U.S. patent application number 11/888511 was filed with the patent office on 2007-11-22 for compositions and methods for coating medical implants.
This patent application is currently assigned to 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 | 20070270447 11/888511 |
Document ID | / |
Family ID | 29584566 |
Filed Date | 2007-11-22 |
United States Patent
Application |
20070270447 |
Kind Code |
A1 |
Hunter; William L. ; et
al. |
November 22, 2007 |
Compositions and methods for coating medical implants
Abstract
Medical implants are provided which release an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, and/or platinum complex, thereby
inhibiting or reducing the incidence of infection associated with
the implant.
Inventors: |
Hunter; William L.;
(Vancouver, CA) ; Gravett; David M.; (Vancouver,
CA) ; Toleikis; Philip M.; (Vancouver, CA) ;
Liggins; Richard T.; (Coquitlam, CA) ; Loss; Troy A.
E.; (North Vancouver, CA) |
Correspondence
Address: |
SEED INTELLECTUAL PROPERTY LAW GROUP PLLC
701 FIFTH AVENUE, SUITE 5400
SEATTLE
WA
98104-7092
US
|
Assignee: |
Angiotech International AG
Zug
CH
|
Family ID: |
29584566 |
Appl. No.: |
11/888511 |
Filed: |
July 31, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10447309 |
May 27, 2003 |
|
|
|
11888511 |
Jul 31, 2007 |
|
|
|
60383419 |
May 24, 2002 |
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Current U.S.
Class: |
514/274 |
Current CPC
Class: |
A61L 29/085 20130101;
A61L 29/16 20130101; A61L 27/34 20130101; A61L 27/54 20130101; A61L
2300/416 20130101; A61P 43/00 20180101; A61P 31/00 20180101; A61L
2300/404 20130101 |
Class at
Publication: |
514/274 |
International
Class: |
A61K 31/513 20060101
A61K031/513; A61P 31/00 20060101 A61P031/00 |
Claims
1. A composition, comprising a polymer and a fluoropyrimidine
wherein said fluoropyrimidine is present in said composition at a
concentration of less than 10.sup.-4 M.
2. The composition according to claim 1 wherein said
fluoropyrimidine is present in said composition at a concentration
of less than any one of 10.sup.-5 M, 10.sup.-6 M, or 10.sup.-7
M.
3. The composition according to claim 1 wherein said polymer is a
non-biodegradable polymer.
4. The composition according to claim 1 wherein said polymer is a
polyurethane.
5. The composition according to claim 1 wherein said polymer is a
poly(lactide-co-glycolide).
6. The composition according to claim 1 wherein said
fluoropyrimidine is 5-fluorouracil.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. patent application
Ser. No. 10/447,309, filed May 27, 2003, 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, which applications
are incorporated herein by reference in their entireties.
BACKGROUND
[0002] 1. Technical Field
[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 DRAWING
[0010] FIG. 1 shows the effect of palmitic acid on the release
profile of 5-fluorouracil from a polyurethane sample.
BRIEF SUMMARY OF THE INVENTION
[0011] 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 an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. Within various
embodiments, the implant is coated in whole or in part with a
composition comprising an anthracycline, fluoropyrimidine, folic
acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or
platinum complex.
[0012] Other aspects of the present invention provide methods for
making medical implants, comprising adapting a medical implant
(e.g., coating the implant) with an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. Within certain
embodiments, the desired therapeutic agent 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
agent when used in the treatment of cancer.
[0013] 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) at a dosage and/or concentration which
is less than a typical dosage and/or concentration which is used
for the treatment of cancer.
[0014] Within further aspects of the invention, there is provided a
catheter which releases an agent selected from the group consisting
of an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In
one embodiment, the catheter releases a fluoropyrimidine and in
still another embodiment the fluoropyrimidine is 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 polyurethane or
poly(lactide-co-glycolide) (PLG). In related embodiments, the
catheter is a vascular catheter or a dialysis catheter. In still
other embodiments, the catheter releases an agent 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.
[0015] Within further aspects of the invention, there is provided a
heart valve which releases an agent selected from the group
consisting of an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum
complex. In one embodiment, the heart valve releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the heart valve
further comprises a polymer wherein the agent is released from a
polymer on the heart valve. In certain embodiments, the heart valve
has a polymer that is polyurethane or PLG. In related embodiments,
the heart valve is a prosthetic heart valve. In still other
embodiments, the heart valve releases an agent that is present on
the heart valve at a concentration which is less than the typical
dosage and/or concentration that is used in the treatment of
cancer.
[0016] Within further aspects of the invention, there is provided a
cardiac pacemaker which releases an agent selected from the group
consisting of an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum
complex. In one embodiment, the cardiac pacemaker releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the cardiac
pacemaker further comprises a polymer wherein the agent is released
from a polymer on the cardiac pacemaker. In certain embodiments,
the cardiac pacemaker has a polymer that is polyurethane or PLG. In
still other embodiments, the cardiac pacemaker releases an agent
that is present on the cardiac pacemaker 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
implantable cardioverter defibrillator which releases an agent
selected from the group consisting of an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex. In one embodiment,
the implantable cardioverter defibrillator releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the implantable
cardioverter defibrillator further comprises a polymer wherein the
agent is released from a polymer on the implantable cardioverter
defibrillator. In certain embodiments, the implantable cardioverter
defibrillator has a polymer that is polyurethane or PLG. In still
other embodiments, the implantable cardioverter defibrillator
releases an agent that is present on the implantable cardioverter
defibrillator at a concentration which is less than the typical
dosage and/or concentration that is used in the treatment of
cancer.
[0018] Within further aspects of the invention, there is provided a
graft which releases an agent selected from the group consisting of
an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex. In
one embodiment, the graft releases a fluoropyrimidine and in still
another embodiment the fluoropyrimidine is 5-FU. In other
embodiments, the graft further comprises a polymer wherein the
agent is released from a polymer on the graft. In certain
embodiments, the graft has a polymer that is polyurethane or PLG.
In related embodiments, the graft is a vascular graft or a
hemodialysis access graft. In still other embodiments, the graft
releases an agent that is present on the graft at a concentration
which is less than the typical dosage and/or concentration that is
used in the treatment of cancer.
[0019] Within further aspects of the invention, there is provided a
ear, nose, or throat implant which releases an agent selected from
the group consisting of an anthracycline, fluoropyrimidine, folic
acid antagonist, podophylotoxin, camptothecin, hydroxyurea, or
platinum complex. In one embodiment, the ear, nose, or throat
implant releases a fluoropyrimidine and in still another embodiment
the fluoropyrimidine is 5-FU. In other embodiments, the ear, nose,
or throat implant further comprises a polymer wherein the agent is
released from a polymer on the ear, nose, or throat implant. In
certain embodiments, the ear, nose, or throat implant has a polymer
that is polyurethane or PLG. In related embodiments, the ear, nose,
or throat implant is a tympanostomy tube or a sinus stent. In still
other embodiments, the ear, nose, or throat implant releases an
agent that is present on the ear, nose, or throat implant at a
concentration which is less than the typical dosage and/or
concentration that is used in the treatment of cancer.
[0020] Within further aspects of the invention, there is provided a
urological implant which releases an agent selected from the group
consisting of an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum
complex. In one embodiment, the urological implant releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the urological
implant further comprises a polymer wherein the agent is released
from a polymer on the urological implant. In certain embodiments,
the urological implant has a polymer that is polyurethane or PLG.
In related embodiments, the urological implant is a urinary
catheter, ureteral stent, urethral stent, bladder sphincter, or
penile implant. In still other embodiments, the urological implant
releases an agent that is present on the urological implant at a
concentration which is less than the typical dosage and/or
concentration that is used in the treatment of cancer.
[0021] Within further aspects of the invention, there is provided a
endotracheal or tracheostomy tube which releases an agent selected
from the group consisting of an anthracycline, fluoropyrimidine,
folic acid antagonist, podophylotoxin, camptothecin, hydroxyurea,
or platinum complex. In one embodiment, the endotracheal or
tracheostomy tube releases a fluoropyrimidine and in still another
embodiment the fluoropyrimidine is 5-FU. In other embodiments, the
endotracheal or tracheostomy tube further comprises a polymer
wherein the agent is released from a polymer on the endotracheal or
tracheostomy tube. In certain embodiments, the endotracheal or
tracheostomy tube has a polymer that is polyurethane or PLG. In
still other embodiments, the endotracheal or tracheostomy tube
releases an agent that is present on the endotracheal or
tracheostomy tube at a concentration which is less than the typical
dosage and/or concentration that is used in the treatment of
cancer.
[0022] Within further aspects of the invention, there is provided a
CNS shunt which releases an agent selected from the group
consisting of an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum
complex. In one embodiment, the CNS shunt releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the CNS shunt
further comprises a polymer wherein the agent is released from a
polymer on the CNS shunt. In certain embodiments, the CNS shunt has
a polymer that is polyurethane or PLG. In related embodiments, the
CNS shunt is a ventriculopleural shunt, a VA shunt, or a VP shunt.
In still other embodiments, the CNS shunt releases an agent that is
present on the CNS shunt at a concentration which is less than the
typical dosage and/or concentration that is used in the treatment
of cancer.
[0023] Within further aspects of the invention, there is provided a
orthopedic implant which releases an agent selected from the group
consisting of an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum
complex. In one embodiment, the orthopedic implant releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the orthopedic
implant further comprises a polymer wherein the agent is released
from a polymer on the orthopedic implant. In certain embodiments,
the orthopedic implant has a polymer that is polyurethane or PLG.
In related embodiments, the orthopedic implant is a prosthetic
joint or fixation device. In still other embodiments, the
orthopedic implant releases an agent that is present on the
orthopedic implant at a concentration which is less than the
typical dosage and/or concentration that is used in the treatment
of cancer.
[0024] Within further aspects of the invention, there is provided a
ocular implant which releases an agent selected from the group
consisting of an anthracycline, fluoropyrimidine, folic acid
antagonist, podophylotoxin, camptothecin, hydroxyurea, or platinum
complex. In one embodiment, the ocular implant releases a
fluoropyrimidine and in still another embodiment the
fluoropyrimidine is 5-FU. In other embodiments, the ocular implant
further comprises a polymer wherein the agent is released from a
polymer on the ocular implant. In certain embodiments, the ocular
implant has a polymer that is polyurethane or PLG. In related
embodiments, the ocular implant is an intraocular lens or a contact
lens. In still other embodiments, the ocular implant releases an
agent that is present on the ocular implant at a concentration
which is less than the typical dosage and/or concentration that is
used in the treatment of cancer.
[0025] Within other aspects of the invention, compositions are
provided comprising a polymer and an anthracycline,
fluoropyrimidine, folic acid antagonist, podophylotoxin,
camptothecin, hydroxyurea, or platinum complex, wherein said
anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex is
present in said composition at a concentration of less than any one
of 10.sup.-4 M, 10.sup.-5 M, 10.sup.-6 M, or, 10.sup.-7 M.
[0026] 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 an anthracycline, fluoropyrimidine, folic acid antagonist,
podophylotoxin, camptothecin, hydroxyurea, or platinum complex.
[0027] Within various embodiments of the above, the anthracycline
is doxorubicin or mitoxantrone, the fluoropyrimidine is
5-fluorouracil, the folic acid antagonist is methotrexate, and the
podophylotoxin is etoposide. Within further embodiments the
composition further comprises a polymer.
[0028] 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
[0029] 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.
[0030] "Medical implant" refers to devices or objects that are
implanted or inserted into a body. Representative examples include
vascular catheters, 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.
[0031] 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).
[0032] 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.
[0033] 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).
[0034] Discussed in more detail below are (I) Agents; (II)
Compositions and Formulations; (III) Devices, and (IV) Clinical
Applications.
I. Agents
[0035] 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 (A) Anthracyclines (e.g., doxorubicin and mitoxantrone),
(B) Fluoropyrimidines (e.g., 5-FU), (C) Folic acid antagonists
(e.g., methotrexate), (D) Podophylotoxins (e.g., etoposide), (E)
Camptothecins, (F) Hydroxyureas, and (G) Platinum complexes (e.g.,
cisplatin).
[0036] A. Anthracyclines
[0037] Anthracyclines have the following general structure, where
the R groups may be a variety of organic groups: ##STR1##
[0038] According to U.S. Pat. No. 5,594,158, suitable R groups are
as follows: R.sub.1 is CH.sub.3 or CH.sub.2OH; R.sub.2 is
daunosamine or H; R.sub.3 and R.sub.4 are independently one of OH,
NO.sub.2, NH.sub.2, F, Cl, Br, I, CN, H or groups derived from
these; R.sub.5 is hydrogen, hydroxy, or methoxy; and R.sub.6-8 are
all hydrogen. Alternatively, R.sub.5 and R.sub.6 are hydrogen and
R.sub.7 and R.sub.8 are alkyl or halogen, or vice versa.
[0039] According to U.S. Pat. No. 5,843,903, R.sub.1 may be a
conjugated peptide. According to U.S. Pat. No. 4,296,105, R.sub.5
may be an ether linked alkyl group. According to U.S. Pat. No.
4,215,062, R.sub.5 may be OH or an ether linked alkyl group.
R.sub.1 may also be linked to the anthracycline ring by a group
other than C(O), such as an alkyl or branched alkyl group having
the C(O) linking moiety at its end, such as
--CH.sub.2CH(CH.sub.2--X)C(O)--R.sub.1, wherein X is H or an alkyl
group (see, e.g., U.S. Pat. No. 4,215,062). R.sub.2 may alternately
be a group linked by the functional group .dbd.N--NHC(O)--Y, where
Y is a group such as a phenyl or substituted phenyl ring.
Alternately R.sub.3 may have the following structure: ##STR2## in
which R.sub.9 is OH either in or out of the plane of the ring, or
is a second sugar moiety such as R.sub.3. R.sub.10 may be H or form
a secondary amine with a group such as an aromatic group, saturated
or partially saturated 5 or 6 membered heterocyclic having at least
one ring nitrogen (see U.S. Pat. No. 5,843,903). Alternately,
R.sub.10 may be derived from an amino acid, having the structure
--C(O)CH(NHR.sub.11)(R.sub.12), in which R.sub.11 is H, or forms a
C.sub.3-4 membered alkylene with R.sub.12. R.sub.12 may be H,
alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or
methylthio (see U.S. Pat. No. 4,296,105).
[0040] Exemplary anthracyclines are Doxorubicin, Daunorubicin,
Idarubicin, Epirubicin, Pirarubicin, Zorubicin, and Carubicin.
Suitable compounds have the structures: TABLE-US-00001 ##STR3##
R.sub.1 R.sub.2 R.sub.3 Doxorubicin: OCH.sub.3 C(O)CH.sub.2OH OH
out of ring plane Epirubicin: OCH.sub.3 C(O)CH.sub.2OH OH in (4'
epimer of ring plane doxorubicin) Daunorubicin: OCH.sub.3
C(O)CH.sub.3 OH out of ring plane Idarubicin: H C(O)CH.sub.3 OH out
of ring plane Pirarubicin: OCH.sub.3 C(O)CH.sub.2OH ##STR4##
Zorubicin: OCH.sub.3 C(CH.sub.3)(.dbd.N)NHC(O)C.sub.6H.sub.5 OH
Carubicin: OH C(O)CH.sub.3 OH out of ring plane
[0041] Other suitable anthracyclines are Anthramycin, Mitoxantrone,
Menogaril, Nogalamycin, Aclacinomycin A, Olivomycin A, Chromomycin
A.sub.3, and Plicamycin having the structures: TABLE-US-00002
##STR5## ##STR6## ##STR7##
[0042] Other representative anthracyclines include, FCE 23762
doxorubicin derivative (Quaglia et al., J. Liq. Chromatogr.
17(18):3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci.
82(11):1151-1154, 1993), ruboxyl (Rapoport et al., J. Controlled
Release 58(2):153-162, 1999), anthracycline disaccharide
doxorubicin analogue (Pratesi et al., Clin. Cancer Res.
4(11):2833-2839, 1998), N-(trifluoroacetyl)doxorubicin and
4'-O-acetyl-N-(trifluoroacetyl)doxorubicin (Berube & Lepage,
Synth. Commun. 28(6):1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy
et al., Proc. Nat'l Acad. Sci. U.S.A. 95(4):1794-1799, 1998),
disaccharide doxorubicin analogues (Arcamone et al., J. Nat'l
Cancer Inst. 89(16):1217-1223, 1997),
4-demethoxy-7-O-[2,6-dideoxy-4-O-(2,3,6-trideoxy-3-amino-.alpha.-L-lyxo-h-
exopyranosyl)-.alpha.-L-lyxo-hexopyranosyl]adriamicinone
doxorubicin disaccharide analog (Monteagudo et al., Carbohydr. Res.
300(1):11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc.
Nat'l Acad. Sci. U.S.A. 94(2):652-656, 1997), morpholinyl
doxorubicin analogues (Duran et al., Cancer Chemother. Pharmacol.
38(3):210-216, 1996), enaminomalonyl-.beta.-alanine doxorubicin
derivatives (Seitz et al., Tetrahedron Lett. 36(9):1413-16, 1995),
cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med.
Chem. 38(8):1380-5, 1995), hydroxyrubicin (Solary et al., Int. J.
Cancer 58(1):85-94, 1994), methoxymorpholino doxorubicin derivative
(Kuhl et al., Cancer Chemother. Pharmacol. 33(1):10-16, 1993),
(6-maleimidocaproyl)hydrazone doxorubicin derivative (Willner et
al., Bioconjugate Chem. 4(6):521-7, 1993),
N-(5,5-diacetoxypent-1-yl)doxorubicin (Cherif & Farquhar, J.
Med. Chem. 35(17):3208-14, 1992), FCE 23762 methoxymorpholinyl
doxorubicin derivative (Ripamonti et al., Br. J. Cancer
65(5):703-7, 1992), N-hydroxysuccinimide ester doxorubicin
derivatives (Demant et al., Biochim. Biophys. Acta 1118(1):83-90,
1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero et
al., Biochim. Biophys. Acta 1129(3):294-302, 1991), morpholinyl
doxorubicin derivatives (EPA 434960), mitoxantrone doxorubicin
analogue (Krapcho et al., J. Med. Chem. 34(8):2373-80. 1991), AD198
doxorubicin analogue (Traganos et al., Cancer Res. 51(14):3682-9,
1991), 4-demethoxy-3'-N-trifluoroacetyldoxorubicin (Horton et al.,
Drug Des. Delivery 6(2):123-9, 1990), 4'-epidoxorubicin (Drzewoski
et al., Pol. J. Pharmacol. Pharm. 40(2):159-65, 1988; Weenen et
al., Eur. J. Cancer Clin. Oncol. 20(7):919-26, 1984), alkylating
cyanomorpholino doxorubicin derivative (Scudder et al., J. Nat'l
Cancer Inst. 80(16):1294-8, 1988), deoxydihydroiodooxorubicin (EPA
275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ.,
16(Biol. 1):21-7, 1988), 4'-deoxydoxorubicin (Schoelzel et al.,
Leuk. Res. 10(12):1455-9, 1986),
4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int.
Congr. Chemother. 16:285-70-285-77, 1983),
3'-deamino-3'-hydroxydoxorubicin (Horton et al., J. Antibiot.
37(8):853-8, 1984), 4-demethyoxy doxorubicin analogues (Barbieri et
al., Drugs Exp. Clin. Res. 10(2):85-90, 1984), N-L-leucyl
doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int.
Symp. Tumor Pharmacother.), 179-81, 1983),
3'-deamino-3'-(4-methoxy-1-piperidinyl)doxorubicin derivatives
(U.S. Pat. No. 4,314,054), 3'-deamino-3'-(4-mortholinyl)doxorubicin
derivatives (U.S. Pat. No. 4,301,277), 4'-deoxydoxorubicin and
4'-o-methyldoxorubicin (Giuliani et al., Int. J. Cancer 27(1):5-13,
1981), aglycone doxorubicin derivatives (Chan & Watson, J.
Pharm. Sci. 67(12):1748-52, 1978), SM 5887 (Pharma Japan 1468:20,
1995), MX-2 (Pharma Japan 1420:19, 1994),
4'-deoxy-13(S)-dihydro-4'-iododoxorubicin (EP 275966), morpholinyl
doxorubicin derivatives (EPA 434960),
3'-deamino-3'-(4-methoxy-1-piperidinyl)doxorubicin derivatives
(U.S. Pat. No. 4,314,054), doxorubicin-14-valerate,
morpholinodoxorubicin (U.S. Pat. No. 5,004,606),
3'-deamino-3'-(3''-cyano-4''-morpholinyl doxorubicin;
3'-deamino-3'-(3''-cyano-4''-morpholinyl)-13-dihydroxorubicin;
(3'-deamino-3'-(3''-cyano-4''-morpholinyl)daunorubicin;
3'-deamino-3'-(3''-cyano-4''-morpholinyl)-3-dihydrodaunorubicin;
and 3'-deamino-3'-(4''-morpholinyl-5-iminodoxorubicin and
derivatives (U.S. Pat. No. 4,585,859),
3'-deamino-3'-(4-methoxy-1-piperidinyl)doxorubicin derivatives
(U.S. Pat. No. 4,314,054) and
3-deamino-3-(4-morpholinyl)doxorubicin derivatives (U.S. Pat. No.
4,301,277).
[0043] B. Fluoropyrimidine Analogs
[0044] In another aspect, the therapeutic agent is a
fluoropyrimidine analog, such as 5-fluorouracil, or an analog or
derivative thereof, including Carmofur, Doxifluridine, Emitefur,
Tegafur, and Floxuridine. Exemplary compounds have the structures:
TABLE-US-00003 ##STR8## 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 B ##STR9## C ##STR10##
[0045] Other suitable fluoropyrimidine analogs 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: TABLE-US-00004 ##STR11##
5-Fluoro-2'-deoxyuridine: R = F 5-Bromo-2'-deoxyuridine: R = Br
5-Iodo-2'-deoxyuridine: R = I
[0046] Other representative examples of fluoropyrimidine 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-toluoyl-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).
[0047] These compounds are believed to function as therapeutic
agents by serving as antimetabolites of pyrimidine.
[0048] C. Folic Acid Antagonists
[0049] In another aspect, the therapeutic agent is a folic acid
antagonist, such as Methotrexate or derivatives or analogs thereof,
including Edatrexate, Trimetrexate, Raltitrexed, Piritrexim,
Denopterin, Tomudex, and Pteropterin. Methotrexate analogs have the
following general structure: ##STR12## The identity of the R group
may be selected from organic groups, particularly those groups set
forth in U.S. Pat. Nos. 5,166,149 and 5,382,582. For example,
R.sub.1 may be N, R.sub.2 may be N or C(CH.sub.3), R.sub.3 and
R.sub.3' may H or alkyl, e.g., CH.sub.3, R.sub.4 may be a single
bond or NR, where R is H or alkyl group. R.sub.5,6,8 may be H,
OCH.sub.3, or alternately they can be halogens or hydro groups.
R.sub.7 is a side chain of the general structure: ##STR13## wherein
n=1 for methotrexate, n=3 for pteropterin. The carboxyl groups in
the side chain may be esterified or form a salt such as a Zn.sup.2+
salt. R.sub.9 and R.sub.10 can be NH.sub.2 or may be alkyl
substituted.
[0050] Exemplary folic acid antagonist compounds have the
structures: TABLE-US-00005 ##STR14## R.sub.0 R.sub.1 R.sub.2
R.sub.3 R.sub.4 R.sub.5 R.sub.6 R.sub.7 R.sub.8 Methotrexate
NH.sub.2 N N H N(CH.sub.3) H H A(n = 1) H Edatrexate NH.sub.2 N N H
CH(CH.sub.2CH.sub.3) H H A(n = 1) H Trimetrexate NH.sub.2 CH
C(CH.sub.3) H NH H OCH.sub.3 OCH.sub.3 OCH.sub.3 Pteropterin OH N N
H NH H H A(n = 3) H Denopterin OH N N CH.sub.3 N(CH.sub.3) H H A(n
= 1) H Peritrexim NH.sub.2 N C(CH.sub.3) H single bond OCH.sub.3 H
H OCH.sub.3 ##STR15## ##STR16##
[0051] Other representative examples include 6-S-aminoacyloxymethyl
mercaptopurine derivatives (Harada et al., Chem. Pharm. Bull.
43(10):793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol.
Pharm. Bull. 18(11):1492-7, 1995),
7,8-polymethyleneimidazo-1,3,2-diazaphosphorines (Nilov et al.,
Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J.
Inorg. Biochem. 56(4):249-64, 1994), methyl-D-glucopyranoside
mercaptopurine derivatives (Da Silva et al., Eur. J. Med. Chem.
29(2):149-52, 1994) and s-alkynyl mercaptopurine derivatives
(Ratsino et al., Khim.-Farm. Zh. 15(8):65-7,1981); indoline ring
and a modified ornithine or glutamic acid-bearing methotrexate
derivatives (Matsuoka et al., Chem. Pharm. Bull.
45(7):1146-1150,1997), alkyl-substituted benzene ring C bearing
methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull.
44(12):2287-2293, 1996), benzoxazine or benzothiazine
moiety-bearing methotrexate derivatives (Matsuoka et al., J. Med.
Chem. 40(1):105-111, 1997), 10-deazaminopterin analogues (DeGraw et
al., J. Med. Chem. 40(3):370-376, 1997), 5-deazaminopterin and
5,10-dideazaminopterin methotrexate analogues (Piper et al., J.
Med. Chem. 40(3):377-384, 1997), indoline moiety-bearing
methotrexate derivatives (Matsuoka et al., Chem. Pharm. Bull.
44(7): 1332-1337,1996), lipophilic amide methotrexate derivatives
(Pignatello et al., World Meet. Pharm., Biopharm. Pharm. Technol.,
563-4,1995), L-threo-(2S,4S)-4-fluoroglutamic acid and
DL-3,3-difluoroglutamic acid-containing methotrexate analogues
(Hart et al., J. Med. Chem. 39(1):56-65,1996), methotrexate
tetrahydroquinazoline analogue (Gangjee, et al., J. Heterocycl.
Chem. 32(1):243-8, 1995), N-(.alpha.-aminoacyl) methotrexate
derivatives (Cheung et al., Pteridines 3(1-2):101-2, 1992), biotin
methotrexate derivatives (Fan et al., Pteridines 3(1-2):131-2,
1992), D-glutamic acid or D-erythrou, threo-4-fluoroglutamic acid
methotrexate analogues (McGuire et al., Biochem. Pharmacol.
42(12):2400-3, 1991), .beta.,.gamma.-methano methotrexate analogues
(Rosowsky et al., Pteridines 2(3):133-9,1991), 10-deazaminopterin
(10-EDAM) analogue (Braakhuis et al., Chem. Biol. Pteridines, Proc.
Int. Symp. Pteridines Folic Acid Deriv, 1027-30, 1989),
.gamma.-tetrazole methotrexate analogue (Kalman et al., Chem. Biol.
Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv.,
1154-7,1989), N-(L-.alpha.-aminoacyl)methotrexate derivatives
(Cheung et al., Heterocycles 28(2):751-8, 1989), meta and ortho
isomers of aminopterin (Rosowsky et al., J. Med. Chem. 32(12):2582,
1989), hydroxymethylmethotrexate (DE 267495),
.gamma.-fluoromethotrexate (McGuire et al., Cancer Res.
49(16):4517-25,1989), polyglutamyl methotrexate derivatives (Kumar
et al., Cancer Res. 46(10):5020-3, 1986), gem-diphosphonate
methotrexate analogues (WO 88/06158), .alpha.- and
.gamma.-substituted methotrexate analogues (Tsushima et al.,
Tetrahedron 44(17):5375-87, 1988), 5-methyl-5-deaza methotrexate
analogues (4,725,687),
N.delta.-acyl-N.alpha.-(4-amino-4-deoxypteroyl)-L-ornithine
derivatives (Rosowsky et al., J. Med. Chem. 31(7):1332-7, 1988),
8-deaza methotrexate analogues (Kuehl et al., Cancer Res.
48(6):1481-8, 1988), acivicin methotrexate analogue (Rosowsky et
al., J. Med. Chem. 30(8):1463-9, 1987), polymeric platinol
methotrexate derivative (Carraher et al., Polym. Sci. Technol.
(Plenum), 35(Adv. Biomed. Polym.):311-24,1987),
methotrexate-.gamma.-dimyristoylphophatidylethanolamine (Kinsky et
al., Biochim. Biophys. Acta 917(2):211-18,1987), methotrexate
polyglutamate analogues (Rosowsky et al., Chem. Biol. Pteridines,
Pteridines Folid Acid Deriv., Proc. Int. Symp. Pteridines Folid
Acid Deriv.: Chem., Biol. Clin. Aspects: 985-8,1986),
poly-.gamma.-glutamyl methotrexate derivatives (Kisliuk et al.,
Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc. Int.
Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin. Aspects:
989-92,1986), deoxyuridylate methotrexate derivatives (Webber et
al., Chem. Biol. Pteridines, Pteridines Folid Acid Deriv., Proc.
Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol. Clin.
Aspects: 659-62,1986), iodoacetyl lysine methotrexate analogue
(Delcamp et al., Chem. Biol. Pteridines, Pteridines Folid Acid
Deriv., Proc. Int. Symp. Pteridines Folid Acid Deriv.: Chem., Biol.
Clin. Aspects: 807-9, 1986), 2, .omega.-diaminoalkanoid
acid-containing methotrexate analogues (McGuire et al., Biochem.
Pharmacol. 35(15):2607-13, 1986), polyglutamate methotrexate
derivatives (Kamen & Winick, Methods Enzymol. 122 (Vitam.
Coenzymes, Pt. G):339-46, 1986), 5-methyl-5-deaza analogues (Piper
et al., J. Med. Chem. 29(6):1080-7, 1986), quinazoline methotrexate
analogue (Mastropaolo et al., J. Med. Chem. 29(1):155-8,1986),
pyrazine methotrexate analogue (Lever & Vestal, J. Heterocycl.
Chem. 22(1):5-6, 1985), cysteic acid and homocysteic acid
methotrexate analogues (4,490,529), .gamma.-tert-butyl methotrexate
esters (Rosowsky et al., J. Med. Chem. 28(5):660-7, 1985),
fluorinated methotrexate analogues (Tsushima et al., Heterocycles
23(1):45-9, 1985), folate methotrexate analogue (Trombe, J.
Bacteriol. 160(3):849-53, 1984), phosphonoglutamic acid analogues
(Sturtz & Guillamot, Eur. J. Med. Chem.--Chim. Ther.
19(3):267-73, 1984), poly(L-lysine)methotrexate conjugates
(Rosowsky et al., J. Med. Chem. 27(7):888-93, 1984), dilysine and
trilysine methotrexate derivates (Forsch & Rosowsky, J. Org.
Chem. 49(7):1305-9, 1984), 7-hydroxymethotrexate (Fabre et al.,
Cancer Res. 43(10):4648-52, 1983), poly-.gamma.-glutamyl
methotrexate analogues (Piper & Montgomery, Adv. Exp. Med.
Biol., 163(Folyl Antifolyl Polyglutamates):95-100, 1983),
3',5'-dichloromethotrexate (Rosowsky & Yu, J. Med. Chem.
26(10):1448-52, 1983), diazoketone and chloromethylketone
methotrexate analogues (Gangjee et al., J. Pharm. Sci.
71(6):717-19, 1982), 10-propargylaminopterin and alkyl methotrexate
homologs (Piper et al., J. Med. Chem. 25(7):877-80, 1982), lectin
derivatives of methotrexate (Lin et al., JNCI-66(3):523-8, 1981),
polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol.
17(1):105-10, 1980), halogentated methotrexate derivatives (Fox,
JNCI 58(4):J955-8, 1977), 8-alkyl-7,8-dihydro analogues (Chaykovsky
et al., J. Med. Chem. 20(10):J1323-7, 1977), 7-methyl methotrexate
derivatives and dichloromethotrexate (Rosowsky & Chen, J. Med.
Chem. 17(12):J1308-11, 1974), lipophilic methotrexate derivatives
and 3',5'-dichloromethotrexate (Rosowsky, J. Med. Chem.
16(10):J1190-3, 1973), deaza amethopterin analogues (Montgomery et
al., Ann. N.Y. Acad. Sci. 186:J227-34, 1971), MX068 (Pharma Japan,
1658:18, 1999) and cysteic acid and homocysteic acid methotrexate
analogues (EPA 0142220);
[0052] These compounds are believed to act as antimetabolites of
folic acid.
[0053] D. Podophyllotoxins
[0054] In another aspect, the therapeutic agent is a
Podophyllotoxin, or a derivative or an analog thereof. Exemplary
compounds of this type are Etoposide or Teniposide, which have the
following structures: ##STR17##
[0055] Other representative examples of podophyllotoxins include
Cu(II)-VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem.
6(7):1003-1008, 1998), pyrrolecarboxamidino-bearing etoposide
analogues (Ji et al., Bioorg. Med. Chem. Lett. 7(5):607-612, 1997),
4.beta.-amino etoposide analogues (Hu, University of North Carolina
Dissertation, 1992), .gamma.-lactone ring-modified arylamino
etoposide analogues (Zhou et al., J. Med. Chem. 37(2):287-92,
1994), N-glucosyl etoposide analogue (Allevi et al., Tetrahedron
Lett. 34(45):7313-16, 1993), etoposide A-ring analogues (Kadow et
al., Bioorg. Med. Chem. Lett. 2(1):17-22, 1992),
4'-deshydroxy-4'-methyl etoposide (Saulnier et al., Bioorg. Med.
Chem. Lett. 2(10):1213-18, 1992), pendulum ring etoposide analogues
(Sinha et al., Eur. J. Cancer 26(5):590-3, 1990) and E-ring desoxy
etoposide analogues (Saulnier et al., J. Med. Chem. 32(7):1418-20,
1989).
[0056] These compounds are believed to act as Topoisomerase II
Inhibitors and/or DNA cleaving agents.
[0057] E. Camptothecins
[0058] In another aspect, the therapeutic agent is Camptothecin, or
an analog or derivative thereof. Camptothecins have the following
general structure. ##STR18##
[0059] In this structure, X is typically 0, but can be other
groups, e.g., NH in the case of 21-lactam derivatives. R.sub.1 is
typically H or OH, but may be other groups, e.g., a terminally
hydroxylated C.sub.1-3 alkane. R.sub.2 is typically H or an amino
containing group such as (CH.sub.3).sub.2NHCH.sub.2, but may be
other groups e.g., NO.sub.2, NH.sub.2, halogen (as disclosed in,
e.g., U.S. Pat. No. 5,552,156) or a short alkane containing these
groups. R.sub.3 is typically H or a short alkyl such as
C.sub.2H.sub.5. R.sub.4 is typically H but may be other groups,
e.g., a methylenedioxy group with R.sub.1.
[0060] Exemplary camptothecin compounds include topotecan,
irinotecan (CPT-11), 9-aminocamptothecin,
21-lactam-20(S)-camptothecin, 10,11-methylenedioxycamptothecin,
SN-38, 9-nitrocamptothecin, 10-hydroxycamptothecin. Exemplary
compounds have the structures: TABLE-US-00006 ##STR19## R.sub.1
R.sub.2 R.sub.3 Camptothecin: H H H Topotecan: OH
(CH.sub.3).sub.2NHCH.sub.2 H SN-38: OH H C.sub.2H.sub.5 X: O for
most analogs, NH for 21-lactam analogs
[0061] Camptothecins have the five rings shown here. The ring
labeled E must be intact (the lactone rather than carboxylate form)
for maximum activity and minimum toxicity.
[0062] Camptothecins are believed to function as Topoisomerase I
Inhibitors and/or DNA cleavage agents.
[0063] F. Hydroxyureas
[0064] The therapeutic agent of the present invention may be a
hydroxyurea. Hydroxyureas have the following general structure:
##STR20##
[0065] Suitable hydroxyureas are disclosed in, for example, U.S.
Pat. No. 6,080,874, wherein R.sub.1 is: ##STR21## 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.
[0066] 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.
[0067] 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.
[0068] 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: ##STR22## wherein m is 1 or 2, n is 0-2 and
Y is an alkyl group.
[0069] In one aspect, the hydroxyurea has the structure:
##STR23##
[0070] These compounds are thought to function by inhibiting DNA
synthesis.
[0071] G. Platinum Complexes
[0072] In another aspect, the therapeutic agent is a platinum
compound. In general, suitable platinum complexes may be of Pt(II)
or Pt(IV) and have this basic structure: ##STR24## wherein X and Y
are anionic leaving groups such as sulfate, phosphate, carboxylate,
and halogen; R.sub.1 and R.sub.2 are alkyl, amine, amino alkyl any
may be further substituted, and are basically inert or bridging
groups. For Pt(II) complexes Z.sub.1 and Z.sub.2 are non-existent.
For Pt(IV) Z.sub.1 and Z.sub.2 may be anionic groups such as
halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See,
e.g., U.S. Pat. Nos. 4,588,831 and 4,250,189.
[0073] Suitable platinum complexes may contain multiple Pt atoms.
See, e.g., U.S. Pat. Nos. 5,409,915 and 5,380,897. For example
bisplatinum and triplatinum complexes of the type: ##STR25##
[0074] Exemplary platinum compounds are Cisplatin, Carboplatin,
Oxaliplatin, and Miboplatin having the structures: ##STR26##
[0075] Other representative platinum compounds include
(CPA).sub.2Pt[DOLYM] and (DACH)Pt[DOLYM]cisplatin (Choi et al.,
Arch. Pharmacal Res. 22(2):151-156, 1999),
Cis-[PtCl.sub.2(4,7-H-5-methyl-7-oxo]1,2,4-[triazolo[1,5-a]pyrimidine).su-
b.2] (Navarro et al., J. Med. Chem. 41(3):332-338, 1998),
[Pt(cis-1,4-DACH)(trans-Cl.sub.2)(CBDCA)].1/2MeOH cisplatin
(Shamsuddin et al., Inorg. Chem. 36(25):5969-5971, 1997),
4-pyridoxate diammine hydroxy platinum (Tokunaga et al., Pharm.
Sci. 3(7):353-356, 1997), Pt(II) . . . Pt(II)
(Pt.sub.2-[NHCHN(C(CH.sub.2)(CH.sub.3))].sub.4) (Navarro et al.,
Inorg. Chem. 35(26):7829-7835, 1996), 254-S cisplatin analogue
(Koga et al., Neurol. Res. 18(3):244-247, 1996), o-phenylenediamine
ligand bearing cisplatin analogues (Koeckerbauer & Bednarski,
J. Inorg. Biochem. 62(4):281-298, 1996), trans,
cis-[Pt(OAc).sub.2I.sub.2(en)] (Kratochwil et al., J. Med. Chem.
39(13):2499-2507, 1996), estrogenic 1,2-diarylethylenediamine
ligand (with sulfur-containing amino acids and glutathione) bearing
cisplatin analogues (Bednarski, J. Inorg. Biochem. 62(1):75, 1996),
cis-1,4-diaminocyclohexane cisplatin analogues (Shamsuddin et al.,
J. Inorg. Biochem. 61(4):291-301, 1996), 5' orientational isomer of
cis-[Pt(NH.sub.3)(4-aminoTEMP-O){d(GpG)}] (Dunham & Lippard, J.
Am. Chem. Soc. 117(43):10702-12, 1995), chelating diamine-bearing
cisplatin analogues (Koeckerbauer & Bednarski, J. Pharm. Sci.
84(7):819-23, 1995), 1,2-diarylethyleneamine ligand-bearing
cisplatin analogues (Otto et al., J. Cancer Res. Clin. Oncol.
121(1):31-8, 1995), (ethylenediamine)platinum(II) complexes (Pasini
et al., J. Chem. Soc., Dalton Trans. 4:579-85, 1995), CI-973
cisplatin analogue (Yang et al., Int. J. Oncol. 5(3):597-602,
1994), cis-diaminedichloroplatinum(II) and its analogues
cis-1,1-cyclobutanedicarbosylato(2R)-2-methyl-1,4-butanediamineplatinum(I-
I) and cis-diammine(glycolato)platinum (Claycamp & Zimbrick, J.
Inorg. Biochem. 26(4):257-67, 1986; Fan et al., Cancer Res.
48(11):3135-9, 1988; Heiger-Bernays et al., Biochemistry
29(36):8461-6, 1990; Kikkawa et al., J. Exp. Clin. Cancer Res.
12(4):233-40, 1993; Murray et al., Biochemistry 31(47):11812-17,
1992; Takahashi et al., Cancer Chemother. Pharmacol. 33(1):31-5,
1993), cis-amine-cyclohexylamine-dichloroplatinum(II) (Yoshida et
al., Biochem. Pharmacol. 48(4):793-9, 1994), gem-diphosphonate
cisplatin analogues (FR 2683529),
(meso-1,2-bis(2,6-dichloro-4-hydroxyplenyl)ethylenediamine)
dichloroplatinum(II) (Bednarski et al., J. Med. Chem.
35(23):4479-85, 1992), cisplatin analogues containing a tethered
dansyl group (Hartwig et al., J. Am. Chem. Soc. 114(21):8292-3,
1992), platinum(II) polyamines (Siegmann et al., Inorg.
Met.-Containing Polym. Mater., (Proc. Am. Chem. Soc. Int. Symp.),
335-61, 1990), cis-(3H)dichloro(ethylenediamine)platinum(II)
(Eastman, Anal. Biochem. 197(2):311-15, 1991),
trans-diamminedichloroplatinum(II) and
cis-(Pt(NH.sub.3).sub.2(N.sub.3-cytosine)CI) (Bellon & Lippard,
Biophys. Chem. 35(2-3):179-88, 1990),
3H-cis-1,2-diaminocyclohexanedichloroplatinum(II) and
3H-cis-1,2-diaminocyclohexane-malonatoplatinum (II) (Oswald et al.,
Res. Commun. Chem. Pathol. Pharmacol. 64(1):41-58, 1989),
diaminocarboxylatoplatinum (EPA 296321),
trans-(D,1)-1,2-diaminocyclohexane carrier ligand-bearing platinum
analogues (Wyrick & Chaney, J. Labelled Compd. Radiopharm.
25(4):349-57, 1988), aminoalkylaminoanthraquinone-derived cisplatin
analogues (Kitov et al., Eur. J. Med. Chem. 23(4):381-3, 1988),
spiroplatin, carboplatin, iproplatin and JM40 platinum analogues
(Schroyen et al., Eur. J. Cancer Clin. Oncol. 24(8):1309-12, 1988),
bidentate tertiary diamine-containing cisplatinum derivatives
(Orbell et al., Inorg. Chim. Acta 152(2):125-34, 1988),
platinum(II), platinum(IV) (Liu & Wang, Shandong Yike Daxue
Xuebao 24(1):35-41, 1986),
cis-diammine(1,1-cyclobutanedicarboxylato-)platinum(II)
(carboplatin, JM8) and ethylenediammine-malonatoplatinum(II) (JM40)
(Begg et al., Radiother. Oncol. 9(2):157-65, 1987), JM8 and JM9
cisplatin analogues (Harstrick et al., Int. J. Androl. 10(1);
139-45, 1987), (NPr4)2((PtCL4).cis-(PtCl2-(NH2Me).sub.2)) (Brammer
et al., J. Chem. Soc., Chem. Commun. 6:443-5, 1987), aliphatic
tricarboxylic acid platinum complexes (EPA 185225), and
cis-dichloro(amino acid) (tert-butylamine)platinum(II) complexes
(Pasini & Bersanetti, Inorg. Chim. Acta 107(4):259-67, 1985).
These compounds are thought to function by binding to DNA, i.e.,
acting as alkylating agents of DNA.
II. Compositions and Formulations
[0076] 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.
[0077] 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, Illum, 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.
[0078] 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.
[0079] 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.
[0080] 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.
[0081] 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).
[0082] 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).
[0083] Other representative examples of thermogelling cellulose
ether derivatives such as hydroxypropyl cellulose, methyl
cellulose, hydroxypropylmethyl cellulose, ethylhydroxyethyl
cellulose, and Pluronics, such as F-127.
[0084] 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.
[0085] 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).
[0086] 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. Further,
therapeutic compositions of the present invention should preferably
be stable for several months and capable of being produced, and
maintained under sterile conditions.
[0087] 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 Mm and from 30 .mu.m to
100 .mu.m.
[0088] 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.
[0089] 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.
[0090] 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).
[0091] 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.
[0092] 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).
[0093] 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.
III. Medical Implants
[0094] A. Representative Medical Implants
[0095] 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 venous 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); 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), opthalmologic 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).
[0096] B. Methods of Making Medical Implants Having Therapeutic
Agents
[0097] 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 stents, in addition to the above properties,
the composition should not render the stent thrombogenic (causing
blood clots to form), or cause significant turbulence in blood flow
(more than the stent itself would be expected to cause if it was
uncoated).
[0098] 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."
[0099] 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.
[0100] 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.
[0101] 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.
[0102] For therapeutic agents 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.
[0103] 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.
[0104] 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.
[0105] 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.
[0106] 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).
[0107] 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.
[0108] 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.
[0109] 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.
[0110] 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.
[0111] The methods above describe methods for incorporation of a
therapeutic agent into or onto a medical implant. Additional
antibacterial or antifungal agents can also be incorporated into or
onto the medical implant. These antibacterial or antifungal agents
can be incorporated into or onto the medical implant prior to,
simultaneously or after the incorporation of the therapeutic
agents, described above, into or onto the medical implant. Agents
that can be used 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.
IV. Clinical Applications
[0112] 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.
[0113] 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 an anthracycline (e.g., doxorubicin and
mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic acid antagonist
(e.g., methotrexate), podophylotoxin (e.g., etoposide),
camptothecin, hydroxyurea, and/or a platinum complexe (e.g.,
cisplatin).
[0114] Particularly preferred agents 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 agents 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.
[0115] A. Vascular Catheter--Associated Infections
[0116] 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).
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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).
[0122] Several classes of anticancer agents are particularly
suitable for incorporation into coatings for vascular catheters,
namely, anthracyclines (e.g., doxorubicin and mitoxantrone),
fluoropyrimidines (e.g., 5-FU), folic acid antagonists (e.g.,
methotrexate), and podophylotoxins (e.g., etoposide). These agents
have a high degree of antibacterial activity against CNS (S.
epidermidis) and Staphylococcus aureus--the most common causes of
vascular catheter infections. Particularly preferred agents are
doxorubicin, mitoxantrone, 5-fluorouracil and analogues and
derivatives thereof which also have activity against Escheridia
coli and Pseudomonas aeruginosa. 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.
[0123] 1. Central Venous Catheters
[0124] 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 to the large (central) veins of the
body (e.g., jugular, pulmary, femoral, iliac, inferior vena cava,
superior vena cava, axillary etc.). Examples of such catheters
include central venous catheters, total parenteral nutrition
catheters, peripherally inserted central venous catheters,
flow-directed balloon-tipped pulmonary artery catheters, long-term
central venous access catheters (such as Hickman lines and Broviac
catheters). Representative examples of such catheters 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.
[0125] 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.
[0126] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the vascular catheter. The drug(s) 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.
[0127] 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], 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.
[0128] 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, the preferred anticancer
agents, used alone or in combination, should be administered under
the following dosing guidelines:
[0129] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the device, or applied without a
polymer carrier, the total dose of doxorubicin applied to the
central venous catheter (and the other components of the infusion
system) should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
to the central venous catheter (and the other components of the
infusion system) should be in the range of 1 .mu.g to 5 mg. The
dose per unit area of the device (i.e. the amount of drug as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.01 .mu.g-100 .mu.g per mm.sup.2 of surface area. In a
particularly preferred embodiment, doxorubicin should be applied to
the device surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the device surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the device
surface. It is necessary to insure that drug concentrations on the
device surface exceed concentrations of doxorubicin known to be
lethal to multiple species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower
concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the device 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
doxorubicin (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 doxorubicin is
administered at half the above parameters, a compound half as
potent as doxorubicin is administered at twice the above
parameters, etc.).
[0130] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the device, or applied without a
carrier polymer, the total dose of mitoxantrone applied to the
central venous catheter (and the other components of the infusion
system) should not exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied
to the central venous catheter (and the other components of the
infusion system) should be in the range of 0.1 .mu.g to 1 mg. The
dose per unit area of the device (i.e. the amount of drug as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.01 .mu.g-20 .mu.g per mm.sup.2 of surface area. In a
particularly preferred embodiment, mitoxantrone should be applied
to the device surface at a dose of 0.05 .mu.g/mm.sup.2-3
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release mitoxantrone at differing rates, the above dosing
parameters should be utilized in combination with the release rate
of the drug from the device surface such that a minimum
concentration of 10.sup.-5-10.sup.-6 M of mitoxantrone is
maintained on the device surface. It is necessary to insure that
drug concentrations on the device surface exceed concentrations of
mitoxantrone known to be lethal to multiple species of bacteria and
fungi (i.e. are in excess of 10.sup.-5 M; although for some
embodiments lower drug levels will be sufficient). In a preferred
embodiment, mitoxantrone is released from the surface of the device
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 mitoxantrone (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
mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
[0131] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the device, or applied
without a carrier polymer, the total dose of 5-fluorouracil applied
to the central venous catheter (and the other components of the
infusion system) 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 central venous catheter (and the other
components of the infusion system) should be in the range of 10
.mu.g to 25 mg. The dose per unit area of the device (i.e. the
amount of drug as a function of the surface area of the portion of
the device 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 device 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 device surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained on the device 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.-4 M; although for some
embodiments lower drug levels will be sufficient). In a preferred
embodiment, 5-fluorouracil is released from the surface of the
device 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.).
[0132] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the device, or applied without a
carrier polymer, the total dose of etoposide applied to the central
venous catheter (and the other components of the infusion system)
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
to the central venous catheter (and the other components of the
infusion system) should be in the range of 1 .mu.g to 5 mg. The
dose per unit area of the device (i.e. the amount of drug as a
function of the surface area of the portion of the device to which
drug is applied and/or incorporated) should fall within the range
of 0.01 .mu.g-100 .mu.g per mm.sup.2 of surface area. In a
particularly preferred embodiment, etoposide should be applied to
the device surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release etoposide at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the device surface such that a concentration of
10.sup.-5-10.sup.-6 M of etoposide is maintained on the device
surface. It is necessary to insure that drug concentrations on the
device surface exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e., are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the device 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 based upon the discussions provided
herein that analogues and derivatives of etoposide (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 etoposide is administered at half the above
parameters, a compound half as potent as etoposide is administered
at twice the above parameters, etc.).
[0133] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the central
venous catheter coating. Similarly an anthracycline (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidine (e.g.,
5-fluorouracil), folic acid antagonist (e.g., methotrexate) and/or
podophylotoxin (e.g., etoposide) can be combined with traditional
antibiotic and/or antifungal agents to enhance efficacy. Since
thrombogenicity of the catheter is associated with an increased
risk of infection, combinations of anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or
podophylotoxins (e.g., etoposide) can be combined with
antithrombotic and/or antiplatelet agents (for example, heparin,
dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,
2-chloroadenosine, aspirin, phenylbutazone, indomethacin,
meclofenamate, hydrochloroquine, dipyridamole, iloprost,
ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban,
streptokinase, and/or tissue plasminogen activator) to enhance
efficacy.
[0134] 2. Peripheral Intravenous Catheters
[0135] 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.
[0136] 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).
[0137] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the peripheral vascular catheter. The
drug(s) 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.
[0138] The formulation and dosing guidelines for this embodiment
are identical to those described for central venous catheters.
[0139] 3. Arterial Lines and Transducers
[0140] 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) and
often remain in place for several days. 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).
[0141] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the arterial line 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.
[0142] The formulation and dosing guidelines for this embodiment
are identical to those described for central venous catheters.
[0143] B. Prosthetic Heart Valve Endocarditis (PVE)
[0144] Prosthetic heart valves, mechanical and bioprosthetic, are
at a significant risk for developing an infection. In fact, 3-6% of
patients develop valvular infection within 5 years of valve
replacement surgery and prosthetic valve endocarditis accounts for
up to 15% of all cases of endocarditis. The risk of developing an
infection is not uniform--the risk is greatest in the first year
following surgery with a peak incidence between the second and
third month postoperatively. Mechanical valves in particular are
susceptible to infection in the 3 months following surgery and the
microbiology is suggestive of nosocomial infection. Therefore, a
drug coating designed to prevent colonization and infection of the
valves in the months following surgery could be of great benefit in
the prevention of this important medical problem. The incidence of
prosthetic valve endocarditis has not changed in the last 40 years
despite significant advances in surgical and sterilization
technique.
[0145] Representative examples of prosthetic heart valves include
those described in 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
[0146] Early after valve implantation, the prosthetic valve sewing
ring and annulus are not yet endothelialized. The accumulation of
platelets and thrombus at the site provide an excellent location
for the adherence and colonization of microorganisms. Bacteria can
be seeded during the surgical procedure itself or as a result of
bacteremia arising in the early postoperative period (usually
contamination from i.v. catheters, catheters to determine cardiac
output, mediastinal tubes, chest tubes or wound infections). Common
causes of PVE include Coagulase Negative Staphylococci
(Staphylococcus epidermidis; 30%), Staphylococcus aureus (23%),
Gram Negative Enterococci (Enterobacteriaceae, Pseudomonas
arugenosa; 14%), Fungi (Candida albicans, Aspergillis: 12%), and
Corynebacterium diptheriae. PVE of bioprosthetic valves is largely
confined to the leaflets (and rarely the annulus), whereas the
annulus is involved in the majority of cases of PVE in mechanical
valves (82%).
[0147] Unfortunately, eradication of the infecting organism with
antimicrobial therapy alone is often difficult or impossible. As a
result, many patients who develop this complication require repeat
open-heart surgery to replace the infected valve resulting in
significant morbidity and mortality. Even if the infection is
successfully treated medically, damage to the leaflets in
bioprosthetic valves reduces the lifespan of the valve.
Particularly problematic are patients who develop an infection
caused by Staphylococcus aureus, as they have a 50-85% mortality
rate and overall reoperation rate of 50-65%. Infections caused by
Staphylococcus epidermidis are also difficult to treat as the
majority are caused by organisms resistant to all currently
available beta-lactam antibiotics. Other complications of
prosthetic valve endocarditis include valve malfunction (stenosis,
regurgitation), abscess formation, embolic complications (such as
stroke, CNS hemorrhage, cerebritis), conduction abnormalities, and
death (55-75% of patients who develop an infection in the first 2
months after surgery).
[0148] An effective therapeutic valve coating would reduce the
incidence of prosthetic valve endocarditis, reduce the mortality
rate, reduce the incidence of complications, prolong the
effectiveness of the prosthetic valve and/or reduce the need to
replace the valve. This would result in lower mortality and
morbidity for patients with prosthetic heart valves.
[0149] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the bioprosthetic or mechanical valve.
The drug(s) can be applied to the prosthetic valve in several
manners: (a) as a coating applied to the surface of the annular
ring (particularly mechanical valves); (b) as a coating applied to
the surface of the valve leaflets (particularly bioprosthetic
valves); (c) incorporated into the polymers which comprise the
annular ring; and/or (d) any combination of the aforementioned.
[0150] Drug-coating of, or drug incorporation into prosthetic heart
valves will allow bacteriocidal drug levels to be achieved locally
on the valvular surface, thus reducing the incidence of bacterial
colonization and subsequent development of PVE, while producing
negligible systemic exposure to the drugs. Although for some agents
polymeric carriers are not required for attachment of the drug to
the valve annular ring and/or leaflets, 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], 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.
[0151] As prosthetic heart valves 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 prosthetic heart valve, the preferred anticancer
agents, used alone or in combination, should be administered under
the following dosing guidelines:
[0152] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the prosthetic heart valve, or
applied without a carrier polymer, the total dose of doxorubicin
applied to the prosthetic heart valve should not exceed 25 mg
(range of 0.1 .mu.g to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied to the prosthetic
heart valve should be in the range of 1 .mu.g to 5 mg. The dose per
unit area of the valve (i.e., the amount of drug as a function of
the surface area of the portion of the valve to which drug is
applied and/or incorporated) should fall within the range of 0.01
.mu.g-100 .mu.g per mm.sup.2 of surface area. In a particularly
preferred embodiment, doxorubicin should be applied to the valve
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release doxorubicin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the valve
surface such that a minimum concentration of 10.sup.-7-10.sup.-4 M
of doxorubicin is maintained on the surface. It is necessary to
insure that drug concentrations on the valve surface exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the valve 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 1-6 months. It should be
readily evident based upon the discussions provided herein that
analogues and derivatives of doxorubicin (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
doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
[0153] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the prosthetic heart valve, or
applied without a carrier polymer, the total dose of mitoxantrone
applied to the prosthetic heart valve should not exceed 5 mg (range
of 0.01 .mu.g to 5 mg). In a particularly preferred embodiment, the
total amount of drug applied to the prosthetic heart valve should
be in the range of 0.1 .mu.g to 1 mg. The dose per unit area of the
valve (i.e. the amount of drug as a function of the surface area of
the portion of the valve to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-20 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the valve surface at
a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As different
polymer and non-polymer coatings will release mitoxantrone at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the valve
surface such that a minimum concentration of 10.sup.-5-10.sup.-6 M
of mitoxantrone is maintained on the valve surface. It is necessary
to insure that drug concentrations on the valve surface exceed
concentrations of mitoxantrone known to be lethal to multiple
species of bacteria and fungi (i.e. are in excess of 10.sup.-5 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released
from the surface of the valve 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 1-6 months.
It should be readily evident based upon the discussions provided
herein that analogues and derivatives of mitoxantrone (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 mitoxantrone is administered at half the above
parameters, a compound half as potent as mitoxantrone is
administered at twice the above parameters, etc.).
[0154] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the prosthetic heart
valve, or applied without a carrier polymer, the total dose of
5-fluorouracil applied to the prosthetic heart valve 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
prosthetic heart valve should be in the range of 10 .mu.g to 25 mg.
The dose per unit area of the valve (i.e. the amount of drug as a
function of the surface area of the portion of the valve 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 valve
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 valve surface such that a minimum concentration of
10.sup.-4-10.sup.-7 M of 5-fluorouracil is maintained on the valve
surface. It is necessary to insure that drug concentrations on the
prosthetic heart valve 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.-4 M; although for some
embodiments lower drug levels will be sufficient). In a preferred
embodiment, 5-fluorouracil is released from the surface of the
valve 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 1-6 months. It should be
readily evident based upon 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.).
[0155] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the prosthetic heart valve, or
applied without a carrier polymer, the total dose of etoposide
applied to the prosthetic heart valve should not exceed 25 mg
(range of 0.1 .mu.g to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied to the prosthetic
heart valve should be in the range of 1 .mu.g to 5 mg. The dose per
unit area of the valve (i.e., the amount of drug as a function of
the surface area of the portion of the valve to which drug is
applied and/or incorporated) should fall within the range of 0.01
.mu.g-100 .mu.g per mm.sup.2 of surface area. In a particularly
preferred embodiment, etoposide should be applied to the prosthetic
heart valve surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release etoposide at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the valve surface such that a concentration of
10.sup.-5-10.sup.-6 M of etoposide is maintained on the valve
surface. It is necessary to insure that drug concentrations on the
valve surface exceed concentrations of etoposide known to be lethal
to a variety of bacteria and fungi (i.e., are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the valve 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 1-6 months.
It should be readily evident based upon the discussions provided
herein that analogues and derivatives of etoposide (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 etoposide is administered at half the above
parameters, a compound half as potent as etoposide is administered
at twice the above parameters, etc.).
[0156] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the prosthetic
heart valve coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy. Since thrombogenicity of the
prosthetic heart valve is associated with an increased risk of
infection, anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
combined with antithrombotic and/or antiplatelet agents (for
example, heparin, dextran sulphate, danaparoid, lepirudin, hirudin,
AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone,
indomethacin, meclofenamate, hydrochloroquine, dipyridamole,
iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide,
tirofiban, streptokinase, and/or tissue plasminogen activator) to
enhance efficacy.
[0157] C. Cardiac Pacemaker Infections
[0158] Overall, slightly greater than 5% of cardiac pacemakers
become infected following implantation. Cardiac pacemakers are
subject to infection in two general manners: (a) infections
involving the pulse generator pocket and/or subcutaneous portion of
the lead, and (b) infections involving the transvenous
intravascular electrode and/or the generator unit. Representative
examples of patents which describe pacemakers and pacemaker leads
include 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.
[0159] The most common type of pacemaker infection involves the
subcutaneous generator unit or lead wires in the period shortly
after placement. This type of infection is thought to be the result
of contamination of the surgical site by skin flora at the time of
placement. Staphylococcus epidermidis (65-75% of cases),
Stapylococcus aureus, Streptococci, Corynebacterium,
Proprionibacterium acnes, Enterobacteriaceae and Candida species
are frequent causes of this type of infection. Treatment of the
infection at this point is relatively straightforward, the infected
portion of the device is removed, the patient is treated with
antibiotics and a new pacemaker is inserted at a different site.
Unfortunately, infections of the generator pocket can subsequently
spread to the epicardial electrodes causing more severe
complications such pericarditis, mediastinitis and bacteremia.
[0160] Infection of the intravascular portion of the tranvenous
electrode poses a more significant clinical problem. This infection
is thought to be caused by infection of the subcutaneous portion of
the pacing apparatus that tracks along the device into the
intravascular and intracardiac portions of the device. This
infection tends to present at a later time (1-6 months
post-procedure) and can result in sepsis, endocarditis, pneumonia,
bronchitis, pulmonary embolism, cardiac vegetations and even death.
Coagulase Negative Staphylococci (56% of infections),
Staphylococcus aureus (27%), Enterobacteriaceae (6%), Pseudomonas
arugenosa (3%) and Candida albicans (2%) are the most common cause
of this serious form of pacemaker infection. Treatment of this form
of infection is more complex. The generator and electrodes must be
removed (often surgically), antibiotics are required for prolonged
periods and an entire new pacemaker system must be inserted.
Mortality rates associated with this condition can be quite
high--41% if treated with antibiotics alone, 20% if treated with
electrode removal and antibiotics.
[0161] An effective cardiac pacemaker coating would reduce the
incidence of subcutaneous infection and subsequent tracking of
infection to the pericardial and endocardial surfaces of the heart.
Clinically, this would result in a reduction in the overall rate of
infection and reduce the incidence of more severe complications
such as sepsis, endocarditis, pneumonia, bronchitis, pulmonary
embolism, cardiac vegetations and even death. An effective coating
could also prolong the effectiveness of the pacemaker and decrease
the number of pacemakers requiring replacement, resulting in lower
mortality and morbidity for patients with these implants.
[0162] In a preferred embodiment, an anthracycline (e.g.,
doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic
acid antagonist (e.g., methotrexate), and/or podophylotoxin (e.g.,
etoposide) is formulated into a coating applied to the surface of
the components of the cardiac pacemaker. The drug(s) can be applied
to the pacemaker in several manners: (a) as a coating applied to
the surface of the generator unit; (b) as a coating applied to the
surface of the subcutaneous portion of the lead wires; (c)
incorporated into, or applied to the surface of, a subcutaneous
"cuff" around the subcutaneous insertion site; (d) as a coating
applied to the surface of the epicardial electrodes; (e) as a
coating applied to the surface of the transvenous electrode; and/or
(f) any combination of the aforementioned.
[0163] Drug-coating of, or drug incorporation into cardiac
pacemakers will allow bacteriocidal drug levels to be achieved
locally on the pacemaker 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 to the generator unit, leads and
electrodes, 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], 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.
[0164] As cardiac pacemakers 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
pacemaker 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 cardiac pacemaker,
the preferred anticancer agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0165] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the pacemaker components, or
applied without a carrier polymer, the total dose of doxorubicin
applied to the pacemaker should not exceed 25 mg (range of 0.1
.mu.g to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 .mu.g to 5 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the pacemaker to which drug is
applied and/or incorporated) should fall within the range of 0.01
.mu.g-100 .mu.g per mm.sup.2 of surface area. In a particularly
preferred embodiment, doxorubicin should be applied to the
pacemaker surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the pacemaker surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the pacemaker 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 week-6 months. It should
be readily evident based upon the discussions provided herein that
analogues and derivatives of doxorubicin (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
doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
[0166] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the pacemaker, or applied without a
carrier polymer, the total dose of mitoxantrone applied should not
exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a particularly
preferred embodiment, the total amount of drug applied should be in
the range of 0.1 .mu.g to 1 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of
the pacemaker to which drug is applied and/or incorporated) should
fall within the range of 0.01 .mu.g-20 .mu.g per mm.sup.2 of
surface area. In a particularly preferred embodiment, mitoxantrone
should be applied to the pacemaker surface at a dose of 0.05
.mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release mitoxantrone at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the pacemaker surface such that a
minimum concentration of 10.sup.-5-10.sup.-6 M of mitoxantrone is
maintained. It is necessary to insure that drug concentrations on
the pacemaker surface exceed concentrations of mitoxantrone known
to be lethal to multiple species of bacteria and fungi (i.e. are in
excess of 10.sup.-5 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, mitoxantrone
is released from the surface of the pacemaker 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 week-6 months. It should be readily evident
based upon the discussions provided herein that analogues and
derivatives of mitoxantrone (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
mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
[0167] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the pacemaker, or
applied without a carrier polymer, the total dose of 5-fluorouracil
applied 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 should be in the range of 10 .mu.g to 25 mg. The dose per
unit area (i.e. the amount of drug as a function of the surface
area of the portion of the pacemaker 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 pacemaker
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 pacemaker surface such that a minimum concentration of
10.sup.-4-10.sup.-7 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed
concentrations of 5-fluorouracil known to be lethal to numerous
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released
from the pacemaker surface 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 week-6
months. It should be readily evident based upon 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.).
[0168] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the cardiac pacemaker, or applied
without a carrier polymer, the total dose of etoposide applied
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the pacemaker to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the pacemaker surface at
a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different
polymer and non-polymer coatings will release etoposide at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the pacemaker
surface such that a concentration of 10.sup.-5-10.sup.-6 M of
etoposide is maintained. It is necessary to insure that surface
drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the pacemaker 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 week-6
months. It should be readily evident based upon the discussions
provided herein that analogues and derivatives of etoposide (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 etoposide is administered at half the
above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
[0169] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the pacemaker
coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy. Since thrombogenicity of the
intravascular portion of the transvenous electrode is associated
with an increased risk of infection, anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate and/or
podophylotoxins (e.g., etoposide) can be combined with
antithrombotic and/or antiplatelet agents (for example heparin,
dextran sulphate, danaparoid, lepirudin, hirudin, AMP, adenosine,
2-chloroadenosine, aspirin, phenylbutazone, indomethacin,
meclofenamate, hydrochloroquine, dipyridamole, iloprost,
ticlopidine, clopidogrel, abcixamab, eptifibatide, tirofiban,
streptokinase, and/or tissue plasminogen activator) to enhance
efficacy.
[0170] D. Infections of Implantable Cardioverter-Defibrillators
(ICD)
[0171] Overall, approximately 5-10% of implantable
cardioverter-defibrillators become infected following implantation
(the rate is highest if surgical placement is required). Like
cardiac pacemakers, implantable defibrillators are subject to
infection in two general manners: (a) infections involving the
subcutaneous portion of the device (subcutaneous electrodes and
pulse generator unit, and (b) infections involving the
intrathoracic components (rate sensing electrode, SVC coil
electrode and epicardial electrodes). Representative examples of
ICD's and associated components are described in 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.
[0172] Most infections present period shortly after placement and
are thought to be the result of contamination of the surgical site
by skin flora. Staphylococcus epidermidis, Stapylococcus aureus,
Streptococci, Corynebacterium, Proprionibacterium acnes,
Enterobacteriaceae and Candida species are frequent causes of this
type of infection. Unfortunately, treatment frequently involves
removal of the entire system and prolonged antibiotic therapy.
[0173] An effective ICD coating would reduce the incidence of
infection-related side effects such subcutaneous infection, sepsis
and pericarditis. An effective coating could also prolong the
effectiveness of the ICD and decrease the number of patients
requiring replacement, resulting in lower mortality and morbidity
associated with these implants.
[0174] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the components of the ICD. The drug(s)
can be applied in several manners: (a) as a coating applied to the
surface of the pulse generator unit; (b) as a coating applied to
the surface of the subcutaneous portion of the lead wires; (c)
incorporated into, or applied to the surface of, a subcutaneous
"cuff" around the subcutaneous insertion site; (d) as a coating
applied to the surface of the SVC coil electrode; (e) as a coating
applied to the surface of the epicardial electrode; and/or (f) any
combination of the aforementioned.
[0175] Drug-coating of, or drug incorporation into prosthetic heart
valves will allow bacteriocidal drug levels to be achieved locally
on the ICD 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 to the generator unit, leads and
electrodes, 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], 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.
[0176] As implantable cardioverter-defibrillators have many design
features similar to those found in cardiac pacemakers, the dosing
guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and
etoposide in coating ICDs are identical to those described above
for cardiac pacemakers.
[0177] E. Vascular Graft Infections
[0178] Infection rates for synthetic vascular grafts range from
1-5% and are highest in grafts that traverse the inguinal region
(such as aorto-femoral grafts and femoral-popliteal grafts).
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. In fact,
more than half of all cases present within the first 3 months after
surgery. The most common causes of infection include Staphylococcus
aureus (25-35% of cases), Enterobacteriaceae, Pseudomonas
aerugenosa, and Coagulase Negative Staphylococci.
[0179] Complications arising from vascular graft infection include
sepsis, subcutaneous infection, false aneurysm formation, graft
thrombosis, haemorrhage, septic or thrombotic emboli and graft
thrombosis. Treatment requires removal of the graft in virtually
all cases combined with systemic antibiotics. Often the surgery
must be performed in a staged manner (complete resection of the
infected graft, debridement of adjacent infected tissues,
development of a healthy arterial stump, reperfusion through an
uninfected pathway) further adding to the morbidity and mortality
associated with this condition. For example, if an aortic graft
becomes infected there is a 37% mortality rate and a 21% rate of
leg amputation in survivors; for infrainguinal grafts the rates are
18% and 40% respectively.
[0180] Representative examples of vascular grafts are described in
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.
[0181] An effective vascular graft coating would reduce the
incidence of complications such as sepsis, haemorrhage, thrombosis,
embolism, amputation and even death. An effective coating would
also decrease the number of vascular grafts requiring replacement,
resulting in lower mortality and morbidity for patients with these
implants.
[0182] In a preferred embodiment, an anthracycline (e.g.,
doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic
acid antagonist (e.g., methotrexate), and/or podophylotoxin (e.g.,
etoposide) is formulated into a coating applied to the surface of
the components of the vascular graft. The drug(s) 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.
[0183] Drug-coating of, or drug incorporation into vascular 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], 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 as well as blends
thereof.
[0184] As vascular 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 vascular graft, the preferred
anticancer agents, used alone or in combination, should be
administered under the following dosing guidelines:
[0185] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the vascular graft components (such
as Dacron or Teflon), or applied without a carrier polymer, the
total dose of doxorubicin applied should not exceed 25 mg (range of
0.1 .mu.g to 25 mg). In a particularly preferred embodiment, the
total amount of drug applied should be in the range of 1 .mu.g to 5
mg. The dose per unit area (i.e. the amount of drug as a function
of the surface area of the portion of the vascular graft to which
drug is applied and/or incorporated) should fall within the range
of 0.01 .mu.g-100 .mu.g per mm.sup.2 of surface area. In a
particularly preferred embodiment, doxorubicin should be applied to
the vascular graft surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the vascular graft surface such that a minimum concentration
of 10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the
surface. It is necessary to insure that surface drug concentrations
exceed concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the vascular graft 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 week-6
months. It should be readily evident based upon the discussions
provided herein that analogues and derivatives of doxorubicin (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 doxorubicin is administered at half
the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
[0186] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the vascular graft (such as Dacron
or Teflon), or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 .mu.g to
5 mg). In a particularly preferred embodiment, the total amount of
drug applied should be in the range of 0.1 .mu.g to 1 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the vascular graft to which drug is applied
and/or incorporated) should fall within the range of 0.01 .mu.g-20
.mu.g per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the vascular graft
surface at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the vascular graft surface such that a minimum concentration of
10.sup.-5-10.sup.-6 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed
concentrations of mitoxantrone known to be lethal to multiple
species of bacteria and fungi (i.e. are in excess of 10.sup.-5 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released
from the vascular graft surface 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 week-6
months. It should be readily evident based upon the discussions
provided herein that analogues and derivatives of mitoxantrone (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 mitoxantrone is administered at half
the above parameters, a compound half as potent as mitoxantrone is
administered at twice the above parameters, etc.).
[0187] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the vascular graft
(such as Dacron or Teflon), or applied without a carrier polymer,
the total dose of 5-fluorouracil applied 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 should be in the range
of 10 .mu.g to 25 mg. The dose per unit area (i.e. the amount of
drug as a function of the surface area of the portion of the
vascular graft 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 vascular graft 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 vascular
graft surface such that a minimum concentration of
10.sup.-4-10.sup.-7 M of 5-fluorouracil is maintained. It is
necessary to insure that surface drug concentrations exceed
concentrations of 5-fluorouracil known to be lethal to numerous
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released
from the vascular graft surface 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 week-6
months. It should be readily evident based upon 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.).
[0188] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the vascular graft (such as Dacron
or Teflon), or applied without a carrier polymer, the total dose of
etoposide applied should not exceed 25 mg (range of 0.1 .mu.g to 25
mg). In a particularly preferred embodiment, the total amount of
drug applied should be in the range of 1 .mu.g to 5 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the vascular graft to which drug is applied
and/or incorporated) should fall within the range of 0.01 .mu.g-100
.mu.g per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the vascular graft
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release etoposide
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the vascular
graft surface such that a concentration of 10.sup.-5-10.sup.-6 M of
etoposide is maintained. It is necessary to insure that surface
drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the vascular graft 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
week-6 months. It should be readily evident based upon the
discussions provided herein that analogues and derivatives of
etoposide (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 etoposide is
administered at half the above parameters, a compound half as
potent as etoposide is administered at twice the above parameters,
etc.).
[0189] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the vascular
graft coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy. Since thrombogenicity of the
vascular graft is associated with an increased risk of infection,
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate and/or podophylotoxins (e.g., etoposide) can be
combined with antithrombotic and/or antiplatelet agents (for
example heparin, dextran sulphate, danaparoid, lepirudin, hirudin,
AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone,
indomethacin, meclofenamate, hydrochloroquine, dipyridamole,
iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide,
tirofiban, streptokinase, and/or tissue plasminogen activator) to
enhance efficacy.
[0190] F. Infections Associated with Ear. Nose and Throat
Implants
[0191] Bacterial infections involving the ear, nose and throat are
common occurrences in both children and adults. For the management
of chronic obstruction secondary to persistent infection, the use
of implanted medical tubes is a frequent form of treatment.
Specifically, chronic otitis media is often treated with the
surgical implantation of tympanostomy tubes and chronic sinusitis
is frequently treated with surgical drainage and the placement of a
sinus stent.
Tympanostomy Tubes
[0192] Acute otitis media is the most common bacterial infection,
the most frequent indication for surgical therapy, the leading
cause of hearing loss and a common cause of impaired language
development in children. The cost of treating this condition in
children under the age of five is estimated at $5 billion annually
in the United States alone. In fact, 85% of all children will have
at least one episode of otitis media and 600,000 will require
surgical therapy annually. The prevalence of otitis media is
increasing and for severe cases surgical therapy is more cost
effective than conservative management.
[0193] Acute otitis media (bacterial infection of the middle ear)
is characterized by Eustachian tube dysfunction leading to failure
of the middle ear clearance mechanism. The most common causes of
otitis media are Streptococcus pneumoniae (30%), Haemophilus
influenza (20%), Branhamella catarrhalis (12%), Streptococcus
pyogenes (3%), and Staphylococcus aureus (1.5%). The end result is
the accumulation of bacteria, white blood cells and fluid which, in
the absence of an ability to drain through the Eustachian tube,
results in increased pressure in the middle ear. For many cases
antibiotic therapy is sufficient treatment and the condition
resolves. However, for a significant number of patients the
condition becomes frequently recurrent or does not resolve
completely. In recurrent otitis media or chronic otitis media with
effusion, there is a continuous build-up of fluid and bacteria that
creates a pressure gradient across the tympanic membrane causing
pain and impaired hearing. Fenestration of the tympanic membrane
(typically with placement of a tympanostomy tube) relieves the
pressure gradient and facilitates drainage of the middle ear
(through the outer ear instead of through the Eustachian tube--a
form of "Eustachian tube bypass").
[0194] Surgical placement of tympanostomy tubes is the most widely
used treatment for chronic otitis media because, although not
curative, it improves hearing (which in turn improves language
development) and reduces the incidence of acute otitis media.
Tympanostomy tube placement is one of the most common surgical
procedures in the United States with 1.3 million surgical
placements per year. Nearly all younger children and a large
percentage of older children require general anaesthesia for
placement. Since general anaesthesia has a higher incidence of
significant side effects in children (and represents the single
greatest risk and cost associated with the procedure), it is
desirable to limit the number of anaesthetics that the child is
exposed to. Common complications of tympanostomy tube insertion
include chronic otorrhea (often due to infection by S. pneumoniae,
H. influenza, Pseudomonas aerugenosa, S. aureus, or Candida),
foreign body reaction with the formation of granulation tissue and
infection, plugging (usually obstructed by granulation tissue,
bacteria and/or clot), tympanic membrane perforation,
myringosclerosis, tympanic membrane atrophy (retraction,
atelectasis), and cholesteatoma.
[0195] An effective tympanostomy tube coating would allow easy
insertion, remain in place for as long as is required, be easily
removed in the office without anaesthesia, resist infection and
prevent the formation of granulation tissue in the tube (which can
not only lead to obstruction, but also "tack down" the tube such
that surgical removal of the tube under anaesthetic becomes
necessary). An effective tympanostomy tube would also reduce the
incidence of complications such as chronic otorrhea (often due to
infection by S. pneumoniae, H. influenza, Pseudomonas aerugenosa,
S. aureus, or Candida); maintain patency (prevent obstruction by
granulation tissue, bacteria and/or clot); and/or reduce tympanic
membrane perforation, myringosclerosis, tympanic membrane atrophy
and cholesteatoma. Therefore, development of a tube which does not
become obstructed by granulation tissue, does not scar in place and
is less prone to infection (thereby reducing the need to
remove/replace the tube) would be a significant medical
advancement.
[0196] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the tympanostomy tube. The drug(s) can be
applied in several manners: (a) as a coating applied to the
external surface of the tympanostomy tube; (b) as a coating applied
to the internal (luminal) surface of the tympanostomy tube; (c) as
a coating applied to all or parts of both surfaces; and/or (d)
incorporated into the polymers which comprise the tympanostomy
tube.
[0197] Drug-coating of, or drug incorporation into, the
tympanostomy tube will allow bacteriocidal drug levels to be
achieved locally on the tube surface, thus reducing the incidence
of bacterial colonization (and subsequent development of middle ear
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 tympanostomy tube 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],
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.
[0198] There are two general designs of tympanostomy tubes:
grommet-shaped tubes, which tend to stay in place for less than 1
year but have a low incidence of permanent perforation of the
tympanic membrane (1%), and T-tubes, which stay in place for
several years but have a higher rate of permanent perforation (5%).
As tympanostomy tubes 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 tympanostomy tube, the preferred anticancer agents, used alone
or in combination, should be administered under the following
dosing guidelines:
[0199] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the tympanostomy tube components,
or applied without a carrier polymer, the total dose of doxorubicin
applied should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the tympanostomy tube to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the tympanostomy tube
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release doxorubicin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
tympanostomy tube surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the tympanostomy tube 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 week-6
months. It should be readily evident based upon the discussions
provided herein that analogues and derivatives of doxorubicin (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 doxorubicin is administered at half
the above parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
[0200] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the tympanostomy tube, or applied
without a carrier polymer, the total dose of mitoxantrone applied
should not exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 0.1 .mu.g to 1 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the tympanostomy tube to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-20 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the tympanostomy tube
surface at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the tympanostomy tube surface such that a minimum concentration of
10.sup.-5-10.sup.-6 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed
concentrations of mitoxantrone known to be lethal to multiple
species of bacteria and fungi (i.e. are in excess of 10.sup.-5 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released
from the tympanostomy tube surface 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
week-6 months. It should be readily evident based upon the
discussions provided herein that analogues and derivatives of
mitoxantrone (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 mitoxantrone is
administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above
parameters, etc.).
[0201] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the tympanostomy tube,
or applied without a carrier polymer, the total dose of
5-fluorouracil applied 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 should be in the range of 10 .mu.g to 25 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the tympanostomy tube 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
tympanostomy tube 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 tympanostomy tube surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug
concentrations 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 tympanostomy tube surface 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 week-6 months. 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.).
[0202] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the tympanostomy tube, or applied
without a carrier polymer, the total dose of etoposide applied
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the tympanostomy tube to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the tympanostomy tube
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release etoposide
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
tympanostomy tube surface such that a concentration of
10.sup.-5-10.sup.-6 M of etoposide is maintained. It is necessary
to insure that surface drug concentrations exceed concentrations of
etoposide known to be lethal to a variety of bacteria and fungi
(i.e. are in excess of 10.sup.-5 M; although for some embodiments
lower drug levels will be sufficient). In a preferred embodiment,
etoposide is released from the surface of the tympanostomy tube
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 week-6 months. It should
be readily evident given the discussions provided herein that
analogues and derivatives of etoposide (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
etoposide is administered at half the above parameters, a compound
half as potent as etoposide is administered at twice the above
parameters, etc.).
[0203] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the tympanostomy
tube coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy.
Sinus Stents
[0204] The sinuses are four pairs of hollow regions contained in
the bones of the skull named after the bones in which they are
located (ethmoid, maxillary, frontal and sphenoid). All are lined
by respiratory mucosa which is directly attached to the bone.
Following an inflammatory insult such as an upper respiratory tract
infection or allergic rhinitis, a purulent form of sinusitis can
develop. Occasionally secretions can be retained in the sinus due
to altered ciliary function or obstruction of the opening (ostea)
that drains the sinus. Incomplete drainage makes the sinus prone to
infection typically with Haemophilus influenza, Streptococcus
pneumoniae, Moraxella catarrhalis, Veillonella, Peptococcus,
Corynebacterium acnes and certain species of fungi.
[0205] When initial treatment such as antibiotics, intranasal
steroid sprays and decongestants are ineffective, it may become
necessary to perform surgical drainage of the infected sinus.
Surgical therapy often involves debridement of the ostea to remove
anatomic obstructions and removal of parts of the mucosa.
Occasionally a stent (a cylindrical tube which physically holds the
lumen of the ostea open) is left in the osta to ensure drainage is
maintained even in the presence of postoperative swelling. Stents,
typically made of stainless steel or plastic, remain in place for
several days or several weeks before being removed.
[0206] Unfortunately, the stents can become infected or overgrown
by granulation tissue that renders them ineffective. An effective
sinus stent coating would allow easy insertion, remain in place for
as long as is required, be easily removed in the office without
anaesthesia, resist infection and prevent the formation of
granulation tissue in the stent (which can not only lead to
obstruction, but also "tack down" the stent such that surgical
removal becomes necessary). Therefore, development of a sinus stent
which does not become obstructed by granulation tissue, does not
scar in place and is less prone to infection would be
beneficial.
[0207] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the sinus stent. The drug(s) can be
applied in several manners: (a) as a coating applied to the
external surface of the sinus stent; (b) as a coating applied to
the internal (luminal) surface of the sinus stent; (c) as a coating
applied to all or parts of both surfaces; and/or (d) incorporated
into the polymers which comprise the sinus stent.
[0208] Drug-coating of, or drug incorporation into, the sinus stent
will allow bacteriocidal drug levels to be achieved locally on the
tube surface, thus reducing the incidence of bacterial colonization
(and subsequent development of sinusitis), while producing
negligible systemic exposure to the drugs. Although for some agents
polymeric carriers are not required for attachment of the drug to
the sinus stent 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], 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.
[0209] As sinus stents are prone to the same complications and
infections from the same bacteria, the dosing guidelines for
doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating
sinus stents are identical to those described above for
tympanostomy tubes.
[0210] G. Infections Associated with Urological Implants
[0211] Implanted medical devices are used in the urinary tract with
greater frequency than in any other body system and have some of
the highest rates of infection. In fact, the great majority of
urinary devices become infected if they remain in place for a
prolonged period of time and are the most common cause of
nosocomial infection.
Urinary (Foley) Catheters
[0212] Four-to-five million bladder catheters are inserted into
hospitalized patients every year in the United States. The duration
of catheterization is the important risk factor for patients
developing a clinically significant infection--the rate of
infection increases 5-10% per day that the patient is catheterized.
Although simple cystitis can be treated with a short course of
antibiotics (with or without removal of the catheter), serious
complications are frequent and can be extremely serious. The
infection can ascend to the kidneys causing acute pyelonephritis
which can result in scarring and long term kidney damage. Perhaps
of greatest concern is the 1-2% risk of developing gram negative
sepsis (the risk is 3-times higher in catheterized patients and
accounts for 30% of all cases) which can be extremely difficult to
treat and can result in septic shock and death (up to 50% of
patients). Therefore, there exists a significant medical need to
produce improved urinary catheters capable of reducing the
incidence of urinary tract infection in catheterized patients.
[0213] The most common cause of infection is bacteria typically
found in the bowel or perineum that are able to track up the
catheter to gain access to the normally sterile bladder. Bacteria
can be carried into the bladder as the catheter is inserted, gain
entry via the sheath of exudates that surrounds the catheter,
and/or travel intraluminally inside the catheter tubing. Several
species of bacteria are able to adhere to the catheter and form a
biofilm that provides a protected site for growth. With short-term
catheterization, single organism infections are most common and are
typically due to Escherichia coli, Enterococci, Pseudomonas
aeruginosa, Klebsiella, Proteus, Enterobacter, Staphylococcus
epidermidis, Staphylococcus aureus and Staphylococcus
saprophyticus. Patients who are catheterized for long periods of
time are prone to polymicrobial infections caused by all of the
organisms previously mentioned as well as Providencia stuartii,
Morganella morganii and Candida. Antibiotic use either systemically
or locally has been largely proven to be ineffective as it tends to
result only in the selection of drug-resistant bacteria.
[0214] An effective urinary catheter coating would allow easy
insertion into the bladder, resist infection and prevent the
formation of biofilm in the catheter. An effective coating would
prevent or reduce the incidence of urinary tract infection,
pyelonephritis, and/or sepsis. In a preferred embodiment,
doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are
formulated into a coating applied to the surface of the urinary
catheter. The drug(s) can be applied in several manners: (a) as a
coating applied to the external surface of the urinary catheter;
(b) as a coating applied to the internal (luminal) surface of the
urinary catheter; (c) as a coating applied to all or parts of both
surfaces; and/or (d) incorporated into the polymers which comprise
the urinary catheter.
[0215] Drug-coating of, or drug incorporation into, the urinary
catheter will allow bacteriocidal drug levels to be achieved
locally on the catheter surface, thus reducing the incidence of
bacterial colonization (and subsequent development of urinary tract
infection and bacteremia), while producing negligible systemic
exposure to the drugs. Although for some agents polymeric carriers
are not required for attachment of the drug to the urinary 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], 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.
[0216] As urinary catheters (e.g. Foley catheters, suprapubic
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 urinary catheter,
the preferred anticancer agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0217] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the urinary catheter components, or
applied without a carrier polymer, the total dose of doxorubicin
applied should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the urinary catheter to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the urinary catheter
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release doxorubicin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the urinary
catheter surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the urinary catheter 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 hour-1
month. It should be readily evident given the discussions provided
herein that analogues and derivatives of doxorubicin (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 doxorubicin is administered at half the above
parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
[0218] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the urinary catheter, or applied
without a carrier polymer, the total dose of mitoxantrone applied
should not exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 0.1 .mu.g to 1 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the urinary catheter to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-20 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the urinary catheter
surface at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the urinary catheter surface such that a minimum concentration of
10.sup.-5-10.sup.-6 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed
concentrations of mitoxantrone known to be lethal to multiple
species of bacteria and fungi (i.e. are in excess of 10.sup.-5 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released
from the urinary catheter surface 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 hour-1
month. It should be readily evident given the discussions provided
herein that analogues and derivatives of mitoxantrone (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 mitoxantrone is administered at half the above
parameters, a compound half as potent as mitoxantrone is
administered at twice the above parameters, etc.).
[0219] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the urinary catheter,
or applied without a carrier polymer, the total dose of
5-fluorouracil applied 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 should be in the range of 10 .mu.g to 25 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the urinary catheter 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
urinary catheter 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 urinary catheter surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of 5-fluorouracil known to be
lethal to numerous species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the urinary catheter surface 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 hour-1 month. 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.).
[0220] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the urinary catheter, or applied
without a carrier polymer, the total dose of etoposide applied
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the urinary catheter to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the urinary catheter
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release etoposide
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the urinary
catheter surface such that a concentration of 10.sup.-5-10.sup.-6 M
of etoposide is maintained. It is necessary to insure that surface
drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the urinary catheter 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
hour-1 month. It should be readily evident given the discussions
provided herein that analogues and derivatives of etoposide (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 etoposide is administered at half the
above parameters, a compound half as potent as etoposide is
administered at twice the above parameters, etc.).
[0221] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the urinary
catheter coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy.
Ureteral Stents
[0222] Ureteral stents are hollow tubes with holes along the sides
and coils at either end to prevent migration. Ureteral stents are
used to relieve obstructions (caused by stones or malignancy), to
facilitate the passage of stones, or to allow healing of ureteral
anastomoses or leaks following surgery or trauma. They are placed
endoscopically via the bladder or percutaneously via the kidney. A
microbial biofilm forms on up to 90% of ureteral stents and 30%
develop significant bacteria with the incidence increasing the
longer the stent is in place. Pseudomonas aeruginosa is the most
common pathogen, but Enterococci, Staphylococcus aureus and Candida
also cause infection. Effective treatment frequently requires stent
removal in addition to antibiotic therapy.
[0223] Unfortunately, ureteral stents can become infected or
encrusted with urinary salts that render them ineffective. An
effective ureteral stent coating would allow easy insertion, remain
in place for as long as is required, be easily removed, resist
infection and prevent the formation of urinary salts. Therefore,
development of a ureteral stent which does not become obstructed by
granulation tissue, does not scar in place and is less prone to
infection would be beneficial.
[0224] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the ureteral stent. The drug(s) can be
applied in several manners: (a) as a coating applied to the
external surface of the ureteral stent; (b) as a coating applied to
the internal (luminal) surface of the ureteral stent; (c) as a
coating applied to all or parts of both surfaces; and/or (d)
incorporated into the polymers which comprise the ureteral
stent.
[0225] Drug-coating of, or drug incorporation into, the ureteral
stent will allow bacteriocidal drug levels to be achieved locally
on the stent surface, thus reducing the incidence of bacterial
colonization (and subsequent development of pyelonephritis and/or
bacteremia), while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required
for attachment of the drug to the ureteral stent 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],
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.
[0226] As ureteral stents are prone to the same complications and
infections from the same bacteria, the dosing guidelines for
doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating
ureteral stents are identical to those described above for urinary
catheters. However, unlike the formulations described for urinary
catheters, drug release should occur over a 2 to 24 week
period.
Urethral Stents
[0227] Urethral stents are used for the treatment of recurrent
urethral strictures, detruso-external sphincter dyssynergia and
bladder outlet obstruction due to benign prostatic hypertrophy. The
stents are typically self-expanding and composed of metal
superalloy, titanium, stainless steel or polyurethane. Infections
are most often due to Coagulase Negative Staphylococci, Pseudomonas
aeruginosa, Enterococci, Staphylococcus aureus, Serratia and
Candida. Treatment of infected stents frequently requires systemic
antibiotic therapy and removal of the device.
[0228] An effective urethral stent coating would allow easy
insertion, remain in place for as long as is required, be easily
removed, resist infection and prevent the formation of urinary
salts. Therefore, development of a urethral stent which does not
become obstructed by granulation tissue, does not scar in place and
is less prone to infection would be beneficial.
[0229] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the urethral stent. The drug(s) can be
applied in several manners: (a) as a coating applied to the
external surface of the urethral stent; (b) as a coating applied to
the internal (luminal) surface of the urethral stent; (c) as a
coating applied to all or parts of both surfaces; and/or (d)
incorporated into the polymers which comprise the urethral
stent.
[0230] Drug-coating of, or drug incorporation into, the urethral
stent will allow bacteriocidal drug levels to be achieved locally
on the stent surface, thus reducing the incidence of bacterial
colonization (and subsequent development of pyelonephritis and/or
bacteremia), while producing negligible systemic exposure to the
drugs. Although for some agents polymeric carriers are not required
for attachment of the drug to the ureteral stent 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],
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.
[0231] As urethral stents are prone to the same complications and
infections from the same bacteria, the dosing guidelines for
doxorubicin, mitoxantrone, 5-fluorouracil and etoposide in coating
ureteral stents are identical to those described above for urinary
catheters. However, unlike the formulations described for urinary
catheters, drug release should occur over a 2 to 24 week
period.
Prosthetic Bladder Sphincters
[0232] Prosthetic bladder sphincters are used to treat incontinence
and generally consist of a periurethral implant. The placement of
prosthetic bladder sphincters can be complicated by infection
(usually in the first 6 months after surgery) with Coagulase
Negative Staphylococci (including Staphylococcus epidermidis),
Staphylococcus aureus, Pseudomonas aeruginosa, Enterococci,
Serratia and Candida. Infection is characterized by fever,
erythema, induration and purulent drainage from the operative site.
The usual route of infection is through the incision at the time of
surgery and up to 3% of prosthetic bladder sphincters become
infected despite the best sterile surgical technique. To help
combat this, intraoperative irrigation with antibiotic solutions is
often employed.
[0233] Treatment of infections of prosthetic bladder sphincters
requires complete removal of the device and antibiotic therapy;
replacement of the device must often be delayed for 3-6 months
after the infection has cleared. An effective prosthetic bladder
sphincter coating would resist infection and reduce the incidence
of re-intervention.
[0234] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the prosthetic bladder sphincter. The
drug(s) can be applied in several manners: (a) as a coating applied
to the external surface of the prosthetic bladder sphincter; and/or
(b) incorporated into the polymers which comprise the prosthetic
bladder sphincter.
[0235] Drug-coating of, or drug incorporation into, the prosthetic
bladder sphincter will allow bacteriocidal drug levels to be
achieved locally, thus reducing the incidence of bacterial
colonization (and subsequent development of urethritis and/or wound
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 prosthetic bladder sphincter
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], 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.
[0236] As prosthetic bladder sphincters are prone to infections
caused by the same bacteria as occur with urinary catheters, the
dosing guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and
etoposide in coating prosthetic bladder sphincters are identical to
those described above for urinary catheters. However, unlike the
formulations described for urinary catheters, drug release should
occur over a 2 to 24 week period.
Penile Implants
[0237] Penile implants are used to treat erectile dysfunction and
are generally flexible rods, hinged rods or inflatable devices with
a pump. The placement of penile implants can be complicated by
infection (usually in the first 6 months after surgery) with
Coagulase Negative Staphylococci (including Staphylococcus
epidermidis), Staphylococcus aureus, Pseudomonas aeruginosa,
Enterococci, Serratia and Candida. The type of device or route of
insertion does not affect the incidence of infection. Infection is
characterized by fever, erythema, induration and purulent drainage
from the operative site. The usual route of infection is through
the incision at the time of surgery and up to 3% of penile implants
become infected despite the best sterile surgical technique. To
help combat this, intraoperative irrigation with antibiotic
solutions is often employed.
[0238] Treatment of infections of penile implants requires complete
removal of the device and antibiotic therapy; replacement of the
device must often be delayed for 3-6 months after the infection has
cleared. An effective penile implant coating would resist infection
and reduce the incidence of re-intervention.
[0239] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the penile implant. The drug(s) can be
applied in several manners: (a) as a coating applied to the
external surface of the penile implant; and/or (b) incorporated
into the polymers which comprise the penile implant.
[0240] Drug-coating of, or drug incorporation into, the penile
implant will allow bacteriocidal drug levels to be achieved
locally, thus reducing the incidence of bacterial colonization (and
subsequent development of local infection and device failure),
while producing negligible systemic exposure to the drugs. Although
for some agents polymeric carriers are not required for attachment
of the drug to the penile implant surface, several polymeric
carriers are particularly suitable for use in this embodiment.
[0241] As penile implants are prone to infections caused by the
same bacteria as occur with urinary catheters, the dosing
guidelines for doxorubicin, mitoxantrone, 5-fluorouracil and
etoposide in coating penile implants are identical to those
described above for urinary catheters. However, unlike the
formulations described for urinary catheters, drug release should
occur over a 2 to 24 week period.
[0242] H. Infections Associated with Endotracheal and Tracheostomy
Tubes
[0243] Endotracheal tubes and tracheostomy tubes are used to
maintain the airway when ventilatory assistance is required.
Endotracheal tubes tend to be used to establish an airway in the
acute setting, while tracheostomy tubes are used when prolonged
ventilation is required or when there is a fixed obstruction in the
upper airway. In hospitalized patients, nosocomial pneumonia occurs
300,000 times per year and is the second most common cause of
hospital-acquired infection (after urinary tract infection) and the
most common infection in ICU patients. In the intensive care unit,
nosocomial pneumonia is a frequent cause death with fatality rates
over 50%. Survivors spend on average 2 weeks longer in hospital and
the annual cost of treatment is close to $2 billion.
[0244] Bacterial pneumonia is the most common cause of excess
morbidity and mortality in patients who require intubation. In
patients who are intubated electively (i.e. for elective surgery),
less than 1% will develop a nosocomial pneumonia. However, patients
who are severely ill with ARDS (Adult Respiratory Distress
Syndrome) have a greater than 50% chance of developing a nosocomial
pneumonia. It is thought that new organisms colonize the oropharynx
in intubated patients, are swallowed to contaminate the stomach,
are aspirated to inoculate the lower airway and eventually
contaminate the endotracheal tube. Bacteria adhere to the tube,
form a biolayer and multiply serving as a source for bacteria that
can aerosolize and be carried distally into the lungs. Chronic
tracheostomy tubes also frequently become colonized with pathogenic
bacteria known to cause pneumonia. The most common causes of
pneumonia in ventilated patients are Staphylococcus aureus (17%),
Pseudomonas aeruginosa (18%), Klebsiella pneumoniae (9%),
Enterobacter (9%) and Haemophilus influenza (5%). Treatment
requires aggressive therapy with antibiotics.
[0245] An effective endotracheal tube or tracheostomy tube coating
would resist infection and prevent the formation of biofilm in the
tube. An effective coating would prevent or reduce the incidence of
pneumonia, sepsis and death. In a preferred embodiment,
doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide are
formulated into a coating applied to the surface of the
endotracheal tube or tracheostomy tube. Due to its activity against
Klebsiella pneumoniae, methotrexate can also be useful for this
embodiment. As cisplatin and hydroxyurea have some activity against
Pseudomonas aeruginosa, they can also be of some utility in the
practice of this embodiment. The drug(s) can be applied in several
manners: (a) as a coating applied to the external surface of the
endotracheal tube or tracheostomy tube; (b) as a coating applied to
the internal (luminal) surface of the endotracheal tube or
tracheostomy tube; (c) as a coating applied to all or parts of both
surfaces; and/or (d) incorporated into the polymers which comprise
the endotracheal tube or tracheostomy tube.
[0246] Drug-coating of, or drug incorporation into, the
endotracheal tube or tracheostomy tube will allow bacteriocidal
drug levels to be achieved locally on the catheter surface, thus
reducing the incidence of bacterial colonization (and subsequent
development of pneumonia and sepsis), while producing negligible
systemic exposure to the drugs. Although for some agents polymeric
carriers are not required for attachment of the drug to the
endotracheal tube or tracheostomy tube 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], 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.
[0247] As endotracheal tube and tracheostomy tubes 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 endotracheal tube or tracheostomy
tube, the preferred anticancer agents, used alone or in
combination, should be administered under the following dosing
guidelines:
[0248] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the endotracheal tube or
tracheostomy tube components, or applied without a carrier polymer,
the total dose of doxorubicin applied should not exceed 25 mg
(range of 0.1 .mu.g to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied should be in the range
of 1 .mu.g to 5 mg. The dose per unit area (i.e. the amount of drug
as a function of the surface area of the portion of the
endotracheal tube or tracheostomy tube to which drug is applied
and/or incorporated) should fall within the range of 0.01 .mu.g-100
.mu.g per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the endotracheal tube
or tracheostomy tube surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the endotracheal tube or tracheostomy tube surface such that a
minimum concentration of 10.sup.-7-10.sup.-4 M of doxorubicin is
maintained on the surface. It is necessary to insure that surface
drug concentrations exceed concentrations of doxorubicin known to
be lethal to multiple species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower
concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the endotracheal tube
or tracheostomy tube 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 from the endotracheal tube for a period
ranging from 1 hour to 1 month, while release from a tracheostomy
tube would range from 1 day to 3 months. It should be readily
evident given the discussions provided herein that analogues and
derivatives of doxorubicin (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
doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
[0249] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the endotracheal tube or
tracheostomy tube, or applied without a carrier polymer, the total
dose of mitoxantrone applied should not exceed 5 mg (range of 0.01
.mu.g to 5 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 0.1 .mu.g to 1 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the endotracheal tube or
tracheostomy tube to which drug is applied and/or incorporated)
should fall within the range of 0.01 .mu.g-20 .mu.g per mm.sup.2 of
surface area. In a particularly preferred embodiment, mitoxantrone
should be applied to the endotracheal tube or tracheostomy tube
surface at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the endotracheal tube or tracheostomy tube surface such that a
minimum concentration of 10.sup.-5-10.sup.-6 M of mitoxantrone is
maintained. It is necessary to insure that drug concentrations on
the surface exceed concentrations of mitoxantrone known to be
lethal to multiple species of bacteria and fungi (i.e. are in
excess of 10.sup.-5 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment, mitoxantrone
is released from the endotracheal tube or tracheostomy tube surface
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 from the endotracheal tube for a period ranging from
1 hour to 1 month, while release from a tracheostomy tube would
range from 1 day to 3 months. It should be readily evident given
the discussions provided herein that analogues and derivatives of
mitoxantrone (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 mitoxantrone is
administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above
parameters, etc.).
[0250] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the endotracheal tube
or tracheostomy tube, or applied without a carrier polymer, the
total dose of 5-fluorouracil applied 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 should be in the range
of 10 .mu.g to 25 mg. The dose per unit area (i.e. the amount of
drug as a function of the surface area of the portion of the
endotracheal tube or tracheostomy tube 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 endotracheal
tube or tracheostomy tube 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 endotracheal
tube or tracheostomy tube surface such that a minimum concentration
of 104-10.sup.-7 M of 5-fluorouracil is maintained. It is necessary
to insure that surface drug concentrations exceed concentrations of
5-fluorouracil known to be lethal to numerous species of bacteria
and fungi (i.e. are in excess of 10.sup.-4 M; although for some
embodiments lower drug levels will be sufficient). In a preferred
embodiment, 5-fluorouracil is released from the endotracheal tube
or tracheostomy tube surface 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 from the endotracheal tube for
a period ranging from 1 hour to 1 month, while release from a
tracheostomy tube would range from 1 day to 3 months. 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.).
[0251] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the endotracheal tube or
tracheostomy tube, or applied without a carrier polymer, the total
dose of etoposide applied should not exceed 25 mg (range of 0.1
.mu.g to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 .mu.g to 5 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the endotracheal tube or
tracheostomy tube to which drug is applied and/or incorporated)
should fall within the range of 0.01 .mu.g-100 .mu.g per mm.sup.2
of surface area. In a particularly preferred embodiment, etoposide
should be applied to the endotracheal tube or tracheostomy tube
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release etoposide
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
endotracheal tube or tracheostomy tube surface such that a
concentration of 10.sup.-5-10.sup.-6 M of etoposide is maintained.
It is necessary to insure that surface drug concentrations exceed
concentrations of etoposide known to be lethal to a variety of
bacteria and fungi (i.e. are in excess of 10.sup.-5 M; although for
some embodiments lower drug levels will be sufficient). In a
preferred embodiment, etoposide is released from the surface of the
endotracheal tube or tracheostomy tube 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 from the endotracheal tube for
a period ranging from 1 hour to 1 month, while release from a
tracheostomy tube would range from 1 day to 3 months. It should be
readily evident given the discussions provided herein that
analogues and derivatives of etoposide (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
etoposide is administered at half the above parameters, a compound
half as potent as etoposide is administered at twice the above
parameters, etc.).
[0252] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the endotracheal
tube or tracheostomy tube coating. Similarly anthracyclines (e.g.,
doxorubicin or mitoxantrone), fluoropyrimidines (e.g.,
5-fluorouracil), folic acid antagonists (e.g., methotrexate) and/or
podophylotoxins (e.g., etoposide) can be combined with traditional
antibiotic and/or antifungal agents to enhance efficacy.
[0253] I. Infections Associated with Dialysis Catheters
[0254] In 1997, there were over 300,000 patients in the United
States with end-stage renal disease. Of these, 63% were treated
with hemodialysis, 9% with peritoneal dialysis and 38% with renal
transplantation. Hemodialysis requires reliable access 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
central venous catheter (32%). Peritoneal dialysis requires regular
exchange of dialysate through the peritoneum via a double-cuffed
and tunnelled peritoneal dialysis catheter. 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
[0255] 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.
[0256] 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.
[0257] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the components of the synthetic
hemodialysis access graft. The drug(s) 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.
[0258] 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], 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.
[0259] 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.
[0260] 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, the preferred anticancer agents, used alone or in
combination, should be administered under the following dosing
guidelines:
[0261] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the hemodialysis access graft
components (such as Dacron or Teflon), or applied without a carrier
polymer, the total dose of doxorubicin applied should not exceed 25
mg (range of 0.1 .mu.g to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied should be in the range
of 1 .mu.g to 5 mg. The dose per unit area (i.e. the amount of drug
as a function of the surface area of the portion of the
hemodialysis access graft to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the hemodialysis
access graft surface at a dose of 0.1 .mu.g/mm.sup.2-10
.mu.g/mm.sup.2. As different polymer and non-polymer coatings will
release doxorubicin at differing rates, the above dosing parameters
should be utilized in combination with the release rate of the drug
from the hemodialysis access graft surface such that a minimum
concentration of 10.sup.-7-10.sup.-4 M of doxorubicin is maintained
on the surface. It is necessary to insure that surface drug
concentrations exceed concentrations of doxorubicin known to be
lethal to multiple species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower
concentrations are sufficient). In a preferred embodiment,
doxorubicin is released from the surface of the hemodialysis access
graft 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 week-6 months. It should
be readily evident given the discussions provided herein that
analogues and derivatives of doxorubicin (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
doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
[0262] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the hemodialysis access graft (such
as Dacron or Teflon), or applied without a carrier polymer, the
total dose of mitoxantrone applied should not exceed 5 mg (range of
0.01 .mu.g to 5 mg). In a particularly preferred embodiment, the
total amount of drug applied should be in the range of 0.1 .mu.g to
1 mg. The dose per unit area (i.e. the amount of drug as a function
of the surface area of the portion of the hemodialysis access graft
to which drug is applied and/or incorporated) should fall within
the range of 0.01 .mu.g-20 .mu.g per mm.sup.2 of surface area. In a
particularly preferred embodiment, mitoxantrone should be applied
to the hemodialysis access graft surface at a dose of 0.05
.mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release mitoxantrone at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the hemodialysis access graft
surface such that a minimum concentration of 10.sup.-5-10.sup.-6 M
of mitoxantrone is maintained. It is necessary to insure that drug
concentrations on the surface exceed concentrations of mitoxantrone
known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 10.sup.-5 M; although for some embodiments lower
drug levels will be sufficient). In a preferred embodiment,
mitoxantrone is released from the hemodialysis access graft surface
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 week-6 months. It should
be readily evident given the discussions provided herein that
analogues and derivatives of mitoxantrone (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
mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
[0263] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the hemodialysis
access graft (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of 5-fluorouracil applied 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 should be in
the range of 10 .mu.g to 25 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of
the hemodialysis access graft 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 hemodialysis access graft
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 hemodialysis access graft surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of 5-fluorouracil known to be
lethal to numerous species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the hemodialysis access graft
surface 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 week-6 months. 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.).
[0264] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the hemodialysis access graft (such
as Dacron or Teflon), or applied without a carrier polymer, the
total dose of etoposide applied should not exceed 25 mg (range of
0.1 .mu.g to 25 mg). In a particularly preferred embodiment, the
total amount of drug applied should be in the range of 1 .mu.g to 5
mg. The dose per unit area (i.e. the amount of drug as a function
of the surface area of the portion of the hemodialysis access graft
to which drug is applied and/or incorporated) should fall within
the range of 0.01 .mu.g-100 .mu.g per mm.sup.2 of surface area. In
a particularly preferred embodiment, etoposide should be applied to
the hemodialysis access graft surface at a dose of 0.1
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release etoposide at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the hemodialysis access graft surface
such that a concentration of 10.sup.-5-10.sup.-6 M of etoposide is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the hemodialysis access graft 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 week-6 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of etoposide (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
etoposide is administered at half the above parameters, a compound
half as potent as etoposide is administered at twice the above
parameters, etc.).
[0265] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the hemodialysis
access graft coating. Similarly anthracyclines (e.g., doxorubicin
or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic
acid antagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy. Since thrombogenicity of the
hemodialysis access graft is associated with an increased risk of
infection, anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and/or podophylotoxins (e.g., etoposide) can
be combined with antithrombotic and/or antiplatelet agents (for
example heparin, dextran sulphate, danaparoid, lepirudin, hirudin,
AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone,
indomethacin, meclofenamate, hydrochloroquine, dipyridamole,
iloprost, ticlopidine, clopidogrel, abcixamab, eptifibatide,
tirofiban, streptokinase, and/or tissue plasminogen activator) to
enhance efficacy.
Central Venous Catheters
[0266] A variety of central venous catheters are available for use
in hemodialysis including, but not restricted to, catheters which
are totally implanted such as the Lifesite (Vasca Inc., Tewksbury,
Mass.) and the Dialock (Biolink Corp., Middleboro, Mass.). Central
venous catheters are prone to infection and embodiments for that
purpose are described above.
Peritoneal Dialysis Catheters
[0267] Peritoneal dialysis catheters are typically double-cuffed
and tunnelled catheters that provide access to the peritoneum. The
most common peritoneal dialysis catheter designs are the Tenckhoff
catheter, the Swan Neck Missouri catheter 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.
[0268] 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.
[0269] 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).
[0270] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the components of the synthetic
peritoneal dialysis graft. The drug(s) 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; (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 graft; and/or (f) as a coating applied
to a combination of these surfaces.
[0271] 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], 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.
[0272] An effective peritoneal dialysis graft 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 grafts requiring
replacement, resulting in lower mortality and morbidity for
patients with these implants.
[0273] As peritoneal dialysis 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 peritoneal dialysis
graft, the preferred anticancer agents, used alone or in
combination, should be administered under the following dosing
guidelines:
[0274] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the peritoneal dialysis graft
components (such as Dacron or Teflon), or applied without a carrier
polymer, the total dose of doxorubicin applied should not exceed 25
mg (range of 0.1 .mu.g to 25 mg). In a particularly preferred
embodiment, the total amount of drug applied should be in the range
of 1 .mu.g to 5 mg. The dose per unit area (i.e. the amount of drug
as a function of the surface area of the portion of the peritoneal
dialysis graft to which drug is applied and/or incorporated) should
fall within the range of 0.01 .mu.g-100 .mu.g per mm.sup.2 of
surface area. In a particularly preferred embodiment, doxorubicin
should be applied to the peritoneal dialysis graft surface at a
dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different polymer
and non-polymer coatings will release doxorubicin at differing
rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the peritoneal
dialysis graft surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the peritoneal dialysis graft 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 week-6
months. It should be readily evident given the discussions provided
herein that analogues and derivatives of doxorubicin (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 doxorubicin is administered at half the above
parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
[0275] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the peritoneal dialysis graft (such
as Dacron or Teflon), or applied without a carrier polymer, the
total dose of mitoxantrone applied should not exceed 5 mg (range of
0.01 .mu.g to 5 mg). In a particularly preferred embodiment, the
total amount of drug applied should be in the range of 0.1 .mu.g to
1 mg. The dose per unit area (i.e. the amount of drug as a function
of the surface area of the portion of the peritoneal dialysis graft
to which drug is applied and/or incorporated) should fall within
the range of 0.01 .mu.g-20 .mu.g per mm.sup.2 of surface area. In a
particularly preferred embodiment, mitoxantrone should be applied
to the peritoneal dialysis graft surface at a dose of 0.05
.mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release mitoxantrone at differing rates,
the above dosing parameters should be utilized in combination with
the release rate of the drug from the peritoneal dialysis graft
surface such that a minimum concentration of 10.sup.-5-10.sup.-6 M
of mitoxantrone is maintained. It is necessary to insure that drug
concentrations on the surface exceed concentrations of mitoxantrone
known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 10.sup.-5 M; although for some embodiments lower
drug levels will be sufficient). In a preferred embodiment,
mitoxantrone is released from the peritoneal dialysis graft surface
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 week-6 months. It should
be readily evident given the discussions provided herein that
analogues and derivatives of mitoxantrone (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
mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
[0276] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the peritoneal
dialysis graft (such as Dacron or Teflon), or applied without a
carrier polymer, the total dose of 5-fluorouracil applied 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 should be in
the range of 10 .mu.g to 25 mg. The dose per unit area (i.e. the
amount of drug as a function of the surface area of the portion of
the peritoneal dialysis graft 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 peritoneal dialysis graft
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 peritoneal dialysis graft surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of 5-fluorouracil known to be
lethal to numerous species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the peritoneal dialysis graft
surface 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 week-6 months. 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.).
[0277] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the peritoneal dialysis graft (such
as Dacron or Teflon), or applied without a carrier polymer, the
total dose of etoposide applied should not exceed 25 mg (range of
0.1 .mu.g to 25 mg). In a particularly preferred embodiment, the
total amount of drug applied should be in the range of 1 .mu.g to 5
mg. The dose per unit area (i.e. the amount of drug as a function
of the surface area of the portion of the peritoneal dialysis graft
to which drug is applied and/or incorporated) should fall within
the range of 0.01 .mu.g-100 .mu.g per mm.sup.2 of surface area. In
a particularly preferred embodiment, etoposide should be applied to
the peritoneal dialysis graft surface at a dose of 0.1
.mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different polymer and
non-polymer coatings will release etoposide at differing rates, the
above dosing parameters should be utilized in combination with the
release rate of the drug from the peritoneal dialysis graft surface
such that a concentration of 10.sup.-5-10.sup.-6 M of etoposide is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the peritoneal dialysis graft 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 week-6 months. It should be readily evident
given the discussions provided herein that analogues and
derivatives of etoposide (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
etoposide is administered at half the above parameters, a compound
half as potent as etoposide is administered at twice the above
parameters, etc.).
[0278] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the peritoneal
dialysis graft coating. Similarly anthracyclines (e.g., doxorubicin
or mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic
acid antagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy.
[0279] J. Infections of Central Nervous System (CNS) Shunts
[0280] Hydrocephalus, or accumulation of cerebrospinal fluid (CSF)
in the brain, is a frequently encountered neurosurgical condition
arising from congenital malformations, infection, hemmorrhage, or
malignancy. The incompressible fluid exerts pressure on the brain
leading to brain damage or even death if untreated. CNS shunts are
conduits placed in the ventricles of the brain to divert the flow
of CSF from the brain to other body compartments and relieve the
fluid pressure. Ventricular CSF is diverted via a prosthetic shunt
to a number of drainage locations including the pleura
(ventriculopleural shunt), jugular vein, vena cava (VA shunt),
gallbladder and peritoneum (VP shunt; most common).
[0281] Unfortunately, CSF shunts are relatively prone to developing
infection, although the incidence has declined from 25% twenty
years ago to 10% at present as a result of improved surgical
technique. Approximately 25% of all shunt complications are due to
the development of infection of the shunt and these can lead to
significant clinical problems such as ventriculitis, ventricular
compartmentalization, meningitis, subdural empyema, nephritis (with
VA shunts), seizures, cortical mantle thinning, mental retardation
or death. Most infections present with fever, nausea, vomiting,
malaise, or signs of increased intracranial pressure such as
headache or altered consciousness. The most common organisms
causing CNS shunt infections are Coagulase Negative Staphylococci
(67%; Staphylococcus epidermidis is the most frequently isolated
organism), Staphylococcus aureus (10-20%), viridans streptococci,
Streptococcus pyogenes, Enterococcus, Corynebacterium, Escherichia
coli, Klebsiella, Proteus and Pseudomonas aeruginosa. It is thought
that the majority of infections are due to inoculation of the
organism during surgery, or during manipulation of the shunt in the
postoperative period. As a result, most infections present
clinically in the first few weeks following surgery.
[0282] Since many of the infections are caused by S. epidermidis,
it is not uncommon to find that the catheter becomes coated with a
bacterial-produced "slime" that protects the organism from the
immune system and makes eradication of the infection difficult.
Therefore, the treatments of most infections require shunt removal
(and often placement of a temporary external ventricular shunt to
relieve hydrocephalus) in addition to systemic and/or
intraventricular antibiotic therapy. Poor therapeutic results tend
to occur if the shunt is left in place during treatment. Antibiotic
therapy is complicated by the fact that many antibiotics do not
cross the blood-brain barrier effectively.
[0283] An effective CNS shunt coating would reduce the incidence of
complications such as ventriculitis, ventricular
compartmentalization, meningitis, subdural empyema, nephritis (with
VA shunts), seizures, cortical mantle thinning, mental retardation
or death. An effective coating would also decrease the number of
CNS shunts requiring replacement, resulting in lower mortality and
morbidity for patients with these implants.
[0284] In a preferred embodiment, an anthracycline (e.g.,
doxorubicin and mitoxantrone), fluoropyrimidine (e.g., 5-FU), folic
acid antagonist (e.g., methotrexate), and/or podophylotoxin (e.g.,
etoposide) is formulated into a coating applied to the surface of
the components of the CNS shunt. The drug(s) can be applied in
several manners: (a) as a coating applied to the external surface
of the shunt; (b) as a coating applied to the internal (luminal)
surface of the shunt; and/or (c) as a coating applied to all or
parts of both surfaces.
[0285] Drug-coating of, or drug incorporation into CNS shunts will
allow bacteriocidal drug levels to be achieved locally on the shunt
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],
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.
[0286] As CNS shunts 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 shunt 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 CNS shunt, the preferred anticancer
agents, used alone or in combination, should be administered under
the following dosing guidelines:
[0287] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the CNS shunt components (such as
Dacron or Teflon), or applied without a carrier polymer, the total
dose of doxorubicin applied should not exceed 25 mg (range of 0.1
.mu.g to 25 mg). In a particularly preferred embodiment, the total
amount of drug applied should be in the range of 1 .mu.g to 5 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the CNS shunt to which drug is
applied and/or incorporated) should fall within the range of 0.01
.mu.g-100 .mu.g per mm.sup.2 of surface area. In a particularly
preferred embodiment, doxorubicin should be applied to the CNS
shunt surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release doxorubicin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the CNS shunt
surface such that a minimum concentration of 10.sup.-7-10.sup.-4 M
of doxorubicin is maintained on the surface. It is necessary to
insure that surface drug concentrations exceed concentrations of
doxorubicin known to be lethal to multiple species of bacteria and
fungi (i.e., are in excess of 10.sup.-4 M; although for some
embodiments lower concentrations are sufficient). In a preferred
embodiment, doxorubicin is released from the surface of the CNS
shunt 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 1-12 weeks. It should be
readily evident given the discussions provided herein that
analogues and derivatives of doxorubicin (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
doxorubicin is administered at half the above parameters, a
compound half as potent as doxorubicin is administered at twice the
above parameters, etc.).
[0288] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the CNS shunt (such as Dacron or
Teflon), or applied without a carrier polymer, the total dose of
mitoxantrone applied should not exceed 5 mg (range of 0.01 .mu.g to
5 mg). In a particularly preferred embodiment, the total amount of
drug applied should be in the range of 0.1 .mu.g to 1 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the CNS shunt to which drug is applied
and/or incorporated) should fall within the range of 0.01 .mu.g-20
.mu.g per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the CNS shunt surface
at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As different
polymer and non-polymer coatings will release mitoxantrone at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the CNS shunt
surface such that a minimum concentration of 10.sup.-5-10.sup.-6 M
of mitoxantrone is maintained. It is necessary to insure that drug
concentrations on the surface exceed concentrations of mitoxantrone
known to be lethal to multiple species of bacteria and fungi (i.e.
are in excess of 10.sup.-5 M; although for some embodiments lower
drug levels will be sufficient). In a preferred embodiment,
mitoxantrone is released from the CNS shunt surface 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 1-12 weeks. It should be readily evident based
upon the discussion provided herein that analogues and derivatives
of mitoxantrone (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 mitoxantrone is
administered at half the above parameters, a compound half as
potent as mitoxantrone is administered at twice the above
parameters, etc.).
[0289] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the CNS shunt (such as
Dacron or Teflon), or applied without a carrier polymer, the total
dose of 5-fluorouracil applied 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 should be in the range of 10 .mu.g to
25 mg. The dose per unit area (i.e. the amount of drug as a
function of the surface area of the portion of the CNS shunt 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 CNS shunt 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 CNS shunt surface such that a minimum
concentration of 104-10.sup.-7 M of 5-fluorouracil is maintained.
It is necessary to insure that surface drug concentrations exceed
concentrations of 5-fluorouracil known to be lethal to numerous
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, 5-fluorouracil is released
from the CNS shunt surface 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 1-12 weeks.
It should be readily evident based upon the discussion 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.).
[0290] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the CNS shunt (such as Dacron or
Teflon), or applied without a carrier polymer, the total dose of
etoposide applied should not exceed 25 mg (range of 0.1 .mu.g to 25
mg). In a particularly preferred embodiment, the total amount of
drug applied should be in the range of 1 .mu.g to 5 mg. The dose
per unit area (i.e. the amount of drug as a function of the surface
area of the portion of the CNS shunt to which drug is applied
and/or incorporated) should fall within the range of 0.01 .mu.g-100
.mu.g per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the CNS shunt surface at
a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As different
polymer and non-polymer coatings will release etoposide at
differing rates, the above dosing parameters should be utilized in
combination with the release rate of the drug from the CNS shunt
surface such that a concentration of 10.sup.-5-10.sup.-6 M of
etoposide is maintained. It is necessary to insure that surface
drug concentrations exceed concentrations of etoposide known to be
lethal to a variety of bacteria and fungi (i.e. are in excess of
10.sup.-5 M; although for some embodiments lower drug levels will
be sufficient). In a preferred embodiment, etoposide is released
from the surface of the CNS shunt 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 1-12 weeks.
It should be readily evident based upon the discussion provided
herein that analogues and derivatives of etoposide (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 etoposide is administered at half the above
parameters, a compound half as potent as etoposide is administered
at twice the above parameters, etc.).
[0291] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the CNS shunt
coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy.
[0292] (g) External Ventricular Drainage (EVD) Device and
Intracranial Pressure (ICP) Monitoring Devices
[0293] EVD and ICP monitoring devices are also used in the
management of hydrocephalus. The therapeutic agents, doses,
coatings and release kinetics for the development of drug-coated
EVD's and drug-coated ICP monitoring devices are identical to those
described for CNS shunts.
[0294] K. Infections of Orthopedic Implants
[0295] Implanted orthopedic devices such as prosthetic joints such
as hip, knee, elbow, shoulder, wrist, metacarpal, and metatarsal
prosthetics are subject to complications as a result of infection
of the implant. Orthopedic implant infection has a variety of
sequela including pain, immobility, failure of the prosthetic
itself, loss/removal the of prosthetic, reoperation, loss of the
affected limb or even death. The cost of treating each infection
exceeds the cost of the primary joint arthroplasty itself by 3 or
4-fold (in excess of $50,000/case). Other orthopedic implant
hardware such as internal and external fixation devices, plates and
screws are also subject to such infection and infection-related
complications. The present treatment includes multiple operations
to remove infected prosthetics, with its own inherent risks,
combined with antibiotic use.
[0296] The rate of orthopedic prosthetic infection is highest in
the first month post operatively then declines continuously there
after. As an example, the combined incidence of rate of prosthetic
joint infection for 2 years is approximately 5.9% per 1,000 joints;
the rate then drops to 2.30% per 1,000 joints from year 2 to 10.
The rate of infection also varies depending on the joint. Knee
prosthetics are infected twice as frequently as hips. Shoulder
prosthetic infections range from 0.5% to 3%, elbows up to 12%,
wrists 1.5% to 5.0% and ankles 1.4% to 2.4%.
[0297] There are three main mechanisms of infection. The most
common is colonization of the implant (prosthetic, fixation plate,
screws--any implantable orthopedic device) at the time of implant,
either directly or through airborne contamination of the wound. The
second method is spread from an adjacent focus of infection, such
as wound infection, abscess or sinus tract. The third is
hematogenous seeding during a systemic bacteremia, likely
accounting for approximately 7% of all implant infections.
[0298] Risk factors are multiple. The host may be compromised as a
result of a systemic condition, an illness, a local condition, or
as a result of medications that decrease the host defence
capability. There is also a predisposition to infections if the
patient has had prior surgery, perioperative wound compilations, or
rheumatoid arthritis. Repeat surgical procedures increase the
likelihood of infection as there is a reported 8-fold elevated risk
of infection as compared to the primary prosthetic replacement
procedure. The presence of a deep infection increases the risk of
prosthetic infection 6-fold. Various diseases also increase the
risk of infection. For example, rheumatoid arthritis patients have
a higher risk of infection possibly as a result of medications that
compromising their immunocompetency, while psoriatic patients have
a higher rate possibly mediated by a compromised skin barrier that
allows entry of microbes.
[0299] The implant itself, and the cements that secure it in place,
can cause a local immunocompromised condition that is poorly
understood. Different implant materials have their own inherent
rate of infection. For example, a metal-to-metal hinged prosthetic
knee has 20-times the risk of infection of a metal-to-plastic
knee.
[0300] An implanted device is most susceptible to infection early
on. Rabbit models have shown that only a few Staphylococcus aureus
inoculated at the time of implant are required to cause an
infection, but bacteremic (hematogenous) seeding at 3 weeks
postoperatively is substantially more difficult and requires
significantly more bacteria. This emphasizes the importance of an
antimicrobial strategy initiated early at the time of
implantation.
[0301] Sixty five percent of all prosthetic joint infections are
caused by gram positive cocci, (Staphylococcus aureus, Coagulase
Negative Staphylococci, Beta-Hemolytic Streptococcus, Viridans
Group Streptococci) and enterococci. Often multiple strains of
staphylococcus can be present in a single prosthetic infection.
Other organisms include aerobic gram negative bacilli,
Enterobacteriacea, Pseudomonas aeruginosa and Anaerobes (such as
Peptostreptococcus and Bacteroides species). Polymicrobial
infections account for 12% of infections.
[0302] The diagnosis of an infected implant is difficult due to the
highly variable presentation; fever, general malaise, swelling,
erythema, joint pain, loosening of the implant, or even acute
septicemia. Fulminate presentations are typically caused by more
virulent organisms such as Stapylococcus arureus and pyogneic
beta-hemolytic streptococci. Chronic indolent courses are more
typical of coagulase-negative staphylococci.
[0303] Management of an infected orthopedic implant usually
requires prolonged use of antibiotics and surgery to remove the
infected device. Surgery requires debridement of the infected
tissue, soft tissue, bone, cement, and removal of the infected
implant. After a period of prolonged antibiotic use (weeks, months
and sometimes a year to ensure microbial eradication), it is
possible to implant a replacement prosthesis. Some authors advocate
the use of antibiotic impregnated cement, but cite concerns
regarding the risk of developing antibiotic resistance; especially
methecillin resistance. If bone loss is extensive, an arthrodesis
is often performed and amputation is necessary in some cases. Even
when an infection is eradicated, the patient can be left severely
compromised physically, have significant pain and carry a high risk
of re-infection.
[0304] It is therefore extremely clinically important to develop
orthopedic implants capable of resisting or reducing the rate of
infection. An effective orthopedic implant coating would reduce the
incidence of joint and hardware infection; lower the incidence of
prosthetic failure, sepsis, amputation and even death; and also
decrease the number of orthopedic implants requiring replacement,
resulting in lower morbidity for patients with these implants.
[0305] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the components of the orthopedic implant.
The drug(s) can be applied in several manners: (a) as a coating
applied to the external intraosseous surface of the prosthesis; (b)
as a coating applied to the external (articular) surface of the
prosthesis; (c) as a coating applied to all or parts of both
surfaces; (d) as a coating applied to the surface of the orthopedic
hardware (plates, screws, etc); (e) incorporated into the polymers
which comprise the prosthetic joints (e.g. articular surfaces and
other surface coatings) and hardware (e.g. polylactic acid screws
and plates); and/or (f) incorporated into the components of the
cements used to secure the orthopedic implants in place.
[0306] Drug-coating of, or drug incorporation into orthopedic
implant will allow bacteriocidal drug levels to be achieved locally
on the implant 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], 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.
[0307] The drugs of interest can also be incorporated into calcium
phosphate or hydroxyapatite coatings on the medical devices.
[0308] As orthopedic implants are made in a variety of
configurations and sizes, the exact dose administered will vary
with implant size, surface area, design and portions of the implant
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 implant 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 orthopedic implant,
the preferred anticancer agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0309] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the orthopedic implant components,
or applied without a carrier polymer, the total dose of doxorubicin
applied should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the orthopedic implant to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the orthopedic implant
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release doxorubicin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
orthopedic implant surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the orthopedic implant such that anti-infective activity is
maintained for a period ranging from several hours to several
months. As described previously, the risk of infectious
contamination of the implant is greatest over the first 3 days.
Therefore, in a particularly preferred embodiment, the majority (or
all) of the drug is released over the first 72 hours to prevent
infection while allowing normal healing to occur thereafter. It
should be readily evident based upon the discussion provided herein
that analogues and derivatives of doxorubicin (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 doxorubicin is administered at half the above
parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
[0310] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the orthopedic implant, or applied
without a carrier polymer, the total dose of mitoxantrone applied
should not exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 0.1 .mu.g to 1 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the orthopedic implant to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-20 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the orthopedic
implant surface at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2.
As different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the orthopedic implant surface such that a minimum concentration of
10.sup.-5-10.sup.-6 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed
concentrations of mitoxantrone known to be lethal to multiple
species of bacteria and fungi (i.e. are in excess of 10.sup.-5 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released
from the orthopedic implant surface such that anti-infective
activity is maintained for a period ranging from several hours to
several months. As described previously, the risk of infectious
contamination of the implant is greatest over the first 3 days.
Therefore, in one embodiment, the majority (or all) of the drug is
released over the first 72 hours to prevent infection while
allowing normal healing to occur thereafter. It should be readily
evident based upon the discussion provided herein that analogues
and derivatives of mitoxantrone (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
mitoxantrone is administered at half the above parameters, a
compound half as potent as mitoxantrone is administered at twice
the above parameters, etc.).
[0311] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the orthopedic
implant, or applied without a carrier polymer, the total dose of
5-fluorouracil applied 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 should be in the range of 10 .mu.g to 25 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the orthopedic 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
orthopedic 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 orthopedic implant surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of 5-fluorouracil known to be
lethal to numerous species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the orthopedic implant surface such
that anti-infective activity is maintained for a period ranging
from several hours to several months. As described previously, the
risk of infectious contamination of the implant is greatest over
the first 3 days. Therefore, in a particularly preferred
embodiment, the majority (or all) of the drug is released over the
first 72 hours to prevent infection while allowing normal healing
to occur thereafter. It should be readily evident based upon the
discussion 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.).
[0312] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the orthopedic implant, or applied
without a carrier polymer, the total dose of etoposide applied
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the orthopedic implant to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the orthopedic implant
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release etoposide
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
orthopedic implant surface such that a concentration of
10.sup.-5-10.sup.-6 M of etoposide is maintained. It is necessary
to insure that surface drug concentrations exceed concentrations of
etoposide known to be lethal to a variety of bacteria and fungi
(i.e. are in excess of 10.sup.-5 M; although for some embodiments
lower drug levels will be sufficient). In a preferred embodiment,
etoposide is released from the surface of the orthopedic implant
such that anti-infective activity is maintained for a period
ranging from several hours to several months. As described
previously, the risk of infectious contamination of the implant is
greatest over the first 3 days. Therefore, in a particularly
preferred embodiment, the majority (or all) of the drug is released
over the first 72 hours to prevent infection while allowing normal
healing to occur thereafter. It should be readily evident based
upon the discussion provided herein that analogues and derivatives
of etoposide (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 etoposide is
administered at half the above parameters, a compound half as
potent as etoposide is administered at twice the above parameters,
etc.).
[0313] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the orthopedic
implant coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy.
[0314] L. Infections Associated with Other Medical Devices and
Implants
[0315] Implants are commonly used in the practice of medicine and
surgery for a wide variety of purposes. These include implants such
as drainage tubes, 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, percutaneous feeding tubes, 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.
[0316] The drug-coating, dosing, surface concentrations and release
kinetics of these implants is identical to the embodiment described
above for orthopedic implants. In addition, doxorubicin,
mitoxantrone, 5-fluorouracil and/or etoposide 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.
[0317] M. Infections Associated with Ocular Implants
[0318] The principle infections of medical device implants in the
eye are endophthalmitis associated with intraocular lens
implantation for cataract surgery and corneal infections secondary
to contact lens use.
Infections of Intraocular Lenses
[0319] The number of intraocular lenses implanted in the United
States has grown exponentially over the last decade. Currently,
over 1 million intraocular lenses are implanted annually, with the
vast majority (90%) being placed in the posterior chamber of the
eye. Endophthalmitis is the most common infectious complication of
intraocular lens placement and occurs in approximately 0.3% of
surgeries (3,000 cases per year). The vast majority are due to
surgical contamination and have an onset within 48 hours of the
procedure.
[0320] The most common causes of endophthalmitis are Coagulase
Negative Staphylococci (principally Staphylococcus epidermidis),
Staphylococcus aureus, Enterococci, and Proteus mirabilis. Symptoms
of the condition include blurred vision, ocular pain, headache,
photophobia, and corneal edema. The treatment of endophthalmitis
associated with cataract surgery includes vitrectomy and treatment
with systemic and/or intravitreal antibiotic therapy. Although most
cases do not require removal of the lens, in complicated cases,
visual acuity can be permanently affected and/or the lens must be
removed and replaced at a later date. An effective intraocular lens
coating would reduce the incidence of endophthalmitis and also
decrease the number of intraocular lens requiring replacement,
resulting in lower morbidity for patients with these implants.
[0321] In a preferred embodiment, doxorubicin, mitoxantrone,
5-fluorouracil and/or etoposide are formulated into a coating
applied to the surface of the components of the intraocular lens.
The drug(s) can be applied in several manners: (a) as a coating
applied to the external surface of the lens; (b) as a coating
applied to the internal (luminal) surface of the lens; (c) as a
coating applied to all or parts of both surfaces of the lens;
and/or (d) incorporated into the polymers which comprise the
lens.
[0322] Drug-coating of, or drug incorporation into intraocular
lenses will allow bacteriocidal drug levels to be achieved locally
on the lens 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], 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.
[0323] As intraocular lenses are made in a variety of
configurations and sizes, the exact dose administered will vary
with lens size, surface area, design and portions of the lens
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 lens 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 intraocular lens,
the preferred anticancer agents, used alone or in combination,
should be administered under the following dosing guidelines:
[0324] (a) Anthracyclines. Utilizing the anthracycline doxorubicin
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the intraocular lens components, or
applied without a carrier polymer, the total dose of doxorubicin
applied should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the intraocular lens to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, doxorubicin should be applied to the intraocular lens
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release doxorubicin
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
intraocular lens surface such that a minimum concentration of
10.sup.-7-10.sup.-4 M of doxorubicin is maintained on the surface.
It is necessary to insure that surface drug concentrations exceed
concentrations of doxorubicin known to be lethal to multiple
species of bacteria and fungi (i.e., are in excess of 10.sup.-4 M;
although for some embodiments lower concentrations are sufficient).
In a preferred embodiment, doxorubicin is released from the surface
of the intraocular lens 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 1-12 weeks.
It should be readily evident based upon the discussion provided
herein that analogues and derivatives of doxorubicin (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 doxorubicin is administered at half the above
parameters, a compound half as potent as doxorubicin is
administered at twice the above parameters, etc.).
[0325] Utilizing mitoxantrone as another example of an
anthracycline, whether applied as a polymer coating, incorporated
into the polymers which make up the intraocular lens, or applied
without a carrier polymer, the total dose of mitoxantrone applied
should not exceed 5 mg (range of 0.01 .mu.g to 5 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 0.1 .mu.g to 1 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the intraocular lens to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-20 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, mitoxantrone should be applied to the intraocular lens
surface at a dose of 0.05 .mu.g/mm.sup.2-3 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release
mitoxantrone at differing rates, the above dosing parameters should
be utilized in combination with the release rate of the drug from
the intraocular lens surface such that a minimum concentration of
10.sup.-5-10.sup.-6 M of mitoxantrone is maintained. It is
necessary to insure that drug concentrations on the surface exceed
concentrations of mitoxantrone known to be lethal to multiple
species of bacteria and fungi (i.e. are in excess of 10.sup.-5 M;
although for some embodiments lower drug levels will be
sufficient). In a preferred embodiment, mitoxantrone is released
from the intraocular lens surface 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 1-12 weeks.
It should be readily evident based upon the discussion provided
herein that analogues and derivatives of mitoxantrone (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 mitoxantrone is administered at half the above
parameters, a compound half as potent as mitoxantrone is
administered at twice the above parameters, etc.).
[0326] (b) Fluoropyrimidines Utilizing the fluoropyrimidine
5-fluorouracil as an example, whether applied as a polymer coating,
incorporated into the polymers which make up the intraocular lens,
or applied without a carrier polymer, the total dose of
5-fluorouracil applied 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 should be in the range of 10 .mu.g to 25 mg.
The dose per unit area (i.e. the amount of drug as a function of
the surface area of the portion of the intraocular lens 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
intraocular lens 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 intraocular lens surface such that a minimum
concentration of 10.sup.-4-10.sup.-7 M of 5-fluorouracil is
maintained. It is necessary to insure that surface drug
concentrations exceed concentrations of 5-fluorouracil known to be
lethal to numerous species of bacteria and fungi (i.e., are in
excess of 10.sup.-4 M; although for some embodiments lower drug
levels will be sufficient). In a preferred embodiment,
5-fluorouracil is released from the intraocular lens surface 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 1-12 weeks. It should be readily evident based
upon the discussion 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.).
[0327] (c) Podophylotoxins Utilizing the podophylotoxin etoposide
as an example, whether applied as a polymer coating, incorporated
into the polymers which make up the intraocular lens, or applied
without a carrier polymer, the total dose of etoposide applied
should not exceed 25 mg (range of 0.1 .mu.g to 25 mg). In a
particularly preferred embodiment, the total amount of drug applied
should be in the range of 1 .mu.g to 5 mg. The dose per unit area
(i.e. the amount of drug as a function of the surface area of the
portion of the intraocular lens to which drug is applied and/or
incorporated) should fall within the range of 0.01 .mu.g-100 .mu.g
per mm.sup.2 of surface area. In a particularly preferred
embodiment, etoposide should be applied to the intraocular lens
surface at a dose of 0.1 .mu.g/mm.sup.2-10 .mu.g/mm.sup.2. As
different polymer and non-polymer coatings will release etoposide
at differing rates, the above dosing parameters should be utilized
in combination with the release rate of the drug from the
intraocular lens surface such that a concentration of
10.sup.-5-10.sup.-6 M of etoposide is maintained. It is necessary
to insure that surface drug concentrations exceed concentrations of
etoposide known to be lethal to a variety of bacteria and fungi
(i.e. are in excess of 10.sup.-5 M; although for some embodiments
lower drug levels will be sufficient). In a preferred embodiment,
etoposide is released from the surface of the intraocular lens 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 1-12 weeks. It should be readily evident based
upon the discussion provided herein that analogues and derivatives
of etoposide (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 etoposide is
administered at half the above parameters, a compound half as
potent as etoposide is administered at twice the above parameters,
etc.).
[0328] (d) Combination therapy. It should be readily evident based
upon the discussions provided herein that combinations of
anthracyclines (e.g., doxorubicin or mitoxantrone),
fluoropyrimidines (e.g., 5-fluorouracil), folic acid antagonists
(e.g., methotrexate) and podophylotoxins (e.g., etoposide) can be
utilized to enhance the antibacterial activity of the intraocular
lens coating. Similarly anthracyclines (e.g., doxorubicin or
mitoxantrone), fluoropyrimidines (e.g., 5-fluorouracil), folic acid
antagonists (e.g., methotrexate) and/or podophylotoxins (e.g.,
etoposide) can be combined with traditional antibiotic and/or
antifungal agents to enhance efficacy.
Corneal Infections Secondary to Contact Lens Use
[0329] Contact lenses are primarily used for the correction of
refractive errors, but are also used after cataract surgery
(Aphakie lenses) and "bandage" lenses are used following corneal
trauma. Over 24 million people wear contact lenses and many of them
will suffer from ulcerative keratitis resulting from contact
lens-associated infection. These infections are typically bacterial
in nature, are secondary to corneal damage/defects, and are caused
primarily by Gram Positive Cocci and Pseudomonas aeruginosa.
[0330] The drug-coating of contact lenses is identical to the
embodiment described above for intraocular lenses. In addition,
doxorubicin, mitoxantrone, 5-fluorouracil and/or etoposide can be
added to contact lens storage solution to prevent infection
transmitted via infected cleaning/storage solutions.
[0331] 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.
EXAMPLES
Example 1
MIC Determination by Microtitre Broth Dilution Method
[0332] A. Mic Assay of Various Gram Negative and Positive
Bacteria
[0333] 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 24 h. (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-00007 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
[0334] B. MIC of Antibiotic-Resistant Bacteria
[0335] 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 pediococcus 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
[0336] A coating solution is prepared by dissolving 20 g ChronoFlex
AI 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
[0337] 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
[0338] 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
[0339] 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
[0340] A coating solution is prepared by dissolving 20 g ChronoFlex
AI 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
[0341] A coating solution is prepared by dissolving 20 g ChronoFlex
AI 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
[0342] 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
[0343] 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
[0344] 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
[0345] A coating solution is prepared by dissolving 20 g ChronoFlex
AI 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
[0346] 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
[0347] 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
[0348] 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
[0349] 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
[0350] 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
[0351] 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
550 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
[0352] 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
[0353] 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
[0354] 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
[0355] 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 0.1N NaOH or 0.1N phosphoric acid.
Example 22
Release Study to Determine Release Profile of The Therapeutic Agent
from a Catheter
[0356] 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
[0357] The following chromatographic conditions were used to
quantify the amount of the therapeutic agent in the release medium:
TABLE-US-00008 Run Injection Detection Therapeutic Flow Rate Time
Volume Wavelength Agent Column Mobile Phase (mL/min) (min) (uL)
(nm) 5-Fluorouracil YMC ODS-AQ 150 .times. 4.6 mm, 5 um PBS, pH 6.8
1 8 100 268 Doxorubicin ACE 5 (V02-742) 150 .times. 4 mm 20% CAN,
26% Methanol, 54% 1 10 10 254 PBS (pH 3.6) Mitoxantrone ACE 5 C18,
150 .times. 4 mm, 5 um Phosphate buffer (pH 2.3) 1 4 10 658
Example 24
Effect of Palmitic Acid on the Release Profile of 5-Fluorouracil
from a Polyurethane Film
[0358] 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 370 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
[0359] 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.
[0360] 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.
[0361] 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.
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