used in medicine
(storage solutions, irrigation fluids, saline, mannitol, glucose
solutions, lipids, nutritional fluids, and anaesthetic solutions)
to prevent infection transmitted via infected solutions/fluids used
in patient management.
[0272] It should be readily evident to one of skill in the art that
any of the previously mentioned agents, or derivatives and
analogues thereof, can be utilized to create variation of the above
compositions without deviating from the spirit and scope of the
invention.
[0273] The following examples are provided by way of illustration,
and not by way of limitation.
EXAMPLES
Example 1
MIC Determination by Microtitre Broth Dilution Method
[0274] A. MIC Assay of Various Gram Negative and Positive
Bacteria
[0275] MIC assays were conducted essentially as described by
Amsterdam, D. 1996. Susceptibility testing of antimicrobials in
liquid media, p. 52-111. In Loman, V., ed. Antibiotics in
laboratory medicine, 4th ed. Williams and Wilkins, Baltimore, Md.
Briefly, a variety of compounds were tested for antibacterial
activity against isolates of P. aeruginosa, K. pneumoniae, E. coli,
S. epidermidus and S. aureus in the MIC (minimum inhibitory
concentration assay under aerobic conditions using 96 well
polystyrene microtitre plates (Falcon 1177), and Mueller Hinton
broth at 37.degree. C. incubated for 24h. (MHB was used for most
testing except C721 (S. pyogenes), which used Todd Hewitt broth,
and Haemophilus influenzae, which used Haemophilus test medium
(HTM)) Tests were conducted in triplicate. The results are provided
below in Table 1.
TABLE-US-00003 TABLE 1 Minimum Inhibitory Concentrations of
Therapeutic Agents Against Various Gram Negative and Positive
Bacteria Bactrial Strain P. aeruginosa K. pneumoniae E. coli S.
aureus PAE/K799 ATCC13883 UB1005 ATCC25923 S. epidermidis S.
pyogenes H187 C238 C498 C622 C621 C721 Wt wt wt wt wt wt Drug Gram-
Gram- Gram- Gram+ Gram+ Gram+ doxorubicin 10.sup.-5 10.sup.-6
10.sup.-4 10.sup.-5 10.sup.-6 10.sup.-7 mitoxantrone 10.sup.-5
10.sup.-6 10.sup.-5 10.sup.-5 10.sup.-5 10.sup.-6 5-fluorouracil
10.sup.-5 10.sup.-6 10.sup.-6 10.sup.-7 10.sup.-7 10.sup.-4
methotrexate N 10.sup.-6 N 10.sup.-5 N 10.sup.-6 etoposide N
10.sup.-5 N 10.sup.-5 10.sup.-6 10.sup.-5 camptothecin N N N N
10.sup.-4 N hydroxyurea 10.sup.-4 N N N N 10.sup.-4 cisplatin
10.sup.-4 N N N N N tubercidin N N N N N N 2- N N N N N N
mercaptopurine 6- N N N N N N mercaptopurine Cytarabine N N N N N N
Activities are in Molar concentrations Wt = wild type N = No
activity
[0276] B. MIC of Antibiotic-Resistant Bacteria
[0277] Various concentrations of the following compounds,
mitoxantrone, cisplatin, tubercidin, methotrexate, 5-fluorouracil,
etoposide, 2-mercaptopurine, doxorubicin, 6-mercaptopurine,
camptothecin, hydroxyurea and cytarabine were tested for
antibacterial activity against clinical isolates of a methicillin
resistant S. aureus and a vancomycin resistant pediocoocus clinical
isolate in an MIC assay as described above. Compounds which showed
inhibition of growth (MIC value of <1.0.times.10-3) included:
mitoxantrone (both strains), methotrexate (vancomycin resistant
pediococcus), 5-fluorouracil (both strains), etoposide (both
strains), and 2-mercaptopurine (vancomycin resistant
pediococcus).
Example 2
Catheter--Dip Coating--Non-Degradable Polymer
[0278] A coating solution is prepared by dissolving 20 g ChronoFlex
Al 85A (CT Biomaterials) in 100 mL DMAC:THF (40:60) at 50.degree.
C. with stirring. Once dissolved, the polymer solution is cooled to
room temperature. 20 mg mitoxantrone is added to 2 mL of the
polyurethane solution. The solution is stirred until a homogenious
mixture is obtained. Polyurethane 7 French tubing is dipped into
the polymer/drug solution and then withdrawn. The coated tube is
air dried (80.degree. C.). The sample is then dried under vacuum to
further reduce the residual solvent in the coating.
Example 3
Catheter--Dip Coating--Degradable Polymer
[0279] A coating solution is prepared by dissolving 2 g PLG (50:50)
in 10 mL dichloromethane:methanol (70:30). Once dissolved, 20 mg
mitoxantrone is added to the polymer solution. Once the solution is
a homogeneous solution, polyurethane 7 French tubing is dipped into
the solution and then withdrawn. The coated tube is air dried. The
sample is then dried under vacuum to further reduce the residual
solvent in the coating.
Example 4
Catheter--Dip Coating--Drug Only
[0280] 1 mL methanol is added to 20 mg mitoxantrone. Polyurethane 7
French tubing is dipped into the solution and then withdrawn. The
coated tube is air dried. The sample is then dried under vacuum to
further reduce the residual solvent in the coating.
Example 5
Catheter--Dip Coating--Drug Impregnation
[0281] 0.6 mL methanol is added to 20 mg mitoxantrone. 1.4 mL DMAC
is added slowly. Polyurethane 7 French tubing is dipped into the
solution. After various periods of time (2 min, 5 min, 10 min, 20
min, 30 min) the tube was withdrawn. The coated tube is air dried
(80.degree. C.). The sample is then dried under vacuum to further
reduce the residual solvent in the coating.
Example 6
Tympanostomy Tubes--Dip Coating--Non-Degradable Polymer
[0282] A coating solution is prepared by dissolving 20 g ChronoFlex
Al 85A (CT Biomaterials) in 100 mL DMAC:THF (50:50) at 50.degree.
C. with stirring. Once dissolved, the polymer solution is cooled to
room temperature. 20 mg mitoxantrone is added to 2 mL of the
polyurethane solution. The solution is stirred until a homogenious
mixture is obtained. A stainless steel tympanostomy tube is dipped
into the polymer/drug solution and then withdrawn. The coated tube
is air dried (80.degree. C.). The sample is then dried under vacuum
to further reduce the residual solvent in the coating.
Example 7
Catheter--Dip Coating--Non-Degradable Polymer
[0283] A coating solution is prepared by dissolving 20 g ChronoFlex
Al 85A (CT Biomaterials) in 100 mL THF at 50.degree. C. with
stirring. Once dissolved, the polymer solution is cooled to room
temperature. 20 mg etoposide is added to 2 mL of the polyurethane
solution. The solution is stirred until a homogenious mixture is
obtained. Polyurethane 7 French tubing is dipped into the
polymer/drug solution and then withdrawn. The coated tube is air
dried (80 C). The sample is then dried under vacuum to further
reduce the residual solvent in the coating.
Example 8
Catheter--Dip Coating--Degradable Polymer
[0284] A coating solution is prepared by dissolving 2 g PLG (50:50)
in 10 mL dichloromethane:methanol (70:30). Once dissolved, 20 mg
etoposide is added to the polymer solution. Once the solution is a
homogeneous solution, polyurethane 7 French tubing is dipped into
the solution and then withdrawn. The coated tube is air dried. The
sample is then dried under vacuum to further reduce the residual
solvent in the coating.
Example 9
Catheter--Dip Coating--Drug Only
[0285] 1 mL THF is added to 20 mg etoposide. Polyurethane 7 French
tubing is dipped into the solution and then withdrawn. The coated
tube is air dried. The sample is then dried under vacuum to further
reduce the residual solvent in the coating.
Example 10
Catheter--Dip Coating--Drug Impregnation
[0286] 0.6 mL methanol is added to 1.4 mL DMAC which contains 20 mg
etoposide. Polyurethane 7 French tubing is dipped into the
solution. After various periods of time (2 min, 5 min, 10 min, 20
min, 30 min) the tube was withdrawn. The coated tube is air dried
(80.degree. C.). The sample is then dried under vacuum to further
reduce the residual solvent in the coating.
Example 11
Tympanostomy Tubes--Dip Coating--Non-Degradable Polymer
[0287] A coating solution is prepared by dissolving 20 g ChronoFlex
Al 85A (CT Biomaterials) in 100 mL DMAC:THF (50:50) at 50.degree.
C. with stirring. Once dissolved, the polymer solution is cooled to
room temperature. 20 mg etoposide is added to 2 mL of the
polyurethane solution. The solution is stirred until a homogenious
mixture is obtained. A stainless steel tympanostomy tube is dipped
into the polymer/drug solution and then withdrawn. The coated tube
is air dried (80.degree. C.). The sample is then dried under vacuum
to further reduce the residual solvent in the coating.
Example 12
Covalent Attachment of Doxorubicin to a Polymer Coated Device
[0288] A piece of polyurethane 7 French tubing, with and without an
oxygen plasma pretreatment step, is dipped into a solution of 5%
(w/w) poly(ethylene-co acrylic acid) in THF. The sample was dried
at 45.degree. C. for 3 hours. The coated tubing was then dipped
into a water:methanol (30:70) solution that contained
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20 mg/mL
Doxorubicin. After various times (15 min, 30 min, 60 min 120 min)
the tubing is removed from the solution and dried at 60.degree. C.
for 2 hours followed by vacuum drying for 24 hours.
Example 13
Covalent Attachment of Doxorubicin to a Device Surface
[0289] A piece of polyurethane 7 French tubing that has undergone a
oxygen plasma pretreatment step is dipped into a water:methanol
(30:70) solution that contained
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and 20 mg/mL
Doxorubicin. After various times (15 min, 30 min, 60 min 120 min)
the tubing is removed from the solution and dried at 60.degree. C.
for 2 hours followed by vacuum drying for 24 hours.
Example 14
Impregnation of 5-Fluorouracil into Polyurethane Catheter
[0290] A solution was prepared by dissolving 100 mg of
5-Fluorouracil into 20 ml anhydrous methanol. Polyurethane catheter
tubing was immersed in this solution for 16 hours. The catheter
tubing was vacuum dried at 50.degree. C. for 16 hours.
Example 15
Impregnation of Mitoxantrone into Polyurethane Catheter
[0291] A solution was prepared by dissolving 20 mg of
Mitoxantrone-2HCl into 20 ml anhydrous methanol. Polyurethane
catheter tubing was immersed in this solution for 16 hours. The
catheter tubing was vacuum dried at 50.degree. C. for 16 hours.
Example 16
Impregnation of Doxorubicin into Polyurethane Catheter
[0292] A solution was prepared by dissolving 20 mg of
Doxorubicin-HCl into 20 ml anhydrous methanol. Polyurethane
catheter tubing was immersed in this solution for 16 hours. The
catheter tubing was vacuum dried at 50.degree. C. for 16 hours.
Example 17
Polyurethane Dip Coating with 5-Fluorouracil
[0293] A solution was prepared by dissolving 125 mg 5-Fluorouracil
and 2.5 g of Chronoflex AL85A (CT Biomaterials) in 50 ml of THF at
55.degree. C. The solution was cooled to room temperature.
Polyurethane catheters were weighted at one end and dipped in
solution and then removed immediately. This process was repeated
three times with 1 minute drying time interval between each dipping
process. The catheter tubing was vacuum dried at 50.degree. C. for
16 hours.
Example 18
Polyurethane Dip Coating with 5-Fluorouracil and Palmitic Acid
[0294] A solution was prepared by dissolving 125 mg 5-Fluorouracil,
62.5 mg of palmitic acid, and 2.437 g of Chronoflex AL85A (CT
Biomaterials) in 50 ml of THF at 55.degree. C. The solution was
cooled to room temperature. Polyurethane catheters were weighted at
one end and dipped in solution and then removed immediately. This
process was repeated three times with a 1 minute drying time
interval between each dipping process. The catheter tubing was
vacuum dried at 50.degree. C. for 16 hours.
Example 19
Catheter Dip Coating with Nafion and Mitoxantrone
[0295] Catheters are weighted at one end and dipped into 5% Nafion
solution (Dupont) and then removed immediately. This process was
repeated three times with a 1 minute drying time interval between
each dipping process. The catheter tubing was dried at room
temperature for 2 hours. A solution was prepared with 1 mg of
mitoxantrone-2HCl in 40 ml of deionized water. The catheter tubing
was immersed in the solution for 5 minutes, and then was washed
with deionized water and dried at room temperature.
Example 20
Catheter Dip Coating with Nafion and Doxorubicin
[0296] Catheters are weighted at one end and dipped into 5% Nafion
solution (Dupont) and then removed immediately. This process was
repeated three times with a 1 minute drying time interval between
each dipping process. The catheter tubing was dried at room
temperature for 2 hours. A solution was prepared with 1 mg of
doxorubicin-HCl in 40 ml of deionized water. The catheter tubing
was immersed in the solution for 5 minutes, and then was washed
with deionized water and dried at room temperature.
Example 21
Preparation of Release Buffer
[0297] The release buffer was prepared by adding 8.22 g sodium
chloride, 0.32 g sodium phosphate monobasic (monohydrate) and 2.60
g sodium phosphate dibasic (anhydrous) to a beaker. 1 L HPLC grade
water was added and the solution was stirred until all the salts
were dissolved. If required, the pH of the solution was adjusted to
pH 7.4.+-.0.2 using either 0.1 N NaOH or 0.1 N phosphoric acid.
Example 22
Release Study to Determine Release Profile of the Therapeutic Agent
from a Catheter
[0298] A sample of the therapeutic agent-loaded catheter was placed
in a 15 mL culture tube. 15 mL release buffer (Example 21) was
added to the culture tube. The tube was sealed with a Teflon lined
screw cap and was placed on a rotating wheel in a 37.degree. C.
oven. At various time point, the buffer is withdrawn from the
culture tube and is replaced with fresh buffer. The withdrawn
buffer is then analysed for the amount of therapeutic agent
contained in this buffer solution.
Example 23
HPLC Analysis of Therapeutic Agents in Release Buffer
[0299] The following chromatographic conditions were used to
quantify the amount of the therapeutic agent in the release
medium:
TABLE-US-00004 Flow Run Injection Detection Therapeutic Rate Time
Volume Wavelength Agent Column Mobile Phase (mL/min) (min) (uL)
(nm) 5-Fluorouracil YMC ODS-AQ PBS, pH 6.8 1 8 100 268 150 .times.
4.6 mm, 5 um Doxorubicin ACE 5 (V02-742) 20% CAN, 26% 1 10 10 254
150 .times. 4 mm Methanol, 54% PBS (pH 3.6) Mitoxantrone ACE 5 C18,
Phosphate buffer (pH 1 4 10 658 150 .times. 4 mm, 5 um 2.3)
Example 24
Effect of Palmitic Acid on the Release Profile of 5-Fluorouracil
from a Polyurethane Film
[0300] A 25% (w/v) Chronoflex AL 85A (CT Biomaterials) solution was
prepared in THF. 50 mg 5-fluorouracil was weighed into each of 4
glass scintillation vials. Various amount of palmitic acid were
added to each vial. 20 mL of the polyurethane solution was added to
each scintillation vial. The samples were rotated at 37.degree. C.
until the solids had all dissolved. Samples were then cast as films
using a casting knife on a piece of release liner. Samples were air
dried and then dried overnight under vacuum. A portion of these
samples were used to perform release studies (Example 22). FIG. 1
show the effect of palmitic acid on the release profile of
5-fluorouracil.
Example 25
Radial Diffusion Assay for Testing Drug Impregnated Catheters
Against Various Strains of Bacteria
[0301] An overnight bacterial culture was diluted 1 to 5 to a final
volume of 5 mls fresh Mueller Hinton broth. Then 100 .mu.l of the
diluted bacterial culture were spread onto Mueller Hinton agar
plates. A test material (e.g., catheter tubing), with or without
drug, was placed on the center of the plate. For example, catheters
are typically 1 cm long and about 3 mm in diameter (which may be
made of polyurethane, silicon or other suitable material) and are
loaded with drug either through dip-coating or through use of a
drug-impregnated coating. The plates were incubated at 37.degree.
C. for 16-18 hours. The zone of clearing around a test material was
then measured (e.g., the distance from the catheter to where
bacterial growth is inhibited), which indicated the degree of
bacterial growth prevention. Various bacterial strains that may be
tested include, but are not limited to, the following: E. coli C498
UB1005, P. aeruginosa H187, S. aureus C622 ATCC 25923, and S.
epidermidis C621.
[0302] One cm polyurethane catheters coated with 5-fluorouracil at
several concentrations (2.5 mg/mL and 5.0 mg/mL) were examined for
their effect against S. aureus. The zone of inhibition around the
catheters coated in a solution of 2.5 mg/mL 5-Fluorouracil and
placed on Mueller Hinton agar plates as described above was
35.times.39 mm, and for the catheters coated in a solution of 5.0
mg/mL 5-Fluorouracil was 30.times.37 mm. Catheters without drug
showed no zone of inhibition. These results demonstrate the
efficacy of 5-fluorouracil coated on a catheter at inhibiting the
growth of S. aureus.
Example 26
Preparation of Coated Central Venous Catheters
[0303] CVC's were cleaned from their proximal ends of the body to
the distal tips by wiping with VWR SPEC-WIPE.RTM. 7 Wiper that was
wetted with 75/25 IPA/MEK. The catheters were allowed to dry for a
minimum of 60 minutes at ambient temperature.
[0304] The catheters were then loaded onto the angle brackets that
were used as fixtures for coating. The coating cup was placed on
the catheter, and the angle bracket was loaded onto the coating
machine. A coating solution prepared in accordance with the
invention was added to the coating cups and the catheters were
coated. During the process the inner lumens of the catheters were
air purged to ensure that the lumen and ports are free from coating
solution occlusion.
[0305] The coated catheters were removed from the coating machine
and dried at 85.+-.5.degree. C. for 20 minutes in a vented oven to
remove residual solvents to acceptable levels. The coated catheters
were removed from the oven and cooled. The coated catheters were
visually inspected under 10.times. magnification for particles in
the coating, damage of the catheter surface, imperfections, and
occlusions. FIGS. 2A and 2B show uncoated CVC and 5-FU coated CVC,
respectively.
[0306] As shown in FIG. 2B, the resulting catheter was uniformly
coated on its exterior surface. In addition, the coating did not
block the outlet ports and had good adhesion to the catheter under
both wet and dry conditions.
[0307] The coated catheters were sterilized using 10% ethylene
oxide (EtO)/90% HFCF gas.
[0308] The total amount of drug on the coated catheters was
measured and the values were expressed as total amount per catheter
(.mu.g) and amount per unit catheter length (.mu.g/cm). 5-FU was
exhaustively extracted from the coated portion of the catheter in
methanol with sonication and the extracts were then analyzed by
high performance liquid chromatography (HPLC). An average drug
loading of 969.+-.23 .mu.g of 5-FU/coated catheter was determined
from the analysis of four separate CVC lots.
[0309] From the foregoing, it will be appreciated that, although
specific embodiments of the invention have been described herein
for purposes of illustration, various modifications may be made
without deviating from the spirit and scope of the invention.
Accordingly, the invention is not limited except as by the appended
claims.
* * * * *