U.S. patent application number 14/033957 was filed with the patent office on 2015-10-01 for mesh pouches for implantable medical devices.
The applicant listed for this patent is TYRX, INC.. Invention is credited to Fatima Buevich, Mason Diamond, Frank Do, William Edelman, William McJames, Arikha Moses, Satish Pulapura, Shari Timothy.
Application Number | 20150273118 14/033957 |
Document ID | / |
Family ID | 52691158 |
Filed Date | 2015-10-01 |
United States Patent
Application |
20150273118 |
Kind Code |
A9 |
Buevich; Fatima ; et
al. |
October 1, 2015 |
Mesh Pouches for Implantable Medical Devices
Abstract
Biodegradable polymer-coated surgical meshes formed into pouches
are described for use with cardiac rhythm management devices (CRMs)
and other implantable medical devices. Such meshes are formed into
a receptacle, e.g., a pouch or other covering, capable of encasing,
surrounding and/or holding the cardiac rhythm management device or
other implantable medical device for the purpose of securing it in
position, inhibiting or reducing bacterial growth, providing pain
relief and/or inhibiting scarring or fibrosis on or around the CRM
or other implantable medical device. Preferred embodiments include
surgical mesh pouches coated with one or more biodegradable
polymers that can act as a stiffening agent by coating the
filaments or fibers of the mesh to temporarily immobilize the
contact points of those filaments or fibers and/or by increasing
the stiffness of the mesh by at least 1.1 times its original
stiffness. The pouches of the invention can also provide relief
from various post-operative complications associated with their
implantation, insertion or surgical use, and, optionally, include
one or more drugs in the polymer matrix of the coating to provide
prophylactic effects and/or alleviate side effects or complications
associated with the surgery or implantation of the CRM or other
implantable medical device.
Inventors: |
Buevich; Fatima; (Highland
Park, NJ) ; Do; Frank; (Jersey City, NJ) ;
McJames; William; (Hillsborough, NJ) ; Pulapura;
Satish; (Bridgewater, NJ) ; Edelman; William;
(Sharon, MA) ; Moses; Arikha; (New York, NY)
; Diamond; Mason; (Wayne, NJ) ; Timothy;
Shari; (N. Brunswick, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
TYRX, INC. |
Monmouth Junction |
NJ |
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20150086604 A1 |
March 26, 2015 |
|
|
Family ID: |
52691158 |
Appl. No.: |
14/033957 |
Filed: |
September 23, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11936054 |
Nov 6, 2007 |
8591531 |
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14033957 |
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|
11672929 |
Feb 8, 2007 |
8636753 |
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11936054 |
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60864597 |
Nov 6, 2006 |
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60771827 |
Feb 8, 2006 |
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60984254 |
Oct 31, 2007 |
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Current U.S.
Class: |
424/426 ;
514/154; 514/2.3; 514/252.13; 514/330; 514/36; 606/151 |
Current CPC
Class: |
A61L 2420/08 20130101;
A61F 2210/0004 20130101; A61L 2300/404 20130101; A61L 31/10
20130101; A61L 31/14 20130101; A61F 2/0063 20130101; A61L 2300/402
20130101; A61L 31/048 20130101; A61L 31/148 20130101; A61L 31/16
20130101; A61N 1/375 20130101; A61L 2300/41 20130101; A61N 1/37512
20170801; A61L 2300/406 20130101; A61L 31/146 20130101; A61B
2090/0815 20160201; A61L 31/048 20130101; C08L 23/12 20130101; A61L
31/10 20130101; C08L 67/04 20130101; A61L 31/10 20130101; C08L
69/00 20130101; A61L 31/10 20130101; C08L 71/02 20130101 |
International
Class: |
A61L 31/16 20060101
A61L031/16; A61N 1/375 20060101 A61N001/375; A61L 27/34 20060101
A61L027/34; A61F 2/00 20060101 A61F002/00; A61L 31/10 20060101
A61L031/10; A61L 31/14 20060101 A61L031/14 |
Claims
1. A mesh pouch comprising a surgical mesh with one or more
biodegradable and resorbable polymer coatings, said pouch being a
prophylactic encasement for a medical device, wherein said mesh
comprises a porous surgical mesh which permits tissue ingrowth into
said mesh pouch and which stabilizes said medical device within
said mesh pouch.
2. The mesh pouch of claim 1, wherein said mesh has one or more
coatings which temporarily stiffen the mesh to at least 1.1 times
its original stiffness; said mesh being formed to encapsulate an
implantable device; and said one or more coatings comprising one or
more biodegradable polymers and one or more drugs which, alone or
in combination, are capable of providing pain relief, inhibiting
scarring or fibrosis and/or inhibiting bacterial growth.
3. The mesh pouch of claim 1, wherein said mesh has one or more
coatings, wherein said one or more coatings comprise one or more
biodegradable polymers which act as a stiffening agent and coat
filaments or fibers of said mesh to temporarily immobilize contact
points of the filaments or fibers of said mesh; said mesh is formed
to encapsulate an implantable device; and said one or more coatings
further comprise one or more drugs which, alone or in combination,
are capable of providing pain relief, inhibiting scarring or
fibrosis and/or inhibiting bacterial growth.
4. The mesh pouch of claim 3, wherein said mesh remains porous when
coated with said agent.
5. The mesh pouch of claim 3, wherein said agent selectively and/or
partially coats said filaments or said fibers.
6. The mesh pouch of claim 3, wherein said contact points comprise
the knots in a woven mesh.
7. The mesh pouch of claim 2, wherein said one or more coatings
increases stiffness of said mesh by at least 1.1 to about 4.5 times
its uncoated stiffness.
8. The mesh pouch of claim 1, wherein said mesh comprises woven
polypropylene.
9. The mesh pouch of claim 1, wherein said one or more
biodegradable polymers are selected from the group consisting of a
polylactic acid, polyglycolic acid, poly(L-lactide),
poly(D,L-lactide), polyglycolic acid,
poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide),
poly(D, L-lactide-co-glycolide), poly(glycolide-co-trimethylene
carbonate), poly(D,L-lactide-co-caprolactone),
poly(glycolide-co-caprolactone), polyethylene oxide, polyoxaester,
polydioxanone, polypropylene fumarate, poly(ethyl
glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl
glutamate), polycaprolactone, polycaprolactone co-butylacrylate,
polyhydroxybutyrate, poly(phosphazene), poly(phosphate ester),
poly(amino acid), polydepsipeptide, maleic anhydride copolymer,
polyiminocarbonates, poly[(97.5% dimethyl-trimethylene
carbonate)-co-(2.5% trimethylene carbonate)], poly(orthoesters),
tyrosine-derived polyarylate, tyrosine-derived polycarbonate,
tyrosine-derived polyiminocarbonate, tyrosine-derived
polyphosphonate, polyalkylene oxide, hydroxypropylmethylcellulose,
polysaccharide, protein, and copolymers, terpolymers and blends of
any thereof.
10. The mesh pouch of claim 1, wherein at least one of said
biodegradable polymers comprise one or more tyrosine-derived
diphenol monomer units.
11. The mesh pouch of claim 10, wherein said polymer is a
polyarylate.
12. The mesh pouch of claim 11, wherein said polyarylate is DT-DTE
succinate having from about 1% DT to about 30% DT.
13. The mesh pouch of claim 11, wherein said polyarylate is a
random copolymer of desaminotyrosyl-tyrosine (DT) and an
desaminotyrosyl-tyrosyl ester (DT ester), wherein said copolymer
comprises from about 0.001% DT to about 80% DT and said ester
moiety can be a branched or unbranched alkyl, alkylaryl, or
alkylene ether group having up to 18 carbon atoms, any of group of
which can, optionally have a polyalkylene oxide therein.
14. The mesh pouch of claim 1, wherein said coating comprises one
or more drugs are selected from the group consisting of
antimicrobial agents, anesthetics, analgesics, anti-inflammatory
agents, anti-scarring agents, anti-fibrotic agents and leukotriene
inhibitors.
15. The mesh pouch of claim 14, wherein said drug is an
anesthetic.
16. The mesh pouch of claim 15, wherein said anesthetic is
bupivacaine HCl.
17. The mesh pouch of claim 14, wherein said drug is an
antimicrobial agent.
18. The mesh pouch of claim 17, wherein said antimicrobial agent is
selected from the group consisting of rifampin, minocycline,
silver/chlorhexidine, vancomycin, a cephalosporin, gentamycin,
triclosan and combinations thereof.
19. The mesh pouch of claim 17, comprising two antimicrobial
agents, said agents being rifampin in combination with gentamycin
or vancomycin.
20. The mesh pouch of claim 17, comprising two antimicrobial
agents, said agents being rifampin and a tetracycline
derivative.
21. The mesh pouch of claim 20, wherein at least one of said
coatings comprises rifampin and minocycline HCl.
22. The mesh pouch of claim 14, wherein ate least one of said
coatings comprises an anti-inflammatory agent selected from
non-selective cox-1 and cox-2 inhibitors.
23. The mesh pouch of claim 14, wherein at least one of said
coatings comprises an anti-inflammatory agent selected from
selective cox-1 or cox-2 inhibitors.
24. The mesh pouch of claim 1, wherein said implantable device is a
pacemaker, a defibrillator, a pulse generator, an implantable
access system, a drug pump or a neurostimulator.
25-34. (canceled)
35. A mesh prosthetic comprising a porous surgical mesh having one
or more biodegradable or resorbable polymer coatings which have
been applied to said porous surgical mesh without substantially
altering a porousity of said surgical mesh, wherein said porous
surgical mesh permits tissue ingrowth into said mesh pouch.
36. The mesh prosthetic of claim 35, wherein said polymer coating
comprises one or more drugs selected from the group consisting of
antimicrobial agents, anesthetics, analgesics, anti-inflammatory
agents, anti-scarring agents, anti-fibrotic agents and leukotriene
inhibitors.
37. The mesh prosthetic of claim 35, wherein said polymer coating
comprises an antimicrobial agent.
38. The mesh prosthetic of claim 35, wherein said polymer coating
comprises rifampin and minocycline.
39. The mesh prosthetic of claim 35, wherein said polymer coating
comprises rifampin, minocycline, and an anesthetic or analgesic
agent.
40. The mesh prosthetic of claim 35, wherein said prosthetic is a
pouch.
41. The mesh prosthetic of claim 35, wherein said prosthetic is a
covering.
Description
[0001] This application is a continuation-in-part of U.S. Ser. No.
11/672,929, filed Feb. 8, 2007, which claims priority under 35
U.S.C. .sctn.119(e)(5) of U.S. Provisional Patent Application No.
60/864,597, filed Nov. 6, 2006 and U.S. Provisional Patent
Application No. 60/772,827, filed Feb. 8, 2006; this application
also claims priority under 35 U.S.C. .sctn.119(e)(5) to U.S.
Provisional Patent Application No. 60/864,597, filed Nov. 6, 2006,
each of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] Biodegradable polymer-coated surgical meshes formed into
pouches are described for use with cardiac rhythm management
devices (CRMs) and other implantable medical devices IMDs). Such
meshes are formed into a receptacle, e.g., a pouch or other
covering, capable of encasing, surrounding and/or holding the CRM
or other IMD for the purpose of securing it in position, inhibiting
or reducing bacterial growth, providing pain relief and/or
inhibiting scarring or fibrosis on or around the CRM or other IMD.
Preferred embodiments include surgical mesh pouches coated with one
or more biodegradable polymers that can act as a stiffening agent
by coating the filaments or fibers of the mesh to temporarily
immobilize the contact points of those filaments or fibers and/or
by increasing the stiffness of the mesh by at least 1.1 times its
original stiffness. The pouches of the invention can also provide
relief from various post-operative complications associated with
their implantation, insertion or surgical use, and, optionally,
include one or more drugs in the polymer matrix of the coating to
provide prophylactic effects and/or alleviate side effects or
complications associated with the surgery or implantation of the
CRM or other IMD.
BACKGROUND OF THE INVENTION
[0003] Prosthetic implants such as meshes, combination mesh
products or other porous prostheses are commonly used to provide a
physical barrier between types of tissue or extra strength to a
physical defect in soft tissue. However, such devices are often
associated with post-surgical complications including post-implant
infection, pain, excessive scar tissue formation and shrinkage of
the prosthesis or mesh. Excessive scar tissue formation, limited
patient mobility, and chronic pain are often attributed to the
size, shape, and mass of the implant and a variety of efforts have
been undertaken to reduce the amount of scar tissue formation. For
example, lighter meshes using smaller fibers, larger weaves, and/or
larger pore sizes as well as meshes woven from both non-resorbable
and resorbable materials are in use to address these concerns.
[0004] For treating acute pain and infection, patients with
implanted prostheses are typically treated post-operatively with
systemic antibiotics and pain medications. Patients will
occasionally be given systemic antibiotics prophylactically;
however, literature review of clinical trials does not indicate
that systemic antibiotics are effective at preventing
implant-related infections.
[0005] In 1992, it was reported that nosocomial infections involved
over 2 million patients each year and cost the healthcare systems
over 4.5 billion dollars annually..sup.1 Today, these numbers are
undoubtedly much higher. Surgical site infections, involving
approximately 500,000 patients, represent the second most common
cause of nosocomial infections and approximately 17% of all
hospital-acquired infections..sup.2 The incidence of infections
associated with the placement of pacemakers has been reported as
0.13 to 19.9% at an average cost of $35,000 to treat these
complications which most often involves complete removal of the
implant..sup.3,4
[0006] Post-operative infection is tied to three elements: lack of
host defense mechanisms, surgical site and bacteria present at the
time of device implantation..sup.5 The general health of the
patient (i.e., the host factor) is always important; however, since
many patients requiring surgery are compromised in some way--and
there is little that can be done to mitigate that
factor--controlling the other two factors becomes important.
[0007] Studies have shown that patients are exposed to bacterial
contamination in the hospital, especially in the operating room
(OR) and along the route to the OR..sup.6 In fact, bacterial counts
of up to 7.0.times.10.sup.4 CFU/m.sup.2 have been found in the OR
dressing area..sup.6 Recent improvements in air handling and
surface cleansing have reduced the environmental levels of
infectious agents, but not eliminated them. Consequently, further
means to reduce bacterial contamination or to reduce the potential
for bacterial infection are desirable.
[0008] Controlling the inoculation levels is the third component to
the intra- and post-operative surgical infection control triad. One
aspect to microbial control is the use antibiotics. For example,
one practice advocates the administration of systemic antibiotics
within 60 minutes prior to incision, with additional dosing if the
surgery exceeds 3 hours..sup.5 Such pre-incision administration has
shown some positive effects on the incidence of infection
associated with the placement of pacemakers..sup.7 An adjunctive
approach to managing the potential for implant contamination has
been the introduction of antimicrobial agents on implantable
medical devices..sup.8,9
[0009] This approach was initially developed to create a barrier to
microbial entry into the body via surface-penetrating devices, such
as indwelling catheters,.sup.9-11 The antimicrobial agents were
applied in solution as a direct coating on the device to prevent or
reduce bacterial colonization of the device and, therefore, reduce
the potential for a device-related infection. While a number of
clinical trials have demonstrated that antimicrobial coating on
devices, such as central venous catheters reduce device
colonization, reduction of infection has not been statistically
significant although the numerical trends show a reduction in
patient infection..sup.12-18 These results are highly relevant
since they tend to establish that, with proper aseptic and surgical
techniques as well as administration of appropriate antibiotic
therapy, the use of surface-modified devices has a positive impact
on the overall procedural/patient outcome..sup.12,13
[0010] The development of post-operative infection is dependent on
many factors, and it is not clear exactly how many colony forming
units (CFUs) are required to produce clinical infection. It has
been reported that an inoculation of 10.sup.3 bacteria at the
surgical site produces a wound infection rate of 20%..sup.5 And
while current air-handling technology and infection-control
procedures have undoubtedly reduced the microbial levels in the
hospital setting, microbial contamination of an implantable device
is still possible. It is known that bacteria, such as
Staphylococcus can produce bacteremia within a short time after
implantation (i.e., within 90 days) with a device or lay dormant
for months before producing an active infection so eradication of
the bacterial inoculum at the time of implantation is key and may
help to reduce late-stage as well as early-stage device-related
infections..sup.22
[0011] For example, the combination of rifampin and minocycline has
demonstrated antimicrobial effectiveness as a coating for catheters
and other implanted devices, including use of those drugs in a
non-resorbable coating such as silicone and polyurethane..sup.13,
19-21 The combination of rifampin and minocycline has also been
shown to reduce the incidence of clinical infection when used as a
prophylactic coating on penile implants.
[0012] The parent case of this application (U.S. Ser. No.
11/672,929) describes a bioresorbable polymer coating on a surgical
mesh as a carrier for the antimicrobial agents rifampin and
minocycline. Such meshes can be fashioned into a pouch of various
sizes and shapes to match the implanted pacemakers, pulse
generators, defibrillators and other implantable medical devices.
The addition of the antimicrobial agents permits the pouch to
deliver antimicrobial agents at the implant site and thus to
provide a barrier to microbial colonization of a CRM during
surgical implantation as an adjunct to surgical and systemic
infection control.
[0013] The present invention addresses these needs (preventing or
inhibiting infections) as well as others, such as pain relief and
inhibition or reduction of scar tissue, fibrosis and the like, by
providing temporarily stiffened meshes formed into pouches or other
receptacles to hold an implantable medical device upon
implantation.
SUMMARY OF THE INVENTION
[0014] The present invention relates to pouches, coverings and the
like made from implantable surgical meshes comprising one or more
biodegradable polymer coatings. The mesh pouches of the invention
can be shaped as desired into pouches, bags, coverings, shells,
skins, receptacles and the like to fit any implantable medical
device. Preferred meshes of the invention are comprised of woven
polypropylene coated with one or more biodegradable polymer to
impart drug elution or other temporary effects.
[0015] As used herein, "pouch," "pouches," "mesh pouch," "mesh
pouches," "pouch of the invention" and "pouches of the invention"
means any pouch, bag, skin, shell, covering, or other receptacle
made from an implantable surgical mesh comprising one or more
biodegradable polymer coatings and shaped to encapsulate, encase,
surround, cover or hold, in whole or in substantial part, an
implantable medical device. The pouches of the invention have
openings to permit leads and tubes of the IMD to extend unhindered
from the IMD though the opening of the pouch. The pouches may also
have porosity to accommodate monopolar devices that require the IMD
to be electrically grounded to the surrounding tissue. An IMD is
substantially encapsulated, encased, surrounded or covered when the
pouch can hold the device and at least 20%, 30%, 50%, 60%, 75%,
85%, 90%, 95% or 98% of the device is within the pouch or coverd by
the pouch.
[0016] In accordance with this invention, the coated surgical
meshes can be formed to encapsulate a pacemaker, a defibrillator, a
generator, an implantable access system, a neurostimulator, or any
other implantable device for the purpose of securing them in
position, providing pain relief, inhibiting scarring or fibrosis
and/or inhibiting bacterial growth. Such coated meshes are formed
into an appropriate shape either before or after coating with the
biodegradable polymers.
[0017] In one aspect, the pouches of the invention may act as
medical prostheses (providing support to the device and the tissue
surrounding the area of implant), and are thus also referred to as
medical prostheses.
[0018] Hence, the pouches of the invention comprise a mesh and one
or more coating which temporarily stiffens the mesh to at least 1.1
times its original stiffness. The coatings on such meshes do not
alter the integrity of the mesh and thus allow the mesh to remain
porous. In general, the coatings do not substantially alter the
porosity of the mesh. More particularly, the pouches of the
invention comprise a mesh with one or more coatings with at least
one of the coatings comprising a stiffening agent(s) that coats the
filaments or fibers of the mesh so to temporarily immobilize the
contact points of those filaments or fibers. Again, the coatings on
such meshes do not alter the integrity or strength of the
underlying mesh and allow the mesh to remain porous after coating.
In general, the coatings do not substantially alter the porosity of
the mesh. The meshes are capable of substantially reverting to
their original stiffness under conditions of use.
[0019] The stiffening agents, i.e., as applied in the coatings of
the invention, can selectively, partially or fully coat the contact
points of the filaments or said fibers of the mesh to create a
coating. The contact points generally include the knots of woven
meshes. Such coating are can be positioned on the mesh in a
templated pattern or in an array such as might be deposited with
ink jet type technology, including computer controlled deposition
techniques. Additionally, the coatings can be applied on one or
both sides of the mesh.
[0020] In some embodiments, the stiffening agents include
hydrogels, either alone or in combination with one or more
biodegradable polymers. In some embodiments, the stiffening agent
is one or more biodegradable polymers, and can be applied in
layers. One or more biodegradable polymers can be used per
individual coating layer. Preferred biodegradable polymer comprises
one or more tyrosine-derived diphenol monomer units as
polyarylates, polycarbonates or polyiminocarbonates.
[0021] In another aspect of the invention, the pouches of the
invention have at least one of the coatings that further comprises
one or more drugs. Such drugs include, but are not limited to,
antimicrobial agents, anesthetics, analgesics, anti-inflammatory
agents, anti-scarring agents, anti-fibrotic agents, leukotriene
inhibitors as well as other classes of drugs, including biological
agents such as proteins, growth inhibitors and the like.
[0022] The biodegradable polymer coatings are capable of releasing
one or more drugs into surrounding bodily tissue and proximal to
the device such that the drug reduces or prevents implant- or
surgery-related complications. For example, by including an
anesthetic agent in the coating that predictably seeps or elutes
into the surrounding bodily tissue, bodily fluid, or systemic
fluid, one has a useful way to attenuate pain experienced at the
implantation site. In another example, replacing the anesthetic
agent with an anti-inflammatory agent provides a way to reduce the
swelling and inflammation associated implantation of the mesh,
device and/or pouch. In yet another example, by delivering an
antimicrobial agent in the same manner, one has a way to provide a
rate of drug release sufficient to prevent colonization of the mesh
pouch, the CRM or other IMD and/or the surgical implantation site
by bacteria for at least the period following surgery necessary for
initial healing of the surgical incision.
[0023] The coatings on the pouches of the invention can deliver
multiple drugs from one or more independent layers, some of which
may contain no drug.
[0024] The invention thus provides a method of delivering drugs at
controlled rates and for set durations of time using biodegradable,
resorbable polymers from a coating on a surgical mesh formed as a
pouch of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1. graphically depicts the zone of inhibition (ZOI) for
polyarylate-coated meshes containing rifampin and minocycline
hydrochloride that have been incubated on Staphylococcus aureus
lawns for the indicated times (Example 1). The symbols represent
the following meshes: .tangle-solidup., P22-25 20 passes;
.box-solid., P22-25 40 passes; .tangle-solidup., P22-25 80 passes;
x, P22-27.5 20 passes; *, P22-27.5 40 passes; , P22-27.5 80 passes;
and |, catheter.
[0026] FIG. 2 graphically depicts cumulative bupivacaine release
from multilayer polyarylate-coated meshes.
[0027] FIG. 3 graphically depicts cumulative bupivacaine release
from multilayer polyarylate-coated meshes having various loadings
of bupivacaine. The symbols represent the following meshes: ,
P22-27.5 (11 passes, 1 dip); .box-solid., P22-27.5 (11 passes, 2
dips); and .tangle-solidup., P22-27.5 (2 passes, 2 dips).
[0028] FIG. 4 graphically depicts the time course of dermal
anesthesia from 1.times.2 cm surgically implanted, polyarylate
meshes containing 7.5 mg/cm.sup.2 bupivacaine. Meshes were
implanted in rats by subcostal laparotomy, pin-prick responses were
determined and are shown as % pain response inhibition (see
Examples for details). The "*" indicates statistically significant
response at p<0.05 compared to the baseline pin-prick
response.
[0029] FIG. 5 graphically depicts mesh stiffness. The bars, from
top to bottom, represent the stiffness for (1) a PPM3 mesh without
a polyarylate coating and without sterilization, (2) a Prolene.TM.
(Ethicon) mesh sterilized with ethylene oxide, (3) a
polyarylate-coated PPM3 mesh 12 months after coating and sterilized
by gamma irradiation with a nitrogen flush, and (4) a
polyarylate-coated PPM3 mesh 12 months after coating and sterilized
by gamma irradiation.
[0030] FIG. 6 graphically depicts the change in mesh stiffness over
time during the course of polymer degradation for a polymer-coated
polypropylene mesh soaking in PBS.
[0031] FIG. 7 depicts micrographs of a tyrosine polyarylate-coated
mesh. The top left panel shows the woven nature of the mesh and the
contact points of the filaments. The bottom left panel demonstrates
the coating over the contact points of the mesh filaments. The
right panel is a scanning electron micrograph of a coated
filament.
[0032] FIG. 8 provides an optical image of a mesh having a tyrosine
polyarylate coating containing rifampin and minocycline. On the
left, the optical image; on the right, a schematic thereof
indicating the areas of intense orange color by the circled areas
filled with diagonal lines.
[0033] FIG. 9 shows a schematic diagram of a polymer-coated CRM
pouch with the CRM inserted in the pouch.
[0034] FIG. 10 is a picture of a polymer-coated pouch containing a
CRM.
[0035] FIG. 11 is a micrograph showing the implant site of a
coated-mesh pouch with device at 14 weeks post-implantation
(4.times. magnification).
DETAILED DESCRIPTION OF THE INVENTION
[0036] The pouches of the invention are formed from the coated
implantable surgical meshes and comprise a surgical mesh and one or
more biodegradable polymer coating layers with each coating layer
optionally, and independently, further containing a drug. The
physical, mechanical, chemical, and resorption characteristics of
the coating enhance the clinical performance of the mesh and the
surgeon's ability to implant the device. These characteristics are
accomplished by choosing a suitable coating thickness and the
biodegradable polymer.
Mesh
[0037] A mesh in accordance with the invention is any web or fabric
with a construction of knitted, braided, woven or non-woven
filaments or fibers that are interlocked in such a way to create a
fabric or a fabric-like material. As used in accordance with the
present invention, "mesh" also includes any porous prosthesis
suitable for temporarily stiffening.
[0038] Surgical meshes are well known in the art and any such mesh
can be coated as described herein. The meshes used in the present
invention are made from biocompatible materials, synthetic or
natural, including but not limited to, polypropylene, polyester,
polytetrafluroethylene, polyamides and combinations thereof. One of
the advantages of the present invention is that the coatings can be
used with any commercially available mesh. A preferred mesh is made
from woven polypropylene. Pore sizes of meshes vary. For example
the Bard Marlex.RTM. mesh has pores of 379+/-143 micrometers or
approx. 0.4 mm, whereas the Johnson and Johnson Vypro.RTM. mesh has
pores of 3058+/-62 micrometers or approx. 3 mm.
[0039] The stiffening agents of the invention include hydrogels,
biodegradable polymers and any other compound capable of imparting
temporary stiffness to the mesh in accordance with the invention.
Temporary stiffness means that, relative to the corresponding
uncoated mesh material, there is an increase in stiffness when one
or more coatings are applied in accordance with the invention. Upon
use, those coatings then soften or degrade over time in a manner
that causes the mesh to revert back to its original stiffness,
revert nearly back to its original stiffness or sufficient close to
its original stiffness to provide the desired surgical outcome and
the expected patient comfort. To determine if the medical
prosthesis has temporary stiffness, the prosthesis can be evaluated
in vitro or in vivo. For example, a coating can be applied to the
mesh and then the mesh left in a physiological solution for a
period of time before measuring its stiffness. The time period of
stiffness is controlled by the degradation rate (for biodegradable
polymers) or absorption ability (for hydrogels). The time period
can vary from days, to weeks or even a few months and is most
conveniently determined in vitro. Meshes with that revert to their
original stiffness in vitro within a reasonable time (from 1 day to
3-4 months) are considered to be temporarily stiffened.
Additionally, animal models can be used to assess temporary
stiffness by implanting the mesh and then removing it from the
animal and determining if its stiffness had changed. Such in vivo
results can be correlated with the in vitro results by those of
skill in the art. Methods to measure stiffness of a mesh or a
coated mesh are known in the art.
[0040] A hydrogel is composed of a network of water-soluble polymer
chains. Hydrogels are applied as coatings and dried on the mesh.
Upon use, e.g., implantation in the body, the hydrogel absorbs
water and become soft (hydrogels can contain over 99% water),
thereby increasing the flexibility of the mesh and reverting to the
original or near original stiffness of the mesh. Typically,
hydrogels possess a degree of flexibility very similar to natural
tissue, due to their significant water content. Common ingredients
for hydrogels, include e.g. polyvinyl alcohol, sodium polyacrylate,
acrylate polymers and copolymers with an abundance of hydrophilic
groups.
[0041] Meshes can have one or more polymer coatings and can
optionally include drugs in the coatings. Meshes with a single
coating are useful to improve handling of the mesh during surgical
implantation and use. Meshes with drugs can be coated with single
or multiple layers, depending on the amount of drug to be
delivered, the type of drug and desired release rate. Each layer
can contain the same or different polymers, the same or different
drugs, and the same or different amounts of polymers or drugs. For
example, a first coating layer can contain drug, while the second
layer coating layer contains either no drug or a lower
concentration of drug.
[0042] The biodegradable coating deposited onto the surface of the
mesh gives the mesh superior handling characteristics relative to
uncoated meshes and facilitates surgical insertion because it
imparts stiffness to the mesh and thereby improves handling
thereof. Over time, however, the coating resorbs, or the stiffening
agents degrades or softens, to leave a flexible mesh that provides
greater patient comfort without loss of strength.
[0043] The surgical mesh can be coated with the biodegradable
polymer using standard techniques such as spray or dip coating to
achieve a uniform coating having a thickness that provides at least
1.1 to 4.5 and more preferably 1.25 to 2 times the stiffness of the
uncoated mesh. In addition, the coating is optimized to provide for
a uniform, flexible, non-flaking layer that remains adhered to the
mesh throughout the implantation and initial wound healing process.
Typically, the polymer coating must maintain its integrity for at
least 1 week. Optimal coating solutions are obtained by choosing a
biodegradable polymer with a solubility between about 0.01 to about
30% in volatile solvents such as methylene chloride or other
chlorinated solvents, THF, various alcohols, or combinations
thereof. Additionally, it is preferred to use biodegradable
polymers with a molecular weight between about 10,000 and about
200,000 Daltons. Such polymers degrade at rates that maintain
sufficient mechanical and physical integrity over about 1 week at
37.degree. C. in an aqueous environment.
[0044] Additionally, a biodegradable polymer-coated implantable
mesh is described in which the biodegradable polymer layer (i.e.,
the coating) has a chemical composition that provide relatively
good polymer-drug miscibility. The polymer layer can contain
between 1-80% drug at room temperature as well as between 1-95%,
2-80%, 2-50%, 5-40%, 5-30%, 5-25% and 10-20% drug or 1, 2, 3, 4, 5,
6, 7, 8, 9, or 10% drug as well as 5% increments from 10-95%, i.e.,
10, 15, 20, 25, etc. In one embodiment, the biodegradable polymer
coating releases drug for at least 2-3 days. Such release is
preferred, for example, when the drug is an analgesic to aide in
localized pain management at the surgical site. Such loading and
release characteristics can be also be obtained for drug
polymer-combinations that do not have good miscibility by using
multiple layering techniques.
[0045] Additionally, the biodegradable polymer for use with the
mesh pouch has a chemical composition complementary to the drug so
that the polymer layer can contain between 2-50% drug at room
temperature. For certain types of drug, the layer can contain as
much as 80-90% drug and acts as drug reservoir (or depot layer) and
drug release can be controlled by using multiple layers with
varying amounts of drug (from none, to a few percent, saturation or
above the solubility limit for the drug in the polymer).
[0046] To achieve an analgesic affect, the anesthetic and/or
analgesic should be delivered to the injured tissue shortly after
surgery or tissue injury. A drug or drugs for inclusion in the
coatings on the pouches of the invention include, but are not
limited to analgesics, anti-inflammatory agents, anesthetics,
antimicrobial agents, antifungal agents, NSAIDS, other biologics
(including proteins and nucleic acids) and the like. Antimicrobial
and antifungal agents can prevent the mesh pouch, the device and/or
the surrounding tissue from being colonized by bacteria. One or
more drugs can be incorporated into the polymer coatings on the
mesh pouches of the invention.
[0047] In another embodiment, a mesh pouch of the invention has a
coating comprising an anesthetic such that the anesthetic elutes
from the implanted coated mesh to the surrounding tissue of the
surgical site for between 1 and 10 days, which typically coincides
with the period of acute surgical site pain. In another embodiment,
delivery of an antimicrobial drug via a mesh pouch of the invention
can create an inhibition zone against bacterial growth and
colonization surrounding the implant during the healing process
(e.g., usually about 30 days or less) and/or prevent undue fibrotic
responses.
[0048] Using biodegradable polymer coatings avoids the issue of
drug solubility, impregnation or adherence in or to the underlying
device since a coating having suitable chemical properties can be
deposited onto the mesh, optionally in concert with one or more
drugs, to provide for the release of relatively high concentrations
of those drugs over extended periods of time. For example, by
modulating the chemical composition of the biodegradable polymer
coating on the mesh pouch and the coating methodology, a
clinically-efficacious amount of anesthetic drug can be loaded onto
a mesh pouch to assure sufficient drug elution and to provide
surgical site, post-operative pain relief for the patient.
[0049] To provide such post-operative, acute pain relief, the mesh
pouch should elute from about 30 mg to about 1000 mg of anesthetic
over 1-10 days, including, e.g., about 30, 50, 100, 200, 400, 500,
750 or 1000 mg over that time period.
[0050] The pouch should elute clinically effective amounts of
anesthetic during the acute post-operative period when pain is most
noticeable to the patient. This period, defined in several clinical
studies, tends to be from 12 hours to 5 days after the operation,
with pain greatest around 24 hours and subsiding over a period of
several days thereafter. Prior to 12 hours, the patient is usually
still under the influence of any local anesthetic injection given
during the surgery itself. After the 5-day period, most of the pain
related to the surgery itself (i.e., incisional pain and
manipulation of fascia, muscle, & nerves) has resolved to a
significant extent.
[0051] Bupivacaine has a known toxicity profile, duration of onset,
and duration of action. Drug monographs recommend the daily dose
not to exceed 400 mg. Those of skill in the art can determine the
amount of anesthetic to include in a polymer coating or a hydrogel
coating to achieve the desired amount and duration of pain relief.
Moreover, anesthetics that contain amines, such as lidocaine and
bupivacaine, are hydrophobic and are difficult to load in
sufficient amounts into the most commonly used plastics employed in
the medical device industry, such as polypropylene and other
non-resorbable thermoplastics. When in their hydrochloride salt
form, anesthetics cannot be effectively loaded in significant
concentration into such non-resorbable thermoplastics because of
the mismatch in hydrophilicity of the two materials.
[0052] There are numerous reports of reduction or complete
elimination of narcotic use and pain scores after open hernia
repair during days 2-5 with concomitant use of catheter pain pump
system. In these cases, the pump delivers either a 0.25% or 0.5%
solution of bupivacaine to the subfascial area (Sanchez, 2004;
LeBlanc, 2005; and Lau, 2003). At a 2 mL/hour flow rate, this
translates into constant "elution" of approximately 120 mg of
bupivacaine per day. However, this system purportedly suffers from
leakage, so the 120 mg per day may only serve as an extremely rough
guide for the amount of bupivacaine that should be delivered to
provide adequate post-operative pain relief.
[0053] One of the most well characterized sustained release depot
systems for post-operative pain relief reported in the literature
is a PLGA microsphere-based sustained release formulation of
bupivacaine. This formulation was developed and tested in humans
for relief of subcutaneous pain as well as neural blocks. Human
trials indicated that subcutaneous pain was relieved via injection
of between 90 to 180 mg of bupivacaine which then eluted into the
surrounding tissue over a 7-day period, with higher concentrations
in the initial 24-hour period followed by a gradual taper of the
concentration. Other depot sustained-release technologies have
successfully suppressed post-operative pain associated with
inguinal hernia repair. For example, external pumps and PLGA
microsphere formulations have each purportedly release drug for
approximately 72 hours.
[0054] To achieve loading at the lower limit of the elution
profile, for example, one can choose a relatively hydrophilic
biodegradable polymer and combine it with the anesthetic
hydrochloride salt so that the anesthetic dissolves in the polymer
at a concentration below the anesthetic's saturation limit. Such a
formulation provides non-burst release of anesthetic. To achieve
loading at the upper limit of the elution profile, one can spray
coat a layer of an anesthetic-polymer mixture that contains the
anesthetic at a concentration above its saturation limit. In this
formulation, the polymer does not act as a control mechanism for
release of the anesthetic, but rather acts as a binder to hold the
non-dissolved, anesthetic particles together and alters the
crystallization kinetics of the drug. A second coating layer, which
may or may not contain further anesthetic, is sprayed on top of the
first layer. When present in the second coating, the anesthetic
concentration is at a higher ratio of polymer to anesthetic, e.g.,
a concentration at which the anesthetic is soluble in the polymer
layer.
[0055] The top layer thus can serve to control the release of the
drug in the bottom layer (aka depot layer) via the drug-polymer
solubility ratio. Moreover, it is possible to alter the release
rate of the drug by changing the thickness of the polymer layer and
changing the polymer composition according to its water uptake. A
polymer that absorbs a significant amount of water within 24 hours
will release the contents of the depot layer rapidly. However, a
polymer with limited water uptake or variable water uptake (changes
as a function of its stage of degradation) will retard release of
the water soluble anesthetic agent.
[0056] In one embodiment, the biodegradable polymer coating
releases drug for at least 2-3 days. Such release is preferred, for
example, when the drug is an analgesic to aide in localized pain
management at the surgical site. To achieve an analgesic affect,
the anesthetic and/or analgesic should be delivered to the injured
tissue shortly after surgery or tissue injury.
[0057] In another embodiment, the coating comprises an anesthetic
such that the anesthetic elutes from the implanted coated mesh to
the surrounding tissue of the surgical site for between 1 and 10
days, which typically coincides with the period of acute surgical
site pain. In another embodiment, delivery of an antimicrobial drug
via a mesh of the invention can create an inhibition zone against
bacterial growth and colonization surrounding the implant during
the healing process (e.g., usually about 7-30 days or less) and/or
prevent undue fibrotic responses.
[0058] Using biodegradable polymer coatings avoids the issue of
drug solubility, impregnation or adherence in or to the underlying
device since a coating having suitable chemical properties can be
deposited onto the mesh pouch, optionally in concert with one or
more drugs, to provide for the release of relatively high
concentrations of those drugs over extended periods of time. For
example, by modulating the chemical composition of the
biodegradable polymer coating and the coating methodology, a
clinically-efficacious amount of anesthetic drug can be loaded onto
a mesh pouch to assure sufficient drug elution and to provide
surgical site, post-operative pain relief for the patient.
[0059] Other elution profiles, with faster or slower drug release
over a different (longer or shorter) times, can be achieved by
altering the thickness of the layers, the amount of drug in the
depot layer and the hydrophilicity of the biodegradable
polymer.
Biodegradable Polymers
[0060] The coatings on the pouches of the invention are formed from
biodegradable polymeric layers that optionally contain one or more
drugs. Methods of making biodegradable polymers are well known in
the art.
[0061] The biodegradable polymers suitable for use in the invention
include but are not limited to:
[0062] polylactic acid, polyglycolic acid and copolymers and
mixtures thereof such as poly(L-lactide) (PLLA), poly(D,L-lactide)
(PLA) polyglycolic acid [polyglycolide (PGA)],
poly(L-lactide-co-D,L-lactide) (PLLA/PLA),
poly(L-lactide-co-glycolide) (PLLA/PGA), poly(D,
L-lactide-co-glycolide) (PLA/PGA), poly(glycolide-co-trimethylene
carbonate) (PGA/PTMC), poly(D,L-lactide-co-caprolactone) (PLA/PCL)
and poly(glycolide-co-caprolactone) (PGA/PCL);
[0063] polyethylene oxide (PEO), polydioxanone (PDS), polypropylene
fumarate, poly(ethyl glutamate-co-glutamic acid),
poly(tert-butyloxy-carbonylmethyl glutamate), polycaprolactone
(PCL), polycaprolactone co-butylacrylate, polyhydroxybutyrate
(PHBT) and copolymers of polyhydroxybutyrate, poly(phosphazene),
poly(phosphate ester), poly(amino acid), polydepsipeptides, maleic
anhydride copolymers, polyiminocarbonates, poly[(97.5%
dimethyl-trimethylene carbonate)-co-(2.5% trimethylene carbonate)],
poly(orthoesters), tyrosine-derived polyarylates, tyrosine-derived
polycarbonates, tyrosine-derived polyiminocarbonates,
tyrosine-derived polyphosphonates, polyethylene oxide, polyethylene
glycol, polyalkylene oxides, hydroxypropylmethylcellulose,
polysaccharides such as hyaluronic acid, chitosan and regenerate
cellulose, and proteins such as gelatin and collagen, and mixtures
and copolymers thereof, among others as well as PEG derivatives or
blends of any of the foregoing.
[0064] In some embodiments, biodegradable polymers of the invention
have diphenol monomer units that are copolymerized with an
appropriate chemical moiety to form a polyarylate, a polycarbonate,
a polyiminocarbonate, a polyphosphonate or any other polymer.
[0065] The preferred biodegradable polymers are tyrosine-based
polyarylates including those described in U.S. Pat. Nos. 4,980,449;
5,099,060; 5,216,115; 5,317,077; 5,587,507; 5,658,995; 5,670,602;
6,048,521; 6,120,491; 6,319,492; 6,475,477; 6,602,497; 6,852,308;
7,056,493; RE37,160E; and RE37,795E; as well as those described in
U.S. Patent Application Publication Nos. 2002/0151668;
2003/0138488; 2003/0216307; 2004/0254334; 2005/0165203; and those
described in PCT Publication Nos. WO99/52962; WO 01/49249; WO
01/49311; WO03/091337. These patents and publications also disclose
other polymers containing tyrosine-derived diphenol monomer units
or other diphenol monomer units, including polyarylates,
polycarbonates, polyiminocarbonates, polythiocarbonates,
polyphosphonates and polyethers.
[0066] Likewise, the foregoing patents and publications describe
methods for making these polymers, some methods of which may be
applicable to synthesizing other biodegradable polymers. Finally,
the foregoing patents and publications also describe blends and
copolymers with polyalkylene oxides, including polyethylene glycol
(PEG). All such polymers are contemplated for use in the present
invention.
[0067] The representative structures for the foregoing polymers are
provide in the above-cited patents and publications which are
incorporated herein by reference.
[0068] As used herein, DTE is the diphenol monomer
desaminotyrosyl-tyrosine ethyl ester; DTBn is the diphenol monomer
desaminotyrosyl-tyrosine benzyl ester; DT is the corresponding free
acid form, namely desaminotyrosyl-tyrosine. BTE is the diphenol
monomer 4-hydroxy benzoic acid-tyrosyl ethyl ester; BT is the
corresponding free acid form, namely 4-hydroxy benzoic
acid-tyrosine.
[0069] P22 is a polyarylate copolymer produced by condensation of
DTE with succinate. P22-10, P22-15, P22-20, P22-xx, etc.,
represents copolymers produced by condensation of (1) a mixture of
DTE and DT using the indicated percentage of DT (i.e., 10, 15, 20
and xx % DT, etc.) with (2) succinate.
[0070] Additional preferred polyarylates are copolymers of
desaminotyrosyl-tyrosine (DT) and an desaminotyrosyl-tyrosyl ester
(DT ester), wherein the copolymer comprises from about 0.001% DT to
about 80% DT and the ester moiety can be a branched or unbranched
alkyl, alkylaryl, or alkylene ether group having up to 18 carbon
atoms, any group of which can, optionally have a polyalkylene oxide
therein. Similarly, another group of polyarylates are the same as
the foregoing but the desaminotyrosyl moiety is replaced by a
4-hydroxybenzoyl moiety. Preferred DT or BT contents include those
copolymers with from about 1% to about 30%, from about 5% to about
30% from about 10 to about 30% DT or BT. Preferred diacids (used
informing the polyarylates) include succinate, glutarate and
glycolic acid.
[0071] Additional biodegradable polymers useful for the present
invention are the biodegradable, resorbable polyarylates and
polycarbonates disclosed in U.S. provisional application Ser. No.
60/733,988, filed Nov. 3, 2005 and in its corresponding PCT Appln.
No. PCT/US06/42944, filed Nov. 3, 2006. These polymers, include,
but are not limited to, BTE glutarate, DTM glutarate, DT
propylamide glutarate, DT glycineamide glutarate, BTE succinate,
BTM succinate, BTE succinate PEG, BTM succinate PEG, DTM succinate
PEG, DTM succinate, DT N-hydroxysuccinimide succinate, DT
glucosamine succinate, DT glucosamine glutarate, DT PEG ester
succinate, DT PEG amide succinate, DT PEG ester glutarate and DT
PEG ester succinate.
[0072] The most preferred polyarylates are the DTE-DT succinate
family of polymers, e.g., the P22-xx family of polymers having from
0-50%, 5-50%, 5-40%, 1-30% or 10-30% DT, including but not limited
to, about 1, 2, 5, 10, 15, 20, 25, 27.5, 30, 35, 40%, 45% and 50%
DT.
[0073] Additionally, the polyarylate polymers used in the present
invention can have from 0.1-99.9% PEG diacid to promote the
degradation process as described in U.S. provisional application
Ser. No. 60/733,988. Blends of polyarylates or other biodegradable
polymers with polyarylates are also preferred.
Drugs
[0074] Any drug, biological agent or active ingredient compatible
with the process of preparing the mesh pouches of the invention can
be incorporated into one or more layers of the biodegradable
polymeric coatings on the mesh. Doses of such drugs and agents are
know in the art. Those of skill in the art can readily determine
the amount of a particular drug to include in the coatings on the
meshes of the invention.
[0075] Examples of drugs suitable for use with the present
invention include anesthetics, antibiotics (antimicrobials),
anti-inflammatory agents, fibrosis-inhibiting agents, anti-scarring
agents, leukotriene inhibitors/antagonists, cell growth inhibitors
and the like. As used herein, "drugs" is used to include all types
of therapeutic agents, whether small molecules or large molecules
such as proteins, nucleic acids and the like. The drugs of the
invention can be used alone or in combination.
[0076] Any pharmaceutically acceptable form of the drugs of the
present invention can be employed in the present invention, e.g.,
the free base or a pharmaceutically acceptable salt or ester
thereof. Pharmaceutically acceptable salts, for instance, include
sulfate, lactate, acetate, stearate, hydrochloride, tartrate,
maleate, citrate, phosphate and the like.
[0077] Examples of non-steroidal anti-inflammatories include, but
are not limited to, naproxen, ketoprofen, ibuprofen as well as
diclofenac; celecoxib; sulindac; diflunisal; piroxicam;
indomethacin; etodolac; meloxicam; r-flurbiprofen; mefenamic;
nabumetone; tolmetin, and sodium salts of each of the foregoing;
ketorolac bromethamine; ketorolac bromethamine tromethamine;
choline magnesium trisalicylate; rofecoxib; valdecoxib;
lumiracoxib; etoricoxib; aspirin; salicylic acid and its sodium
salt; salicylate esters of alpha, beta, gamma-tocopherols and
tocotrienols (and all their d, l, and racemic isomers); and the
methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl,
esters of acetylsalicylic acid.
[0078] Examples of anesthetics include, but are not limited to,
licodaine, bupivacaine, and mepivacaine. Further examples of
analgesics, anesthetics and narcotics include, but are not limited
to acetaminophen, clonidine, benzodiazepine, the benzodiazepine
antagonist flumazenil, lidocaine, tramadol, carbamazepine,
meperidine, zaleplon, trimipramine maleate, buprenorphine,
nalbuphine, pentazocain, fentanyl, propoxyphene, hydromorphone,
methadone, morphine, levorphanol, and hydrocodone. Local
anesthetics have weak antibacterial properties and can play a dual
role in the prevention of acute pain and infection.
[0079] Examples of antimicrobials include, but are not limited to,
triclosan, chlorhexidine, rifampin, minocycline (or other
tetracycline derivatives), vancomycin, gentamycine, cephalosporins
and the like. In preferred embodiments the coatings contain
rifampin and another antimicrobial agent, preferably that agent is
a tetracycline derivative. In another preferred embodiment, the
coatings contains a cephalosporin and another antimicrobial agent.
Preferred combinations include rifampin and minocycline, rifampin
and gentamycin, and rifampin and minocycline.
[0080] Further antimicrobials include aztreonam; cefotetan and its
disodium salt; loracarbef; cefoxitin and its sodium salt; cefazolin
and its sodium salt; cefaclor; ceftibuten and its sodium salt;
ceftizoxime; ceftizoxime sodium salt; cefoperazone and its sodium
salt; cefuroxime and its sodium salt; cefuroxime axetil; cefprozil;
ceftazidime; cefotaxime and its sodium salt; cefadroxil;
ceftazidime and its sodium salt; cephalexin; cefamandole nafate;
cefepime and its hydrochloride, sulfate, and phosphate salt;
cefdinir and its sodium salt; ceftriaxone and its sodium salt;
cefixime and its sodium salt; cefpodoxime proxetil; meropenem and
its sodium salt; imipenem and its sodium salt; cilastatin and its
sodium salt; azithromycin; clarithromycin; dirithromycin;
erythromycin and hydrochloride, sulfate, or phosphate salts
ethylsuccinate, and stearate forms thereof; clindamycin;
clindamycin hydrochloride, sulfate, or phosphate salt; lincomycin
and hydrochloride, sulfate, or phosphate salt thereof; tobramycin
and its hydrochloride, sulfate, or phosphate salt; streptomycin and
its hydrochloride, sulfate, or phosphate salt; vancomycin and its
hydrochloride, sulfate, or phosphate salt; neomycin and its
hydrochloride, sulfate, or phosphate salt; acetyl sulfisoxazole;
colistimethate and its sodium salt; quinupristin; dalfopristin;
amoxicillin; ampicillin and its sodium salt; clavulanic acid and
its sodium or potassium salt; penicillin G; penicillin G
benzathine, or procaine salt; penicillin G sodium or potassium
salt; carbenicillin and its disodium or indanyl disodium salt;
piperacillin and its sodium salt; ticarcillin and its disodium
salt; sulbactam and its sodium salt; moxifloxacin; ciprofloxacin;
ofloxacin; levofloxacins; norfloxacin; gatifloxacin; trovafloxacin
mesylate; alatrofloxacin mesylate; trimethoprim; sulfamethoxazole;
demeclocycline and its hydrochloride, sulfate, or phosphate salt;
doxycycline and its hydrochloride, sulfate, or phosphate salt;
minocycline and its hydrochloride, sulfate, or phosphate salt;
tetracycline and its hydrochloride, sulfate, or phosphate salt;
oxytetracycline and its hydrochloride, sulfate, or phosphate salt;
chlortetracycline and its hydrochloride, sulfate, or phosphate
salt; metronidazole; dapsone; atovaquone; rifabutin; linezolide;
polymyxin B and its hydrochloride, sulfate, or phosphate salt;
sulfacetamide and its sodium salt; and clarithromycin.
[0081] Examples of antifungals include amphotericin B;
pyrimethamine; flucytosine; caspofungin acetate; fluconazole;
griseofulvin; terbinafin and its hydrochloride, sulfate, or
phosphate salt; ketoconazole; micronazole; clotrimazole; econazole;
ciclopirox; naftifine; and itraconazole.
[0082] Other drugs that can be incorporated into the coatings on
the mesh pouches of the invention include, but are not limited to,
keflex, acyclovir, cephradine, malphalen, procaine, ephedrine,
adriamycin, daunomycin, plumbagin, atropine, quinine, digoxin,
quinidine, biologically active peptides, cephradine, cephalothin,
cis-hydroxy-L-proline, melphalan, penicillin V, aspirin, nicotinic
acid, chemodeoxycholic acid, chlorambucil, paclitaxel, sirolimus,
cyclosporins, 5-flurouracil and the like.
[0083] Additional, drugs include those that act as angiogenensis
inhibitors or inhibit cell growth such as epidermal growth factor,
PDGF, VEGF, FGF (fibroblast growth factor) and the like. These
drugs include anti-growth factor antibodies (neutrophilin-1),
growth factor receptor-specific inhibitors such as endostatin and
thalidomide. Examples of useful proteins include cell growth
inhibitors such as epidermal growth factor.
[0084] Examples of anti-inflammatory compound include, but are not
limited to, anecortive acetate; tetrahydrocortisol,
4,9(11)-pregnadien-17.alpha.,21-diol-3,20-dione and its -21-acetate
salt; 11-epicortisol; 17.alpha.-hydroxyprogesterone;
tetrahydrocortexolone; cortisona; cortisone acetate;
hydrocortisone; hydrocortisone acetate; fludrocortisone;
fludrocortisone acetate; fludrocortisone phosphate; prednisone;
prednisolone; prednisolone sodium phosphate; methylprednisolone;
methylprednisolone acetate; methylprednisolone, sodium succinate;
triamcinolone; triamcinolone-16,21-diacetate; triamcinolone
acetonide and its -21-acetate, -21-disodium phosphate, and
-21-hemisuccinate forms; triamcinolone benetonide; triamcinolone
hexacetonide; fluocinolone and fluocinolone acetate; dexamethasone
and its -21-acetate, -21-(3,3-dimethylbutyrate), -21-phosphate
disodium salt, -21-diethylaminoacetate, -21-isonicotinate,
-21-dipropionate, and -21-palmitate forms; betamethasone and its
-21-acetate, -21-adamantoate, -17-benzoate, -17,21-dipropionate,
-17-valerate, and -21-phosphate disodium salts; beclomethasone;
beclomethasone dipropionate; diflorasone; diflorasone diacetate;
mometasone furoate; and acetazolamide.
[0085] Examples of leukotriene inhibitors/antagonists include, but
are not limited to, leukotriene receptor antagonists such as
acitazanolast, iralukast, montelukast, pranlukast, verlukast,
zafirlukast, and zileuton.
[0086] Another useful drug that can be incorporated into the
coatings of the invention is sodium 2-mercaptoethane sulfonate
(Mesna). Mesna has been shown to diminish myofibroblast formation
in animal studies of capsular contracture with breast implants
[Ajmal et al. (2003) Plast. Reconstr. Surg. 112:1455-1461] and may
thus act as an anti-fibrosis agent.
[0087] Those of ordinary skill in the art will appreciate that any
of the foregoing disclosed drugs can be used in combination or
mixture in coatings of the present invention.
Coating Methods
[0088] In accordance with the invention, one method to coat the
mesh with a stiffening agent is to spray a solution of polymer to
coat the filaments or fibers of the mesh to temporarily immobilize
contact points of the filaments or fibers of said mesh. This method
comprises (a) preparing a coating solution comprising a solvent and
the stiffening agent; (b) spraying a mesh one or more times to
provide an amount of solution on the mesh to produce a coating
having a thickness and placement sufficient to temporarily
immobilize contact points of the filaments or fibers of the mesh
that coats filaments or fibers; and (c) drying the mesh to produce
said coating. An example of ratio of coating thickness to polymer
coating is shown in the scanning electron micrograph of FIG. 7.
When used with a drug (or combination of drugs), the drug is
included in the coating solution at the desired concentration.
[0089] Spraying can be accomplished by known methods. For example,
the coating can be applied to the entire mesh or to that portion of
the mesh necessary to stiffen it. One technique is to dip the mesh
in the coating material; another is to push the mesh through
rollers that transfer the coating on the mesh. Spraying the mesh
with a microdroplets is also effective. Techniques for selectively
coating only those areas necessary to stiffen the mesh include
deposition the coating through a template or mask that exposes only
the desired areas of coverage for the coating, including dispensing
the coating with micro needles or similar means. More preferably
the coating can be applied using a photoresist-like mask that
expose the desired portions, applying the coating over the
photomask and the removing the photomask.
[0090] The coated meshes can be laser cut to produce the desired
shaped and sized pouches, coverings and the like. The pouches can
be shaped to fit relatively snugly or more loosely around the
implantable medical device. Two pieces can be sealed, by heat, by
ultrasound or other method known in the art, leaving one side open
to permit insertion of the device at the time of the surgical
procedure and to allow the leads or other wires to extend out of
the pouch stick out/protrude.
[0091] Additionally, the mesh pouches of the invention have a space
or opening sufficient to allow the leads from the device to pass
through the pouch. The number of spaces or opening in the pouch
that are provided can match the number and placement of the leads
or other tubes extending from the CRM or other IMD, as applicable
for the relevant device.
[0092] In preferred embodiments, the shape and size of the pouch of
the invention is similar to that of the CRM or IMD with which it is
being used, and the pouch has a sufficient number of openings or
spaces to accommodate the leads or tubings of the particular CRM or
other IMD.
[0093] The pouches of the invention are porous from the mesh but
can have additional prosity. For example, additional porosity can
be imparted by laser cutting additional holes in the coated. mesh
Porous pouches Hence, the pouch need not completely encase or
surround the IMD. An IMD is thus substantially encapsulated,
encased, surrounded or covered when the pouch can hold the device
and at least 20%, 30%, 50%, 60%, 75%, 80%, 85%, 90%, 95% or 98% of
the device is within the pouch. Porous pouches and partially
encased pouches permit contact with tissue and body fluids and are
particularly useful with monopole CRM or other IMD devices.
Porosity will contribute to the percentage of the IMD covered by
the pouch. That is, an IMD is considered to be 50% covered if it is
completely surrounded by a pouch that is constructed of a film with
50% voids or holes.
CRMs and Other IMDs
[0094] The CRMs and other IMDs used with the pouches of the
invention include but are not limited to pacemakers,
defibrillators, implantable access systems, neurostimulators, other
stimulation devices, ventricular assist devices, infusion pumps or
other implantable devices (or implantable components thereof) for
delivering medication, hydrating solutions or other fluids,
intrathecal delivery systems, pain pumps, or any other implantable
system to provide drugs or electrical stimulation to a body
part.
[0095] Implantable cardiac rhythm management devices (CRMs) are a
form of IMDs and are life-long medical device implants. CRMs ensure
the heart continually beats at a steady rate. There are two main
types of CRM devices: implantable cardiac rhythm management devices
and implantable defibrillators.
[0096] The ICDs, or implantable cardioverter defibrillator, and
pacemakers share common elements. They are permanent implants
inserted through relatively minor surgical procedures. Each has 2
basic components: a generator and a lead. The generator is usually
placed in a subcutaneous pocket below the skin of the breastbone
and the lead is threaded down and into the heart muscle or
ventricle. The common elements of placement and design result in
shared morbidities, including lead extrusion, lead-tip fibrosis,
and infection. Although infection rates are purportedly quite low,
infection is a serious problem as any bacterial contamination of
the lead, generator, or surgical site can travel directly to the
heart via bacterial spreading along the generator and leads.
Endocarditis, or an infection of the heart, has reported mortality
rates as high as 33%.
[0097] An ICD is an electronic device that constantly monitors
heart rate and rhythm. When it detects a fast, abnormal heart
rhythm, it delivers energy to the heart muscle. This action causes
the heart to beat in a normal rhythm again in an attempt to return
it to a sinus rhythm.
[0098] The ICD has two parts: the lead(s) and a pulse generator.
The lead(s) monitor the heart rhythm and deliver energy used for
pacing and/or defibrillation (see below for definitions). The
lead(s) are directly connected to the heart and the generator. The
generator houses the battery and a tiny computer. Energy is stored
in the battery until it is needed. The computer receives
information on cardiac function via the leads and reacts to that
information on the basis of its programming.
[0099] The different types of ICDs include, but are not limited to,
single chamber ICDs in which a lead is attached in the right
ventricle. If needed, energy is delivered to the ventricle to help
it contract normally; dual chamber ICDs in which the leads are
attached in the right atrium and the right ventricle. Energy is
delivered first to the right atrium and then to the right ventricle
to ensure that the heart beats in a normal sequence; and
biventricular ICDs in which leads are attached in the right atrium,
the right ventricle and the left ventricle. This arrangement helps
the heart beat in a more balanced way and is specifically used for
patients with heart failure.
[0100] A pacemaker is a small device that sends electrical impulses
to the heart muscle to maintain a suitable heart rate and rhythm. A
pacemaker can also be used to treat fainting spells (syncope),
congestive heart failure, and hypertrophic cardiomyopathy.
Pacemakers are generally implanted under the skin of the chest
during a minor surgical procedure. The pacemaker is also comprised
of leads and a battery-driven pulse generator. The pulse generator
resides under the skin of the chest. The leads are wires that are
threaded through the veins into the heart and implanted into the
heart muscle. They send impulses from the pulse generator to the
heart muscle, as well as sense the heart's electrical activity.
[0101] Each impulse causes the heart to contract. The pacemaker may
have one to three leads, depending on the type of pacemaker needed
to treat your heart problem.
[0102] The different types of pacemakers include, but are not
limited to single chamber pacemakers which use one lead in the
upper chambers (atria) or lower chambers (ventricles) of the heart;
dual chamber pacemakers which use one lead in the atria and one
lead in the ventricles of your heart; and biventricular pacemakers
which use three leads: one placed in the right atrium, one placed
in the right ventricle, and one placed in the left ventricle (via
the coronary sinus vein).
[0103] The pouches of the invention can thus be designed to fit a
wide range of pacemakers and implantable defibrillators from a
variety of manufacturers (see Table 1). Sizes of the CRMs vary and
typically size ranges are listed in Table 1.
TABLE-US-00001 TABLE 1 CRM Devices Size Manufacturer Device Type
Model (H'' .times. L'' .times. W'') Medtronic EnPulse Pacing Pacing
system E2DR01 1.75 .times. 2 .times. 0.33 system Medtronic EnPulse
Pacing Pacing system E2DR21 1.75 .times. 1.63 .times. 0.33 system
Medtronic EnRhythm Pacing system P1501DR 1.77 .times. 2 .times.
0.31 Pacing system Medtronic AT500 Pacing Pacing system AT501 1.75
.times. 2.38 .times. 0.33 system Medtronic Kappa DR900 Pacing
system DR900, DR700 1.75-2 .times. 1.75-2 .times. 0.33 & 700
series Medtronic Kappa DR900 Pacing system SR900, SR700 1.5-1.75
.times. 1.75-2 .times. 0.33 & 700 series Medtronic Sigma Pacing
system D300, D200, D303, 1.75 .times. 2 .times. 0.33 D203 Medtronic
Sigma Pacing system DR300, DR200, 1.75-2 .times. 2 .times. 0.33
DR303, DR306, DR203 Medtronic Sigma Pacing system VDD300, VDD303
1.75 .times. 1.75 .times. 0.33 Medtronic Sigma Pacing system S300,
S200, S100, 1.63 .times. 2 .times. 0.33 S303, S203, S103, S106,
VVI-103 Medtronic Sigma SR Pacing system SR300, S200, 1.63 .times.
2 .times. 0.33 SR303, SR306, SR203 Medtronic Entrust Defibrillator
D154VRC 35J 2.44 .times. 2 .times. 0.6 Medtronic Maximo &
Defibrillator Size of a pager Marquis family Medtronic Gem family
Defibrillator III T, III R, III R, II Size of a pager R, II VR
Guidant Contak Renewal Pacing system H120, H125 2.13 .times. 1.77
.times. 033 TR St. Jude Identity Pacing system ADx DR, ADx SR,
1.6-1.73 .times. 1.73-2.05 .times. 0.24 ADx XL, ADx VDR St. Jude
Integrity Pacing system ADx DR, ADx SR 1.6-1.73 .times. 1.73-2.05
.times. 0.24
[0104] Implantable neurostimulators are similar to pacemakers in
that the devices generate electrical impulses. These devices send
electrical signals via leads to the spine and brain to treat pain
and other neurological disorders. For example, when the leads are
implanted in the spine, the neurostimulation can be used to treat
chronic pain (especially back and spinal pain); when the leads are
implanted in the brain, the neurostimulation can be used to treat
epilepsy and essential tremor including the tremors associated with
Parkinson's disease and other neurological disorders.
Neurostimulation can be used to treat severe, chronic nausea and
vomiting as well as urological disorders. For the former,
electrical impulses are sent to the stomach; for the latter, the
electrical impulses are sent to the sacral nerves in the lower
back. The implant location of the neurostimulator varies by
application but, in all cases, is placed under the skin and is
susceptible to infection at the time of implantation and
pos-implantation. Likewise, reintervention and replacement of
batteries in the neurostimulators can occur at regular
intervals.
[0105] The pouches of the invention can thus be designed to fit a
wide range of neurostimulators from a variety of manufacturers (see
Table 2). Sizes of the neurostimulators vary and typically size
ranges are listed in Table 2.
TABLE-US-00002 TABLE 2 Neurostimulators Size Manufacturer Device
Type Model (H'' .times. L'' .times. W'') Medtronic InterStim
Neurostimulation 3023 2.17 .times. 2.4 .times. 0.39 INS Medtronic
InterStim Neurostimulation 3058 1.7 .times. 2.0 .times. 0.3 INS II
Medtronic RESTORE Neurostimulation 37711 2.56 .times. 1.93 .times.
0.6 Advanced Precision Neurostimulation/Spinal 2.09 .times. 1.70
.times. 0.35 Bionics IPG Cord Stimulator (Boston Scientific)
Cyberonics VNS Neurostimulation/Epilepsy 102 2.03 .times. 2.06
.times. 0.27 Therapy system Cyberonics VNS
Neurostimulation/Epilepsy 102R 2.03 .times. 2.32 .times. 0.27
Therapy system ANS (St. Jude) Eon Neurostimulation Comparable to
Medtronic Restore ANS (St. Jude) Genesis RC Neurostimulation
Comparable to Medtronic Restore ANS (St. Jude) Genesis XP
Neurostimulation Comparable to Medtronic Restore
[0106] Reported infection rates for first implantation are usually
quite low (less than 1%); however, they increase dramatically when
a reintervention is necessary. Reintervention often requires the
removal of the generator portion of the ICD, pacemaker,
neurostimulator, drug pump or other IMD and having a resorbable
pouch enhances that process.
[0107] Other IMDs for use in the invention are drug pumps,
especially pain pumps and intrathecal delivery systems. These
devices generally consist of an implantable drug pump and a
catheter for dispensing the drug. The implantable drug pump is
similar in size to the neurostimulators and CRMs. Further
implantable medical devices include, but are not limited to,
implantable EGM monitors, implantable access systems, or any other
implantable system that utilizes battery power to provide drugs or
electrical stimulation to a body part.
Antimicrobial Efficacy
[0108] Antimicrobial efficacy of the pouches of the invention can
be demonstrated in laboratory (in vitro), for example, using the
modified Kirby-Bauer Antibiotic Susceptibility Test (Disk Diffusion
Test) (in vitro) to assess bacterial zones of inhibitions or by the
Boburden Test Method (in vitro). In such experiments, a small disk
of the pouch is cut and used, Antimicrobial efficacy can also be
demonstrated in vivo using animal models of infection. For example,
a pouch and device combination are implanted in an animal, the
surgical site is deliberately infected with a pathogenic
microorganism, such as Staphylococcus aureus or Staphylococcus
epidermis, and the animal is monitored for signs of infection and
inflammation. At sacrifice, the animal is assessed for
inflammation, fibrosis and bacterial colonization of the pouch,
device and the surrounding tissues.
[0109] It will be appreciated by those skilled in the art that
various omissions, additions and modifications may be made to the
invention described above without departing from the scope of the
invention, and all such modifications and changes are intended to
fall within the scope of the invention, as defined by the appended
claims. All references, patents, patent applications or other
documents cited are herein incorporated by reference in their
entirety.
Example 1
Antibiotic Release from DTE-DT Succinate Coated Mesh
A. Preparation of Mesh by Spray-Coating
[0110] A 1% solution containing a ratio of 1:1:8
rifampin:minocycline:polymer in 9:1 tetrahydrofuran/methanol was
spray-coated onto a surgical mesh by repeatedly passing the spray
nozzle over each side of the mesh until each side was coated with
at least 10 mg of antimicrobial-embedded polymer. Samples were
dried for at least 72 hours in a vacuum oven before use.
[0111] The polymers are the polyarylates P22-xx having xx being the
% DT indicated in Table 3. In Table 3, Rxx or Mxx indicates the
percentage by weight of rifampin (R) or minocycline (M) in the
coating, i.e., R10M10 means 10% rifampin and 10% minocycline
hydrochloride with 80% of the indicated polymer. Table 3 provides a
list of these polyarylates with their % DT content, exact sample
sizes, final coating weights and drug coating weights.
TABLE-US-00003 TABLE 3 Polyarylate Coated Meshes with Rifampin and
Minocycline HCl Avg. Coating Coating Sample Coating Parameters Wt.
per 116 cm.sup.2 Wt. per cm.sup.2 Rifampin Minocycline HCl No. (No.
Spray Passes) (mg) (mg) (.mu.g) (.mu.g) 1 P22-25 R10M10 (20) 100
0.86 86 86 2 P22-25 R10M10 (40) 150 1.29 129 129 3 P22-25 R10M10
(80) 200 1.72 172 172 4 P22-27.5 R10M10 (1) 20 0.17 17 17 5
P22-27.5 R10M10 (2) 40 0.34 34 34 6 P22-27.5 R10M10 (3) 60 0.52 52
52
B. Zone of Inhibition (ZOI) Studies
[0112] The ZOI for antibiotic coated meshes was determined
according to the Kirby-Bauer method. Staphylococcus epidermidis or
Staphylococcus aureus were inoculated into Triplicate Soy Broth
(TSB) from a stock culture and incubated at 37.degree. C. until the
turbidity reached McFarland #0.5 standard (1-2 hours). Plates were
prepared by streaking the bacteria onto on Mueller-Hinton II agar
(MHA) three times, each time swabbing the plate from left to right
to cover the entire plate and rotating the plate between swabbing
to change direction of the streaks.
[0113] A pre-cut piece (1-2 cm.sup.2) of spray-coated mesh was
firmly pressed into the center of pre-warmed Mueller Hinton II agar
plates and incubated at 37.degree. C. Pieces were transferred every
24 h to fresh, pre-warmed Mueller Hinton II agar plates using
sterile forceps. The distance from the sample to the outer edge of
the inhibition zone was measured every 24 h and is reported on the
bottom row in Table 4 and 5 for each sample. The top row for each
sample represents difference between the diameter of the ZOI and
the diagonal of the mesh. Table 4 shows the ZOI results for meshes
placed on S. epidermidis lawns and Table 5 show s the ZOI results
for meshes placed on S. aureus lawns. Additionally, three pieces
were removed every 24 h for analysis of residual minocycline and
rifampin.
[0114] FIG. 1 shows the total ZOI on S. aureus for meshes with 10%
each of minocycline hydrochloride and rifampin in a DTE-DT
succinate polyarylate coating having 25% or 27.5% DT. The catheter
is a COOK SPECTRUM venous catheter impregnated with rifampin and
minocycline hydrochloride.
TABLE-US-00004 TABLE 4 S. epidermidis ZOI Sam- Day Day Day Day Day
Day ple Coating 1 2 3 4 6 7 No. Parameters (mm) (mm) (mm) (mm) (mm)
(mm) 1 P22-25 R10M10 18.65 31.70 33.04 29.63 25.43 15.66 31.30
44.36 45.70 42.29 38.08 28.31 2 P22-25 R10M10 19.28 30.59 33.67
31.74 0.60 8.56 32.10 43.45 46.53 44.60 13.45 21.42 3 P22-25 R10M10
26.59 34.70 30.31 31.75 23.65 17.29 39.48 47.59 43.20 46.16 36.54
30.18 4 P22-27.5 R10M10 18.33 31.58 35.25 30.45 2.08 6.72 31.06
44.31 47.98 43.18 14.81 19.45 5 P22-27.5 R10M10 17.48 32.81 33.68
28.06 7.89 12.86 30.17 45.51 46.38 40.76 20.59 25.56 6 P22-27.5
R10M10 31.73 29.81 35.03 24.99 12.55 16.22 44.42 42.50 47.72 37.68
25.24 28.91
TABLE-US-00005 TABLE 5 S. aureus ZOI Sam- Day Day Day Day Day Day
ple Coating 1 2 3 4 5 7 No. Parameters (mm) (mm) (mm) (mm) (mm)
(mm) 1 P22-25 R10M10 12.75 17.90 18.22 22.44 12.35 11.94 25.84
30.66 30.97 35.20 25.11 24.69 2 P22-25 R10M10 14.23 11.28 20.04
28.24 16.31 10.35 26.90 23.94 32.71 40.91 28.98 23.02 3 P22-25
R10M10 17.87 21.52 23.45 25.36 17.42 14.72 30.57 34.22 36.15 36.02
30.12 27.42 4 P22-27.5 R10M10 9.77 19.02 19.06 23.01 13.81 5.61
22.76 32.01 32.05 36.00 26.80 18.6 5 P22-27.5 R10M10 9.70 21.77
19.55 24.00 11.84 3.89 22.30 34.36 35.48 36.60 24.44 16.49 6
P22-27.5 R10M10 20.92 21.29 22.40 24.27 11.06 4.99 33.68 34.05
35.15 37.02 23.82 17.75
[0115] Table 6 shows that the duration of in vitro drug release
increases with the hydrophilicity of the resorbable polymer.
Solvent cast films were soaked in PBS and antibiotic release was
monitored by HPLC.
TABLE-US-00006 TABLE 6 Antibiotic Release as a Function of Polymer
Hydrophilicity Days releasing Days releasing Films Rifampin
MinocyclineHCl P22-15 R10M10 32 32 P22-20 R10M10 25 25 P22-25
R10M10 7 7 P22-27.5 R10M10 10 10 P22-30 R10M10 4 4
Example 2
Bupivacaine Release from DTE-DT Succinate Coated Mesh
A. Preparation of Mesh
[0116] For the experiment shown in FIG. 2, a first depot coating
containing 540 mg of bupivacaine HCl as a 4% solution with 1%
P22-27.5 polyarylate in a mixture of THF Methanol was spray coated
onto a mesh. A second layer consisting of 425 mg of the same
polyarylate alone was deposited on top of the first layer.
[0117] For the experiment shown in FIG. 3, a solution of
approximately 4% bupivacaine in DTE-DT succinate polymer having
27.5% DT was sprayed onto a mesh using the indicted number of
passes followed by the indicated number of dips into a solution of
the same polyarylate in THF:Methanol (9:1)
B. Anesthetic Release
[0118] Pre-weighed pieces of mesh were placed in PBS at 37.degree.
C. and a sample withdrawn periodically for determination of
bupivacaine by HPLC. FIG. 2 shows the cumulative release of
bupivacaine into PBS from the multilayer polyarylate coating as a
function of time. Nearly 80% of the bupivacaine had been released
after 25 hours of incubation.
[0119] FIG. 3 is an example of the changes in release
characteristics that can be achieved by altering both the amount of
drug in the depot layer and the thickness of the outer layer. These
coated surgical meshes are much stiffer than their uncoated
counterparts.
Example 3
In Vivo Bupivacaine Release from DTE-DT Succinate Coated Meshes
A. Overview
[0120] Rats with jugular cannulas for pharmacokinetic studies were
surgically implanted with a 1.times.2 cm P22-27.5
polyarylate-coated mesh containing 7.5 mg of bupivacaine/cm.sup.2.
Before surgery, baseline pin-prick responses to nociception were
measured at the planned surgical incision site, and baseline blood
samples were obtained. A hernia was created by incision into the
peritoneal cavity during via subcostal laparotomy, and a
Lichtenstein non-tension repair was performed using the
bupivacaine-impregnated polyarylate-coated mesh. Blood samples were
drawn at 3, 6, 24, 48, 72, 96, and 120 hours after implantation.
Prior to drawing blood, the rats were subjected to a pin prick test
to assess dermal anesthesia from bupivacaine release. The
behavioral results indicate that moderate levels of dermal
anesthesia appeared from 3 to 120 hours, with the amount at 6 and
48 hours significantly above baseline (p<0.05). Pharmacokinetic
analysis indicates that the plasma bupivacaine levels fit a
one-compartment model with first-order absorption from 0 to 24
hours.
B. Preparation of Surgical Mesh
[0121] A polypropylene mesh was spray coated as described in the
first paragraph of Example 2. Individual meshes were cut to
1.times.2 cm, individually packaged, and sterilized by gamma
irradiation. The mesh was loaded with 7.5 mg/cm.sup.2 of
bupivacaine HCl for a total of 15 mg of bupivacaine loaded per
1.times.2 cm mesh.
C. Surgical Implantation of Mesh
[0122] Eight male rats, 59-63 days old and weighing from 250-275 g,
were obtained from Taconic Laboratory (Germantown, N.Y.) with an
external jugular cannula (SU007). Each rat was anesthetized with
isoflurane to a plane of surgical anesthesia, as determined by the
absence of a response to toe pinch and corneal reflex and
maintained at 2% isoflurane during surgery. The subcostal site was
shaved, washed with 10% providone iodine and rinsed with 70%
ethanol. Sterile drapes were used to maintain an aseptic surgical
field, and sterilized instruments were re-sterilized between rats
using a hot-bead sterilizer. A 2.5 cm skin incision was made 0.5 cm
caudal to and parallel to the last rib. The underlying subcutaneous
space (1 cm on both sides of the incision) was loosened to
accommodate the mesh. A 2 cm incision was made through the muscle
layers along the same plane as the skin incision, penetrating the
peritoneal cavity and the peritoneum was closed with 6-0 Prolene
sutures in a continuous suture pattern. Rather than suturing the
inner and outer oblique muscles using the classic "tension
closure," a Lichtenstein "non-tension" repair was undertaken using
the mesh as the repair material. The mesh prepared in Section A was
positioned over the incisional hernia, and sutured into the
internal and external oblique muscles using 6-0 Prolene sutures.
The subcutaneous tissue was then sutured in a continuous pattern
with 6 to 8 6-0 Prolene sutures to prevent the rats from accessing
the mesh, followed by 6 to 8 skin sutures. Total surgical time was
10 min for anesthetic induction and preparation and 20 min for the
surgery.
[0123] The rats were allowed to recover in their home cages, and
monitored post-surgically until they awoke. Blood samples were
drawn for determination of plasma bupivacaine levels at 3, 6, 24,
48, 72, 96, and 120 hours after surgery. The rats were assessed for
guarding the incision, and the incision was assessed for signs of
inflammation, swelling or other signs of infection. No rats
exhibited toxicity or seizures, or were in a moribund state from
infection or the release of bupivacaine.
D. Dermal Anesthetic Tests
[0124] The nociceptive pin prick test was used to assess dermal
anesthesia (Morrow and Casey, 1983; Kramer et al., 1996; Haynes et
al., 2000; Khodorova and Strichartz, 2000). Holding the rat in one
hand, the other hand was used to apply the pin. Nociception was
indicated by a skin-flinch or by a nocifensive (i.e., startle or
attempt to escape) response from the rat. While the presence of the
mesh interfered with the skin flinch response, nocifensive response
remained completely intact.
[0125] Baseline nocifensive responses to 10 applications of the pin
from a Buck neurological hammer were obtained at the planned
incision site prior to mesh implantation. After surgery, the pin
prick test was applied rostral to the incision. The nerves caudal
to the incision were transected during the procedure, and therefore
did not respond to pin application and were not tested. The
post-implantation test was repeated using the same force as before
surgery and with 10 pin applications, and the percent inhibition of
nocifensive responding was calculated by: [1-(test responses/10
base responses)].times.100. The data was analyzed using repeated
measures ANOVA followed by post hoc analysis using the Tukey's
test. The results are shown in FIG. 4.
Example 4
Mesh Stiffness
[0126] A. Meshes prepared as described in Example 1 were subject to
stiffness testing according to the method of TyRx Pharma Inc. Mesh
Stiffness Test Protocol, ATM 0410, based on ASTM 4032-94. Meshes
were sealed in foil bags before sterilization using gamma
irradiation. Where indicated by "Gamma N.sub.2", the bags were
flushed with nitrogen before sealing and irradiation. Meshes were
tested in triplicate. The results are shown in Table 7 and indicate
that aging does not affect the flexibility of the coated
meshes.
TABLE-US-00007 TABLE 7 Stiffness Testing Sample 1 Sample 2 Sample 3
Average t- Mesh (Newtons) (Newtons) (Newtons) (Newtons) test PPM3,
Gamma, 1.84 2.36 1.62 1.94 0.016 12 month aged coating PPM3, Gamma
2.2 2.24 2.56 2.3 0.014 N.sub.2 flush, 12 month aged coat- ing
Prolene, Ethylene 2.78 2.16 1.94 2.29 0.019 oxide sterilization
PPM3, No Sterili- 1.2 1.3 1 1.17 zation, No Coat- ing
[0127] B. Meshes were prepared by spray coating a solution of
P22-27.5 onto a PPM3 mesh as generally described in Example 1. the
coated meshes were cut into 3'' by 3'' squares to provide 80 mg
polymer coating per square. The squares were incubated in 1 L of
0.01 M PBS for the indicated times then removed for stiffness
testing as described in part A of this Example. All experiments
were done in triplicate. As a control, non-coated PPM3 meshes were
incubated under the same conditions. The stiffness of the control
when dry was 1.42.+-.0.23 N when dry and 1.12 N after both 1 hour
and 24 hour in 0.01 M PBS. The results are shown in FIG. 6.
Example 5
Micrographs of Coated Meshes
[0128] A tyrosine polyarylate-coated mesh without antibiotics,
i.e., only a polymer coating, was prepared as described in Example
1 and omitting the antibiotics in the spray coating solution. An
optical image of the coated mesh is shown in the top left panel of
FIG. 7 at a magnification that readily shows the woven nature of
the mesh and the contact points of the filaments. A close up of a
contact point is shown in the bottom left panel of FIG. 7 and
demonstrates that the coating immobilizes the contact points of the
mesh filaments. The right panel of FIG. 7 is a scanning electron
micrograph of a coated filament.
[0129] FIG. 8 shows an optical image of a mesh from Example 1,
i.e., coated with polymer, rifampin and minocycline. In color, this
photograph shows the mesh on a blue background with the filaments
appearing greenish with some orange and the knots (or filament
contact points) appearing mostly solid orange. The orange color is
due to the antibiotics and is more visible on the knots due to the
greater surface area of the mesh in that region. The color
differentiation is difficult to visualize in the black and white
version of this photograph so on the right panel the areas of
orange are indicated by circled areas filled with diagonal
lines.
Example 6
Antimicrobial, Coated Mesh, Pacemaker Pouch
[0130] The antimicrobial pacemaker pouch is a dual component
(resorbable and non-resorbable), sterile prosthesis designed to
hold a pacemaker pulse generator or defibrillator to create a
stable environment when implanted in the body. The pouch is
constructed of a non-resorbable mesh comprised of knitted filaments
of polypropylene and a bioresorbable polyarylate coating on the
mesh containing the antimicrobial agents rifampin and minocycline.
The antimicrobial agents are released for a minimum of 7 days
followed by full resorption of the polymer, leaving a light-weight
permanent mesh incorporated into the tissue and providing a stable
environment for the pacemaker or defibrillator (see FIGS. 9 and
10).
[0131] The mesh for the pouch can be prepared in the same manner as
antimicrobial polymer-coated surgical meshes described in U.S.
provisional application 60/771,827, filed Feb. 8, 2006. The pouch
is constructed of two pieces of flat, coated mesh placed one on top
of the other and sealed and cut into the shape using an ultrasonic
weld. This results in the formation of a pouch 2.5''.times.2.75''
in size, sealed on approximately 3 and one-half sides, and coated
with approximately 50 to 75 mg of polymer and 6.1 mg of rifampin
and 6.1 mg of minocycline (of 86.11 .mu.g/cm.sup.2 for each drug).
Such pouches can be designed to fit a wide range of pacemakers,
implantable defibrillators, neurostimulators and other IMDs (see
Table 1 and 2).
Antimicrobial Efficacy
[0132] Antimicrobial efficacy was demonstrated in laboratory (in
vitro) and in animal (in vivo) testing. Results indicate that
coated mesh pouch is effective in preventing microbial colonization
of the mesh and generator (see Table 8).
[0133] Histological results from a dog study show that the pouch is
rapidly incorporated into the tissue surrounding the pacemaker,
facilitating the formation of a stable environment for holding the
pacemaker (FIG. 3).
TABLE-US-00008 TABLE 8 Antimicrobial Efficacy Antimicrobial Test
Test Results Dog Implantation No positive cultures (0/4) detected
in the Study (in vivo) coated mesh pouch + generator implant sites
compared with 100% positive culture (4/4) for generator alone in
response to a 5 .times. 10.sup.4 CFU inoculum of S. aureus Rabbit
Implantation Significantly (p < 0.05) fewer colonized Study (in
vivo)* mesh implants (16.6%) compared to Prolene mesh comparator
(43.3%) in response to a 10.sup.5 CFU inoculum of S. aureus*
Modified Kirby--Bauer ZOI > 10 mm for >7 days against to
Antibiotic Susceptibility S. aureus and S. epidermidis and Test
(Disk Diffusion MRSA Test) (in vitro)* Boburden Test Method No
growth to 10.sup.6 CFU/mL (in vitro)* inoculum of S. aureus and, S.
epidermidis after 7 days incubation, and no growth to a 10.sup.8
CFU/mL inoculum of MRSA after 7 days incubation* *Testing on
antimicrobial mesh alone of the same composition
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