U.S. patent application number 09/357584 was filed with the patent office on 2001-12-06 for antimicrobial annuloplasty ring having a biodegradable insert.
This patent application is currently assigned to Blossom E. Loo. Invention is credited to CASANOVA, R. MICHAEL, CHINN, JOSEPH A..
Application Number | 20010049557 09/357584 |
Document ID | / |
Family ID | 23406218 |
Filed Date | 2001-12-06 |
United States Patent
Application |
20010049557 |
Kind Code |
A1 |
CHINN, JOSEPH A. ; et
al. |
December 6, 2001 |
ANTIMICROBIAL ANNULOPLASTY RING HAVING A BIODEGRADABLE INSERT
Abstract
This invention provides an antimicrobial annuloplasty rings, and
methods for making the same, wherein the annuloplasty rings have a
desired degree of initial rigidity to facilitate ease of handling
during implantation but which becomes flexible some time after
implantation. The annuloplasty ring contains a relatively rigid
insert enclosed by a fabric sheath, the insert being at least
partly comprised of a biodegradable material. Following surgical
implantation of the annuloplasty ring, the rigid insert component
of the ring, upon exposure to blood and/or other physiological
fluids, undergoes a controlled biodegradation which decreases its
rigidity, thereby increasing the flexibility of the implanted
annuloplasty ring. Furthermore, at least some portion of the
annuloplasty ring of the invention has incorporated therein one or
more antimicrobial agents in a manner which reduces the likelihood
of device infection following implantation.
Inventors: |
CHINN, JOSEPH A.; (AUSTIN,
TX) ; CASANOVA, R. MICHAEL; (AUSTIN, TX) |
Correspondence
Address: |
Blossom E. Loo
SULZER MEDICA USA INC
3 EAST GREENWAY PLAZA SUITE 1600
HOUSTON
TX
77046
US
|
Assignee: |
Blossom E. Loo
|
Family ID: |
23406218 |
Appl. No.: |
09/357584 |
Filed: |
July 20, 1999 |
Current U.S.
Class: |
623/2.36 |
Current CPC
Class: |
A61F 2/2445 20130101;
A61F 2250/0067 20130101; Y10S 623/901 20130101 |
Class at
Publication: |
623/2.36 |
International
Class: |
A61F 002/24 |
Claims
What is claimed:
1. An annuloplasty ring comprising: a ring insert at least partly
comprised of a biodegradable material selected from the group
consisting of polyanhydrides, polylactides, polyglycolides,
dextran, hydroxyethyl starch, gelatin, polyvinylpyrolidone,
polyvinyl alcohol, poly-N-(2-hydroxypropyl) methacrylamide,
polyglycols, polyesters, polyorthoesters, and polyester-amides; and
a fabric sheath enclosing said ring insert; wherein one or more
antimicrobial agents are incorporated into at least some portion of
the annuloplasty ring.
2. The annuloplasty ring of claim 1, wherein the antimicrobial
agents are incorporated into the annuloplasty ring by dissolving
the antimicrobial agents in a solvent to form an antimicrobial
solution and contacting the antimicrobial solution with at least
some portion of the annuloplasty ring.
3. The annuloplasty ring of claim 2, wherein said solvent is
selected from the group consisting of alcohols, ethers, aldehydes,
acetonitrile, acetic acid, and aprotic heterocyclics.
4. The method of claim 2, wherein said solvent is selected from the
group consisting of methanol, ethanol, or n-methyl
pyrrolidinone.
5. The annuloplasty ring of claim 1, wherein the biodegradable
material comprises a polyanhydride or polyorthoester.
6. The annuloplasty ring of claim 1, wherein the biodegradable
material comprises a photopolymerizable polyanhydride.
7. The annuloplasty ring of claim 1, wherein the biodegradable
material comprises a polyanhydride polymerized from methacrylate
anhydride monomers.
8. The annuloplasty ring of claim 7, wherein the methacrylate
anhydride monomers are synthesized from diacid molecules of sebacic
acid or 1,6-bis(p-carboxyphenoxy)-hexane.
9. The annuloplasty ring of claim 7, wherein the biodegradable
material comprises a a copolymer of methacrylate anhydride monomers
synthesized from diacid molecules of sebacic acid and
1,6-bis(p-carboxyphenoxy)-hexan- e.
10. The annuloplasty ring of claim 1, wherein the fabric sheath is
comprised of a polymeric material.
11. The annuloplasty ring of claim 1, wherein the fabric sheath is
comprised of a polymeric material selected from the group
consisting of polyethyleneterephthalate, polytetrafluoroethylene
and polyester (polyacetate).
12. The annuloplasty ring of claim 1, further comprising a covering
material enclosing the biodegradable insert, said covering
positioned between the biodegradable insert and the fabric
sheath.
13. The annuloplasty ring of claim 12, wherein the covering
material is comprised of a silicone rubber, a poly(ether urethane)
or a polytetrafluoroethylene.
14. The annuloplasty ring of claim 1, wherein the biodegradable
insert further comprises one or more plasticizers, stabilizers,
pigments, dyes, radio-opaque materials, lubricants, antioxidants,
bioactive agents or antithrombogenic agents.
15. A method for making an annuloplasty ring comprising: forming a
ring insert at least partly comprised of a biodegradable material
selected from the group consisting of polyanhydrides, polylactides,
polyglycolides, dextran, hydroxyethyl starch, gelatin,
polyvinylpyrolidone, polyvinyl alcohol, poly-N-(2-hydroxypropyl)
methacrylamide, polyglycols, polyesters, polyorthoesters, and
polyester-amides; and enclosing said ring insert within a fabric
sheath; incorporating one or more antimicrobial agents into at
least some portion of the annuloplasty ring.
16. The method of claim 15, wherein incorporating one or more
antimicrobial agents comprises dissolving at least one
antimicrobial agents in a solvent to form and antimicrobial
solution and contacting the antimicrobial solution with at least
some portion of the annuloplasty ring.
17. The method of claim 16, wherein the solvent is selected from
the group consisting of alcohols, ethers, aldehydes, acetonitrile,
acetic acid, and aprotic heterocyclics.
18. The method of claim 16, wherein the solvent is selected from
the group consisting of methanol, ethanol, or n-methyl
pyrrolidinone.
19. The method of claim 15, wherein the ring insert is formed by
molding, extrusion or machining the biodegradable material.
20. The method of claim 15, wherein the biodegradable material
comprises a polyanhydride or polyorthoester.
21. The method of claim 15, wherein the biodegradable material
comprises a photopolymerizable polyanhydride.
22. The method of claim 15, wherein the biodegradable material
comprises a polyanhydride polymerized from methacrylate anhydride
monomers.
23. The method of claim 22, wherein the methacrylate anhydride
monomers are synthesized from diacid molecules of sebacic acid or
1,6-bis(p-carboxyphenoxy)-hexane.
24. The method of claim 22, wherein the biodegradable material
comprises a copolymer of methacrylate anhydride monomers
synthesized from diacid molecules of sebacic acid and
1,6-bis(p-carboxyphenoxy)-hexane.
25. The method of claim 15, wherein said fabric sheath is comprised
of a polymeric material.
26. The method of claim 15, wherein said fabric sheath comprises a
polymeric material selected from the group consisting of
polyethyleneterephthalate, polytetrafluoroethylene and polyester
(polyacetate).
27. The method of claim 15, further comprising providing a covering
material enclosing the biodegradable insert, said covering
positioned between the biodegradable insert and the fabric
sheath.
28. The method of claim 27, wherein the covering material is
comprised of a silicone rubber, a poly(ether urethane) or a
polytetrafluoroethylene.
29. The method of claim 15, wherein the biodegradable insert
further comprises one or more plasticizers, stabilizers, pigments,
dyes, radio-opaque materials, lubricants, antioxidants, bioactive
agents or antithrombogenic agents.
30. An annuloplasty ring produced according to the method of claim
15.
Description
FIELD OF THE INVENTION
[0001] This invention relates generally to devices for use in the
surgical repair of heart pathologies, and, more particularly, to
antimicrobial annuloplasty rings which contain relatively rigid
biodegradable inserts.
DESCRIPTION OF THE RELATED ART
[0002] Human heart valves can become deformed or otherwise damaged
by any of a number of processes brought on by normal aging and/or
disease pathologies. For example, degenerative diseases can cause
the valve annulus to become enlarged to the point where the
leaflets attached to it cannot fully close. This situation, known
as valve incompetence, eventually requires surgical correction by
valve repair or replacement procedures. Of the surgical options
available for valve reconstruction, valvular annuloplasty
represents the procedure most frequently performed, particularly
for the tricuspid and mitral valves. Valvular annuloplasty is an
operation whereby ring-shaped devices or bands, known as
annuloplasty rings, are sewn to the distended valve annulus in
order to restore it to its normal, undilated circumference.
[0003] Annuloplasty rings are most typically either highly flexible
or are stiff and comparatively rigid. Rigid rings typically
consists of an open wire element completely covered with cloth. The
wire is somewhat stiff yet resiliently deformable and is not
intended to be removable from the cloth covering. These
annuloplasty rings, because of their rigidity, lie flat and
maintain their somewhat oval shape during implantation. Although a
rigid ring's oval shape has been claimed to enhance the competence
of the repaired valve, its rigidity can also impede the beneficial
flexing movements of the native annulus during the cardiac cycle.
Flexible annuloplasty rings generally consist of a soft core of
elastomeric material, e.g., silicone rubber, completely enclosed by
a sheath of biocompatible cloth. Because of their flexibility,
these rings can be difficult to handle during surgical
manipulations and generally must be supported during implantation
by a holder which is subsequently removed before tying off the
implanting sutures.
[0004] To overcome some of the deficiencies of flexible and rigid
ring structures, an annuloplasty ring would desirably be stiff
during handling and implantation, but then become flexible after
implantation. As disclosed in U.S. Pat. No. 5,716,397, an
annuloplasty ring may consist of a flexible ring into which a rigid
structure is inserted to provide temporary rigidity during
implantation. Once the ring is implanted and tested, the rigid
structure may be removed. However, this approach requires
undesirable additional handling after the ring is implanted.
Another annuloplasty ring, as disclosed in U.S. Pat. No. 5,104,407,
consists of a ring constructed partially of a flexible material and
partially of a rigid material. Unfortunately, this ring will be
difficult and costly to manufacture and will suffer from the
drawbacks afflicting both flexible and rigid rings. In an
alternative approach, Chachques et al. (Circulation 82(5),
Supplement IV, 82-88, 1990) describes absorbable prosthetic rings
for use in pediactric valvular annuloplasty. The rings are reported
to address concerns over secondary valvular stenosis in children
that can result from implantation of known annuloplasty rings. The
rings described by Chachques et al. are synthesized from
biodegradable polydioxanone and covered with a porous extensible
sewing sheath to allow contact between the polydioxanone, the blood
and the endocardium. As a result of this contact, the polydioxanone
ring is reported to undergo degradation following implantation.
[0005] Colonization of microorganisms on the surfaces of
annuloplasty rings and other implantable medical devices can
produce serious and costly complications, including the need to
remove and/or replace the implanted device and/or vigorous
treatment of secondary infections. Although infection of implanted
medical devices is a relatively infrequent complication associated
with their clinical use, the threat to infected patients, and the
cost to the medical care system, are significant.
[0006] Numerous approaches for providing antimicrobial surfaces
and/or devices have been described in the art. Unfortunately, such
approaches have had only limited success. For example, although
coating a material with immobilized antimicrobial compounds has
been reported to effectively reduce bacterial colonization of
devices in a laboratory setting, similar results have been
difficult to replicate in the clinical setting. To be effective in
vivo, antimicrobial agents immobilized on the surface of a medical
device preferably should intimately contact the colonizing bacteria
that has infected the device. Unfortunately, many clinically
relevant bacteria produce a slimy protective substance called
biofilm within which they grow. This biofilm, among other things,
prevents direct contact of the bacterial cells with a substrate
surface to which they adhere, making the bacteria resistant to
otherwise toxic materials that may be present on the substrate
surface.
[0007] In the laboratory, the antimicrobial efficacy of medical
devices that have been treated in one way or another in attempt to
confer some degree of antimicrobial activity to the device, has
often been evaluated by exposing the devices to bacterial cultures.
The selection and source of bacteria for such testing is critical
to obtaining meaningful results, since it is now known that
microorganisms floating free in a cell culture (called planktonic
bacteria) behave differently than those adherent to a substrate,
such as a bacterial culture vessel or an implanted medical device.
Planktonic bacteria are more susceptible to antimicrobial agents
immobilized on a surface than are biofilm-producing bacteria. Thus,
devices coated with immobilized antimicrobial agents may
effectively prevent colonization of planktonic bacteria in the
laboratory, but may be completely ineffective in preventing
infection of devices by clinically relevant biofilm-enclosed
bacteria. As a result, the experimental use of planktonic bacteria
cultured in the laboratory, rather than biofilm bacteria derived
from clinical infections, has led to the commercialization of
numerous antimicrobial medical devices lacking clinical
efficacy.
[0008] To effectively inhibit biofilm bacterial growth, an
antimicrobial agent should preferably penetrate the biofilm. To
achieve this, the antimicrobial agent should be able to diffuse
from the surface of the medical device following implantation.
Therefore, antimicrobial agents immobilized on the surface of a
medical device, and therefore not subject to diffusion, have less
than optimal activity against many clinically relevant
microorganisms. A more effective medical device will have the
ability to deliver diffusable antimicrobial agent to the local
environment following implantation.
[0009] Various methods have been described for coating or otherwise
incorporating antimicrobial agents into or onto medical devices in
a manner which allows for their release into the local environment
of an implanted medical device. For example, U.S. Pat. No.
5,624,704 reports a method for impregnating a non-metallic medical
implant with an antimicrobial agent by first dissolving the
antimicrobial agent in an organic solvent to form an antimicrobial
composition. Thereafter, a separate penetrating agent and
alkalinizing agent must be added to the antimicrobial composition.
The antimicrobial composition is then applied to a medical device
of interest in order to cause the incorporation of the composition
into the material of the medical device. Thus, the method of U.S.
Pat. No. 5,624,704 teaches the necessity of using additional
components, i.e., penetrating and alkalinizing agents, in a
dissolved antimicrobial composition, in order to achieve effective
incorporation into the medical device. Unfortunately, the use of
these additional components can substantially increase the
materials and processing costs associated with such a method, and
can also lead to degradation of the antimicrobial agents.
[0010] The present invention is directed to providing alternatives
to the currently available annuloplasty rings which overcome, or at
least reduce the effects of, one or more of the problems set forth
above.
SUMMARY OF THE INVENTION
[0011] This invention provides an antimicrobial annuloplasty ring
having sufficient initial rigidity, i.e., prior to implantation, to
facilitate ease of handling during surgical manipulations, but
which becomes flexible to a desired extent following implantation.
The foregoing is accomplished by use of a relatively rigid
biodegradable annuloplasty ring insert as a component of an
annuloplasty ring. Upon implantation of an annuloplasty ring
containing a biodegradable ring insert of this invention, the
insert undergoes degradation in the patient's body as a result of
its contact with blood and/or other physiological fluids. The
degradation of the biodegradable insert causes a decreasing degree
of rigidity of the annuloplasty ring as the insert material is
degraded and/or resorbed by the patient's body.
[0012] Therefore, in one aspect of the present invention, there is
provided an annuloplasty ring which comprises a biodegradable ring
insert and a fabric sheath enclosing the ring insert, wherein the
fabric sheath and/or the biodegradable insert have undergone one or
more antimicrobial treatment processes. The ring insert portion of
the annuloplasty ring is at least partly comprised of a
biodegradable material selected from any of a variety of
biodegradable polymers, including polyanhydrides, polyglycolides,
polylactides, polyorthoesters, and other like materials. In one
illustrative embodiment, the biodegradable insert is comprised of a
highly cross-linked polyanhydride material, particularly one that
is photopolymerizable, such as that produced by the
photopolymerization of methacrylate anhydride monomers. The fabric
sheath which encloses the biodegradable insert, or the
biodegradable insert itself, is preferably treated either before,
after, or simultaneous with the fabrication of the annuloplasty
ring in a manner which causes the incorporation of one or more
antimicrobial agents into or onto the fabric sheath.
[0013] In a further aspect of the invention, there is provided a
method for making an antimicrobial annuloplasty ring by forming a
biodegradable ring insert at least partly comprised of a material
selected, for example, from polyanhydrides, polyglycolides,
polylactides and polyorthoesters, and enclosing the ring insert
within a fabric sheath. The ring insert may be formed as a solid
part, may be comprised of fibrous materials, or some combination
thereof, and is fabricated by any of a variety conventional
techniques available for forming shaped articles from polymeric
materials, including, without limitation, extrusion, molding,
machining, casting, spinning, and other like processes. At some
point during fabrication and/or assembly of the annuloplasty ring,
or after assembly but prior to implantation, at least some portion
of the ring insert and/or the fabric sheath, or some other
component of the annuloplasty ring, is treated by an antimicrobial
treatment process in order to cause the incorporation of at least
some antimicrobial agent into or onto a desired portion or portions
of the annuloplasty ring.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The invention may be understood by reference to the
following description taken in conjunction with the accompanying
drawings, in which like reference numerals identify like elements,
and in which:
[0015] FIG. 1A illustrates one embodiment of the present invention
in which the annuloplasty ring is a complete ring;
[0016] FIG. 1B illustrates one embodiment of the present invention
in which the annuloplasty ring is an incomplete ring; and
[0017] FIG. 2 illustrates a partial section of an annuloplasty ring
according to one embodiment of the present invention, showing the
positional relationship between the biodegradable ring insert, the
covering material, and the outer fabric sheath.
[0018] While the invention is susceptible to various modifications
and alternative forms, specific embodiments thereof have been shown
by way of example in the drawings and are herein described in
detail. It should be understood, however, that the description
herein of specific embodiments is not intended to limit the
invention to the particular forms disclosed, but on the contrary,
the intention is to cover all modifications, equivalents, and
alternatives falling within the spirit and scope of the invention
as defined by the appended claim.
DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS
[0019] Illustrative embodiments of the invention are described
below. In the interest of clarity, not all features of an actual
implementation are described in this specification. It will of
course be appreciated that in the development of any such actual
embodiment, numerous implementation-specific decisions must be made
to achieve the developers' specific goals, such as compliance with
system-related and business-related constraints, which will vary
from one implementation to another. Moreover, it will be
appreciated that such a development effort might be complex and
time-consuming, but would nevertheless be a routine undertaking for
those of ordinary skill in the art having the benefit of this
disclosure.
[0020] FIGS. 1A and 1B depict two illustrative annoloplasty rings,
10 and 10a, respectively, according to the present invention. The
annuloplasty rings each comprise a biodegradable ring insert (not
shown) and a sheath 12 enclosing the biodegradable insert, the
sheath 12 being constructed of a biocompatible material. The
annuloplasty ring 10 of FIG. 1A represents a complete, i.e.,
closed, annuloplasty ring, whereas the annuloplasty ring 10 of FIG.
1B represents an incompete ring. In FIG. 2, a partial section of an
annuloplasty ring is shown in order to illustrate the biodegradable
ring insert 14 enclosed within the fabric sheath 24. FIG. 2 further
depicts an elastomeric-like covering material 22 positioned between
the ring insert 14 and the fabric sheath 24, which may be desired
for certain embodiments. As described herein, the fabric sheath 24,
the elastometric-like covering material 22 and/or the ring insert
14 will have incorporated therein or thereon one or more
antimicrobial agents to provide protection from infection following
implantation of the device.
[0021] The biodegradable annuloplasty ring insert of the present
invention is generally comprised of one or more materials capable
of being formed into a desired ring shaped article which has a
sufficent degree of rigidity and which degrades with acceptable
kinetics upon exposure to the physiological environment into which
an annuloplasty ring is implanted. Examples of materials suitable
for use in forming a biodegradable insert according to this
invention may include, without limitation, polyanhydrides,
polylactides, polyglycolides, dextran, hydroxyethyl starch,
gelatin, derivatives of gelatin, polyvinylpyrolidone, polyvinyl
alcohol, poly-N-(2-hydroxypropyl) methacrylamide, polyglycols,
polyesters, poly(orthoesters), poly(ester-amides) and other like
materials.
[0022] In one preferred aspect of the present invention, the
material used to form the biodegradable insert is selected from
"surface eroding" polymers, e.g., those which undergo a controlled
degradation primarily along the surface of the insert, rather than
a material which undergoes bulk degradation and is more subject to
fragmentation. Such materials are generally characterized by a
substantially microscopic degradation, rather than one which
results in the generation of macroscopic particulate matter. By
employing surface eroding polymers in the fabrication of the ring
insert, there is a reduced possibility of embolic complications
associated with the release of fragments of the insert material
during degradation. Such fragments may become lodged in the fabric
sheath which surrounds the insert, possibly leading to an
undesirable inflammatory response, or may make their way into the
blood stream of the patient, possibly leading to a stroke. Surface
eroding polymers suitable for use in forming a biodegradable ring
insert according to this invention may include, for example,
polyanhydrides and polyorthoesters.
[0023] One particularly illustrative surface eroding polymer that
may be used for forming a biodegradable ring insert is a
polyanhydride. A cross-linked polyanhydride material may be
produced using essentially any synthetic approach available to the
skilled individual. In one example, a polyanhydride material may be
produced from photopolymerizable methacrylate anhydride monomers.
Dimethacrylated anhydride monomers may be synthesized, for example,
from precursor diacid molecules of sebacid acid or
1,6-bis(p-carboxyphenoxy)-hexane, as described in Anseth et al.
(Surfaces in Biomaterials, 1997 Symposium Notebook, pgs. 58-62).
The resulting monomers may be polymerized into homopolymers or
copolymers by dissolving a suitable photoinitiator, such as
2,2-dimethoxy-2-phenylaceto- phenone (DMPA, Ciba Geigy) or
camphorquinone (CQ, Aldrich) and ethyld-4-N,N-dimethylaminobenzoate
(4EDMAB, Aldrich), in the monomer at a concentration typically
ranging from about 0.01 wt. % to about 10 wt. %. Polymerization may
be initiated with ultraviolet light, visible light, or with another
suitable energy source, at an intensity and for a duration
effective to produce the desired polymeric material. Other
photopolymerizable anhydride monomers, and their methods of
synthesis and polymerization into cross-linked polyanhydride
networks are known and will also be apparent to the skilled
individual in view of this disclosure.
[0024] The biodegradable materials used for fabricating an
annuloplasty ring insert according to this invention will
advantageously exhibit controllable biodegradability,
bioresorbability, and/or overall biocompatibility within living
tissue. Of course, it is preferred that the biodegradable insert
material is substantially biocompatible, such that both the insert
material and the products resulting from its degradation are
physiologically benign, e.g., are not overly toxic to the point of
compromising the outcome of the annuloplasty procedure or the
health of the patient. The biodegradation of these materials will
preferably result in degradation products having a physiologically
neutral pH, or having a pH sufficiently near to physiological
neutrality that the products do not induce any pH-related
disturbances in or around the tissue into which the annuloplasty
ring is implanted. It should be recognized that variations in the
degradation rate of the ring insert may depend not only on the
characteristics of the insert composition, but also on the overall
health of the patient, variations in anticipated immune reactions
of the patient to the implant, the site of implantation, and other
clinical indicia.
[0025] The degradation kinetics and mechanical properties of the
biodegradable insert may be independently controlled. For example,
the skilled individual will recognize that the initial rigidity of
the biodegradable insert may vary somewhat depending on the
composition of the insert, but that this parameter is quite
controllable through the manipulation of synthesis, cross-linking,
and/or other processing conditions, to provide the insert with a
desired rigidity. By controlling the cross-linking density of a
polyanhydride material, e.g., by varying the molecular weight
between the double bonds, the mechanical properties of the
resulting cross-linked polyanhydride material can be altered from
being quite flexible to highly rigid. Moreover, by changing the
hydrophobicity of the monomer molecules or comonomer mixture that
is reacted, the degradation time scale of the final polymer network
may be controlled. For example, a significant increase in the
degradation rate occurs as the amount sebacic acid is increased in
copolymers produced from sebacid acid and
1,6-bis(p-carboxyphenoxy)-hexane. Polyanhydride homopolymers
comprised of cross-linked sebacid acid degrade within a matter of
days, while homopolymers of 1,6-bis(p-carboxyphenoxy)-hexane
degrade in approximately one year (Anseth, 1997). Thus, by
copolymerizing sebacic acid and 1,6-bis(p-carboxyphenoxy)-hexane at
various ratios, copolymers can be provided with desired degradation
kinetics.
[0026] The method of making the biodegradable insert is not
specifically restricted, and is limited only by the techniques
available in the art for forming shaped articles from polymeric
materials. The ring insert may be comprised of a solid article, may
be a fibrous article constructed, for example, of cabled fibers,
woven or non-woven fabric, or may be a combination of solid and
fibrous materials. Typically, the devices are composed of
substantially solid articles which are fabricated from the
biodegradable materials described herein using conventional polymer
processing techniques such as injection molding, gel or melt
extrusion, machining, and the like. A ring insert containing some
fibrous component may be fabricated using conventional
fiber-forming techniques such as melt spinning, gel spinning,
solution spinning, dry spinning, etc. Such processing techniques
and procedures are well known in the art and will not be described
herein in further detail.
[0027] Preferably, the biodegradable insert will be fabricated
using conventional molding techniques, wherein polymerization
and/or cross-linking occur either in the mold or just prior to
filling the mold, depending on the properties and characteristics
of the material being used. In one illustrative process, monomer
molecules are provided in an appropriate medium within a mold
having the desired ring or partial ring geometry and a suitable
stimulus is applied to effect polymerization and/or cross-linking
within the mold. For example, when using the methacrylated
anhydride monomers described above, polymerization may be effected
in the presence of a photoinitiator by exposure of the mold to an
appropriate light source, generally in the ultraviolet or visible
spectrum, at an intensity and for a duration effective to result in
the desired degree of polymerization and/or cross-linking of the
material within the mold. Of course, in this situation, the mold
will be one that is comprised of a material that is sufficiently
transparent to the light energy necessary to effect
polymerization.
[0028] As is known in the art, the shape of the biodegradable
insert will generally be that of an oval or annular shaped partial
or complete ring, although other shapes could be tailored, as
desired, for the unique requirements of a given implementation. A
partial, incomplete ring, i.e., one having a shape similar to the
letter "C", may be preferred over a completely closed ring in that
it allows for a somewhat improved degree of manipulation during
surgical implantation.
[0029] In addition to the biodegradable insert described above, the
annuloplasty ring of this invention will generally further comprise
an extensible fabric sheath surrounding the biodegradable insert.
The use of a cloth or fabric mesh to enclose various plastic and/or
metal members which are subsequently surgically implanted in the
human body is known. Such polymeric sheaths are typically comprised
of a fabric or fabric-like polymeric material having a relatively
high porosity, and are made by conventional techniques. For
example, the sheath may be a fabric material made from
polyethyleneterephthalate, polytetrafluoroethylene, polyester
(polyacetate), polyethylene, or other such materials known in the
art. During implantation, the sheath serves to facilitate surgical
fixation of the annuloplasty ring by the surgeon. In addition,
during biodegradation of the insert in the patient, the fabric
sheath may advantageously participate in the fibroblastic reaction
occurring at the site of implantation involving interstitial
fibroblast proliferation as well as production of elastin and
collagen fibers.
[0030] It is generally preferred that the porosity of the fabric
sheath is sufficiently high to allow an adequate flow of
physiological fluids and other materials necessary to stimulate
degradation of the biodegradable insert. However, the porosity of
the sheath should not be so high that unacceptably large fragments
of biological insert may reach the bloodstream if such fragments
are released during degradation of the insert. In this regard, one
important advantage of using a surface eroding biodegradable
polymer described herein for the production of a ring insert is
that these materials do not release undesirably large particulate
fragments during degradation. Consequently, there is a reduced risk
of embolic complications when surface eroding polymers are
employed, even when used in conjunction with fabric sheaths of very
high porosity.
[0031] In one preferred embodiment of the invention, as depicted in
FIG. 2, the annuloplasty ring may further comprise a flexible,
elastomeric-like covering material 22 surrounding the biodegradable
ring insert 14, positioned between the ring insert 14 and the
fabric sheath 24. For example, the ring insert may be inserted into
or otherwise enclosed within a material such as silicone rubber,
poly(ether urethane), polytetraflouorethylene, or other like
materials. This may be most readily achieved by inserting the
biodegradable insert into a length of elastomeric tubing having an
appropriate internal diameter similar to or slightly smaller than
the diameter of the biodegradable insert. The use of these
elastomeric tubing materials in modern annuloplasty rings is well
known and therefore not described in further detail herein. Once
the biodegradable ring insert is enclosed within this elastomeric
covering, the insert and covering are then inserted and sealed
within the described fabric sheath prior to use.
[0032] As would be apparent to the skilled individual in this art,
other materials and/or compounds may be combined before, during, or
subseqent to formation of one or more of the compenents of the
present annuloplasty ring, or added to, coated onto, etc, during or
after its fabrication. These compounds may include essentially
anything which will not unacceptably interfere with the desired
properties of the biodegradable insert, e.g., its desired initial
rigidity, its biodegradability, and/or its ability to degrade into
components that are substantially innocuous to living systems.
Examples of such substances may include, without limitation,
plasticizers, stabilizers, pigments, dyes, radio-opaque materials,
lubricants, antioxidants, bioactive agents, antithrombogenic
agents, and the like.
[0033] According to the present invention, at least some portion of
the annuloplasty ring described above has incorporated therein one
or more antimicrobial agents, preferably in a manner which allows
for some degree of diffusion of the antimicrobial agents following
implantation. For example, one or more antimicrobial agents may be
incorporated into or onto the biodegradeable ring insert 14, the
elastometric-like covering 22, or, more preferably, the fabric
sheath 24 (See FIG. 2). Numerous antimicrobial treatment processes
have been described for causing the incorporation of antimicrobial
and other bioactive agents into or onto a medical device, and the
skilled individual would recognize the applicability of such
approaches to the present invention.
[0034] "Antimicrobial agent", as used herein, refers to essentially
any antibiotic, antiseptic, disinfectant, etc., or combination
thereof, effective for inhibiting the viability and/or
proliferation of one or more microorganisms. Numerous classes of
antibiotics are known and may be suitable for use in accordance
with this invention. Such antibiotics may include, but are not
necessarily limited to, tetracyclines (e.g., minocycline),
rifamycins (e.g., rifampin), macrolides (e.g., erythromycin),
penicilins (e.g., nafcillin), cephalosporins (e.g., cefazolin),
other beta-lactam antibiotics (e.g., imipenem and aztreonam),
aminoglycosides (e.g., gentamicin), chloramphenicol, sufonamides
(e.g., sulfamethoxyazole), glycopeptides (e.g., vancomycin),
quinolones (e.g., ciprofloxacin), fusidic acid, trimethoprim,
metronidazole, clindamycin, mupirocin, polyenes (e.g., amphotericin
B), azotes (e.g., fluconazole), beta-lactam inhibitors, etc.
[0035] Examples of illustrative antibiotic agents that may be used
in accordance with the present invention include minocycline,
rifampin, erythromycin, nafcillin, cefazolin, imipenem, aztreonam,
gentamycin, sulfamethoxazole, vanomycin, ciprofloxacin,
trimethoprim, metronidazole, clindamycin, telcoplanin, mupirocin,
azithromycin, clarithromycin, ofloxacin, lomefloxacin, norfloxacin,
nalidixic acid, sparfloxacin, pefloxacin, amifloxacin, enoxacin,
fleroxacin, temafloxacin, tosufloxacin, clinafloxacin, sulbactam,
clavulanic acid, amphotericin B, fluconazole, itraconazole,
ketoconazole, nystatin, and other like compounds. The antibiotics
used in accordance with this invention will generally be selected
so as to have relatively low water solubility such that their
period of dissolution into the body is prolonged. Moreover, it may
be desired for many applications that one or more antimicrobial
agents having distinct modes of action are incorporated into the
annuloplasty ring in order to broaden its range of antimicrobial
activity.
[0036] Suitable antiseptics and disinfectants for use in this
invention may include, for example, hexachlorophene, cationic
bisiguanides (e.g., chlorohexidine, chclohexidiene, etc.), iodine
and iodophores (e.g., povidone-iodine), para-chloro-meta-xylenol,
furan medical preparations (e.g., nitrofurantoin, nitrofurazone),
methenamine, aldehydes (glutaraldehyde, formaldehyde, etc.),
alcohols, and the like.
[0037] In one illustrative embodiment of the present invention, the
antimicrobial agent used to treat an annuloplasty ring according to
this invention is comprised of minocycline, rifampin, or a mixture
thereof. Minocycline is a semisynthetic antibiotic derived from
tetracycline that functions by inhibiting protein synthesis.
Rifampin is a semisynthetic derivative of rifamycin B, a
macrocyclic antibiotic compound produced by the mold, Streptomyces
mediterranic. Rifampin inhibits bacterial DNA-dependent RNA
polymerase activity and is bactericical in nature. Both minocycline
and rifampin are commercially available, are soluble in numerous
organic solvents, and are active against a wide range of
gram-positive and gram-negative organisms.
[0038] Various methods can be employed to incorporate the desired
antimicrobial agents into or onto some portion of the annuloplasty
ring. One such method of coating the devices involves applying or
absorbing to the surface of the medical device a layer of
tridodecylmethyl ammonium chloride (TDMAC) surfactant followed by a
coating layer of antibiotic combination. For example, a medical
device having a polymeric surface, such as polyethylene, silastic
elastomers, polytetrafluoroethylene or Dacron, can be soaked in a
5% by weight solution of TDMAC for 30 minutes at room temperature,
air dried, and rinsed in water to remove excess TDMAC. The device
carrying the absorbed TDMAC surfactant coated can then incubated in
a solution of the desired antibiotic combination, washed in sterile
water to remove unbound antibiotic and stored in a sterile package
until ready for implantation. In general, the solution of
antibiotic combination in this method is composed of a
concentration of about 0.01 mg/ml to 50 mg/ml of each antibiotic in
an aqueous pH 7.4-7.6 buffered solution or sterile water.
Alternative processes and reagents for bonding antibiotics to
surfactant coated implantable medical devices are provided, for
example, in U.S. Pat. Nos. 4,442,133, 4,678,660 and 4,749,585, the
entire contents of which are incorporated herein by reference.
[0039] A further method useful to coat the surface of medical
devices with the desired antibiotics can involve first coating the
selected surfaces with benzalkonium chloride followed by ionic
bonding of the antibiotic composition. See, e.g., Solomon, D. D.
and Sherertz, R. J., J. Controlled Release 6:343-352 (1987) and
U.S. Pat. No. 4,442,133. In another method, antibiotics can be
dispersed within uncured silicone rubber prior to molding and
curing of the material in its device configuration (Olanoff, et
al., Trans. Am. Soc. Artif Intern. Organs, XXV, 334-338 (1979).
Additional illustrative methods of coating surfaces of medical
devices with antibiotics can be found in U.S. Pat. No. 4,895,566 (a
medical device substrate carrying a negatively charged group having
a pKa of less than 6 and a cationic antibiotic bound to the
negatively charged group); U.S. Pat. No. 4,917,686 (antibiotics are
dissolved in a swelling agent which is adsorbed into the matrix of
the surface material of the medical device); U.S. Pat. No.
4,107,121 (constructing the medical device with ionogenic
hydrogels, which thereafter absorb or ionically bind antibiotics);
U.S. Pat. No. 5,013,306 (laminating an antibiotic to a polymeric
surface layer of a medical device); U.S. Pat. No. 4,952,419
(applying a film of silicone oil to the surface of an implant and
then contacting the silicone film bearing surface with antibiotic
powders), and U.S. Pat. No. 5,624,704 (antibiotics are dissolved in
solvent with alkanizing agents and penetrating agents and applied
to a medical device surface), the disclosures of which are
incorporated herein by reference.
[0040] According to a preferred antimicrobial treatment process,
the desired antimicrobial agent or agents are first dissolved in an
appropriate solvent or combination of solvents to form an
antimicrobial solution. Suitable solvents in this regard include
essentially any solvent that will effectively dissolve the
antimicrobial agent or agents of interest, and that are conducive
with the incorporation of the at least some of the dissolved
antimicrobial agent into the medical device. The solvent is
generally selected from one that will readily spread onto and/or
along the particular annuloplasty ring surface to which it is
applied. The degree of this spreading may be influenced by the
surface tension of the solvent and by the surface characteristics
and configuration of the material used to produce the medical
device. Advantageously, the incorporation of the antimicrobial
agents into the annuloplasty ring occurs in the substantial absence
of additional constituents, e.g., penetrating agents, alkalinizing
agents, etc., that have been conventionally used, e.g., in U.S.
Pat. No. 5,624,704, for facilitating antimicrobial agent
penetration and/or adherence into or onto the medical device.
Illustrative examples of suitable solvents for use in this
invention include, but are not necessarily limited to, C.sub.1 to
C.sub.6 alcohols (e.g., methanol, ethanol, etc.), C.sub.1 to
C.sub.6 ethers (e.g., tetrahydrofuran), C.sub.1 to C.sub.6
aldehydes, aprotic heterocyclics (e.g., n-methyl pyrrolidinone,
dimethyl sulfoxide, dimethyl formamide), acetonitrile, acetic acid,
and other like solvents.
[0041] The concentration of the antibiotic agent in the antibiotic
solution is not specifically restricted. Optimal concentration
ranges will likely vary depending upon the particular antimicrobial
agent/solvent system used, on the conditions under which the
antimicrobial solution is contacted with the annuloplasty ring, and
on the particular component or components being treated, but can
nonetheless be readily determined by the skilled individual in the
art. In general, a higher concentration of an antimicrobial agent
in the antimicrobial solution will result in greater incorporation
into or onto the annuloplasty ring under an otherwise constant set
of application conditions. However, an upper concentration limit
will typically characterize a particular combination of
antimicrobial solution and medical device, above which further
antimicrobial incorporation will become limited. Generally, the
concentration of the antimicrobial agent in the antimicrobial
solution is essentially in the range of about 1 mg/ml to 60 mg/ml
for each antimicrobial agent present in the composition.
[0042] The antimicrobial solution of the present invention is
applied to, or otherwise contacted with, at least some portion of
the annuloplasty ring of interest in order to effect incorporation
of the antimicrobial agent into said portion. As will be apparent
to the skilled individual in this art, the means by which the
antimicrobial solution is contacted with the medical device is not
critical, and may vary depending on the type and portion of device
being treated, the area of the device being treated, etc.
Typically, the biodegradable insert, the fabric sheath and/or the
assembled annuloplasty ring will simply be dipped or otherwise
immersed in an antimicrobial solution. Alternatively, the
antimicrobial solution may be applied to the annuloplasty ring or
the area of the annuloplasty ring being treated, e.g., by
injection, flushing, spraying, etc. Other techniques for the
contacting the antimicrobial solution with the annuloplasty ring
will be readily apparent to the skilled individual in this art.
[0043] Subsequent to contacting the antimicrobial solution with the
annuloplasty ring, the antimicrobial solution is generally allowed
to remain in contact with the device for a duration and under
conditions effective to cause a desired degree of incorporation of
the antimicrobial agent into or onto the annuloplasty ring. The
temperature of the solution during this treatment step is not
critical, and can be essentially any temperature which does not
adversely effect the desired antimicrobial agent incorporation.
Excessively high temperatures should be avoided if they are in a
range which can cause degradation of the antimicrobial agent.
Furthermore, care should be taken when treating the device at
temperatures that are sufficiently low since they may adversely
impact the solubility of the antimicrobial agent(s) in the
antimicrobial solution. A desired treatment temperature will
typically be in the range of about 10 deg.C. to about 60 deg.C.,
more typically it will be in the range of about 20 deg.C. to about
50 deg.C. The duration of the treatment step is not specifically
restricted, and may be in the range of 0.1 minutes to several hours
or more. Typically, treatment duration in the range of about 0.1
hours to about 2 hours will result in a desirable degree of
antimicrobial agent incorporation into the portion of the
annuloplasty ring being treated. Of course, the optimal treatment
time for a given application may vary depending on a number of
parameters, e.g., the antimicrobial solution being used, reaction
temperature, etc., but this can be readily determined by one
skilled in the art.
[0044] The treated annuloplasty ring component or components are
typically dried to eliminate any remaining solvent, e.g., by
air-drying, heating, etc. After drying, the antimicrobial agent
incorporated into or onto the desired portion of the annuloplasty
ring is preferably not subject to substantial diffusion until
implanted in vivo, or otherwise exposed to comparable environment,
wherein the incorporated antimicrobial agent becomes redissolved,
and therefore more subject to diffusion from the device into the
surrounding environment.
[0045] The phrases "incorporation into" and "incorporating into,"
as used herein, means that the antimicrobial agent permeates,
adheres to, or otherwise becomes associated with one or more
polymeric structure of the annuloplasty ring. Thus, the
antimicrobial agent may be largely associated with the surface of
the ring insert and/or the fabric sheath, may penetrate within or
between the polymeric structures that make up these components,
etc. The nature of the association between the antimicrobial agent
and the annuloplasty ring may depend on the antimicrobial agent,
the solvent system, and/or the composition and structure of the
annuloplasty ring being treated. The extent of incorporation of the
antimicrobial agent into or onto the annuloplasty ring may be
evaluated, for example, by simple mass analysis of the device
before and after treatment. Alternatively, the incorporated
antimicrobial agent can be extracted from the device using an
appropriate solvent and analyzed by any one of a variety of
suitable quantitative technique, e.g., high-performance liquid
chromatography or ultraviolet/visible spectroscopy.
[0046] By practice of this preferred antimicrobial treatment
process of the present invention, an annuloplasty ring is provided
which exhibits the release of antimicrobial agent from at least
some portion of the annuloplasty ring for a period of time after
the annuloplasty ring has been implanted or otherwise exposed to an
in vivo environment. The release profile of the antimicrobial agent
from the annuloplasty ring may be evaluated using any one of a
variety of approaches. For example, this may involve sequentially
monitoring over time the diffusion of antimicrobial agent from the
annuloplasty ring into a solution in which the device is immersed.
The solution may be replaced at certain time points, and the
quantity of antimicrobial agent evaluated at the various time
points by a suitable analytic technique, such as high-performance
liquid chromatography.
[0047] The annuloplasty ring treated in accordance with this
invention preferably exhibits antimicrobial activity, i.e., the
antimicrobial agent is released from the annuloplasty ring at
sufficient levels to inhibit the growth of antimicrobial organisms
adherent to the device or in close proximity thereto. The
antimicrobial activity of the annuloplasty ring resulting from
release of the antimicrobial agent may be evaluated by a variety of
approaches. For example, zone of inhibition (ZOI) analyses, and
other similar variations thereof, may be used (see, for example,
Sherertz, et al. Antimicrobial Agents and Chemotherapy, August
1989, p.1174, 1989). Using this approach, a medical device is
placed directly on an agar plate covered with growing bacteria. The
plates are evaluated over time to determine the extent of bacterial
growth in the agar surrounding the device. A bacterial free zone
surrounding the device, called a zone of inhibition, is indicative
of inhibition of bacterial growth by agents that have diffused from
a treated medical device into the surrounding agar.
[0048] The antimicrobial release and/or activity from the
annuloplasty ring is generally sustained for an extended number of
days, or even weeks. In this way, the susceptibility to device
infection may be inhibited for a clinically relevant duration
following implantation in vivo. In an illustrative embodiment of
the invention, the medical device of this invention will exhibit
some degree of antimicrobial release and/or activity for at least a
day, more typically for several days, and in some instances for up
to a week or more, following exposure to an in vivo
environment.
[0049] The following examples are provided to demonstrate certain
illustrative embodiments of this invention. It should be
appreciated by those skilled in the art that the techniques
disclosed in the illustrative examples which follow represent those
found by the inventors to function in the practice of the
invention. However, those skilled in the art should, in light of
the present disclosure, appreciate that many changes can be made in
the specific embodiments which are disclosed and still obtain a
like or similar result without departing from the spirit and scope
of the invention.
EXAMPLE 1
Preparation of Antimicrobial Solutions
[0050] A process was performed essentially in accordance with U.S.
Pat. No. 5,624,704. Briefly, in a dark glass bottle, 40 ml of
methanol was heated to about 45 deg.C. on a magnetic stirrer-hot
plate and 0.2 g of sodium hydroxide was dissolved therein. Heating
was removed and 5 g minocycline, 8 g rifampin, and 80 ml butyl
acetate, were dispersed in the solvent. 20 ml aliquots of the
mixture were transferred to glass beakers containing either a
pre-weighed polyethylene terepthalate sewing cuff assembly
(Carbomedics Prosthetic Heart Valve, CPHV.TM., 27 Mitral) or a
polytetrafluoroethylene felt ring (27 Mitral), prepared at Sulzer
Carbomedics Inc. (Austin, Tex.). The samples were incubated in the
antimicrobial solutions for approximately 1.5 hours at about 45
deg.C. After incubation, the treated cuffs and felts were removed
from the antimicrobial solution and air-dried overnight. After
drying, each sample was weighed and transferred to a sterile bag.
Exposure to light was minimized during and after the drying process
until further studies were performed.
[0051] In an illustrative process according to the present
invention, 2000 ml of methanol was added to a dark glass bottle and
heated to about 45 deg.C. on a magnetic stirrer-hot plate. 5 g
minocycline and 8 g rifampin were dispersed in the methanol. 20 ml
aliquots of the mixture were transferred to glass beakers
containing either a pre-weighed polyethylene terepthalate sewing
cuffs (CPIIV.TM.27 Mitral) or a polytetrafluoroethylene felt ring
(27 Mitral), prepared at Sulzer Carbomedics Inc. The samples were
incubated in the antimicrobial solutions for approximately 1.5
hours at about 45 deg.C. After incubation, the treated cuffs and
felts were removed from their respective solutions and air-dried
overnight. After drying, each sample was weighed and transferred to
a sterile bag. Sample exposure to light was minimized during and
after the drying process.
[0052] Table 1 below compares the formulations of the antimicrobial
solutions used in producing minocycline/rifampin sewing cuffs and
felts in accordance with either U.S. Pat. No. 5,624,704, or
according to an illustrative example of the present invention. The
antimicrobial solutions prepared according to U.S. Pat. No.
5,624,704 contained antimicrobial agents, an alkalinizing agent
(e.g., sodium hydroxide), an organic solvent (e.g., methanol), and
a penetrating agent (e.g., butyl acetate). In contrast, the
illustrative antimicrobial solution of this invention contained
only the antimicrobial agents dissolved in solvent (e.g.,
methanol).
1TABLE 1 COMPARISON OF FORMULATIONS USED REAGENTS U.S. PAT.
5,624,704 PRESENT INVENTION Sodium Hydroxide 0.1% w/v 0% Methanol
20% v/v 100% v/v Butyl Acetate 80% v/v 0% Rifampin 4% w/v 4% w/v
Minocycline 2.5% w/v 2.5% w/v
EXAMPLE 2
Antimicrobial Agent Incorporation
[0053] Antibiotic incorporation into or onto the sewing cuff and
felt samples was monitored by determining the change in mass before
and after incorporation, and also by high-performance liquid
chromatography (HPLC) analysis. For HPLC analysis, the dried
samples were placed in glass beakers containing 30 ml of methanol,
and this extraction solution was sonicated for about 30 minutes.
The supernatant was poured into a dark glass jar. The extraction
process was repeated up to three times and the extracts were
combined and analyzed by HPLC using a Beckman Nouveau Gold HPLC
system (Beckman Instruments; Fullerton, Calif.). The samples were
diluted as necessary and injected in 0.1 M sodium phosphate, pH
3.2. 25 ul of each sample was injected by an auto sampler into the
HPLC system. Sample separation was achieved using
acetonitrile:water (4:6 v/v), with a flow rate of 1 ml/min, using a
Water's C18 Nova Pak 60A, 4 um, 3.9.times.150 mm column, maintained
at about 30 deg.C. Ultraviolet detection at 339 nm detected the
minocycline and rifampin peaks at about 1.4 and 4.0 minutes,
respectively, under these conditions. A calibration curve was
generated using 1:1 mixtures of minocycline and rifampin in the
mobile phase at a concentration range between 1 ug/ml and 100
ug/ml.
[0054] Table 2 below summarizes the results for total antibiotic
incorporation into the sewing cuffs and felts treated according to
U.S. Pat. No. 5,624,704, and according to the present invention.
From these results, it is apparent that the method of the present
invention achieves levels of antibiotic incorporation into the
sewing cuffs and felts comparable to those observed for the method
of U.S. Pat. No. 5,624,704. For the HPLC analysis, total
incorporation values were calculated by adding the weight values
obtained for minocycline and rifampin. The cuffs generally had
higher loading compared with the felts, possibly due to the greater
mass and surface area associated with the polyester material. The
values obtained by the HPLC method were slightly lower compared
with the values obtained by the total mass method. This may be
attributed to the extraction method employed for HPLC sample
preparation, which may not have been complete.
2TABLE 2 ANTIBIOTIC INCORPORATION IN SEWING CUFFS AND FELTS TOTAL
LOADING TOTAL LOADING SAMPLES BY WEIGHT (mg) BY HPLC (mg) Cuff 112
105 (U.S. Pat. No. 5,624,704 Cuff 115 91 (methanol only) Felt 51 81
(U.S. Pat. No. 5,624,704) Felt 48 43 (methanol only)
[0055] Ultraviolet spectra of minocycline and rifampin obtained
during HPLC analysis demonstrated that they have distinctive
lambda.sub.max values of 350 and 334, respectively. The spectral
properties observed did not change as a result of incorporation
method (not shown), indicating that the compounds maintained their
structure during the medical device treatment processes.
EXAMPLE 3
Release Profiles for Rifampin and Minocycline
[0056] The kinetics of antibiotic release from the treated samples
was evaluated by incubating the samples in 15 ml phosphate buffered
saline (PBS) at about 37 deg.C. for 30 days. For about the first
hour, the samples were gently agitated in PBS at room temperature
in 15 ml PBS. This PBS solution was removed and frozen until
further analysis. Fresh PBS was added and the samples were placed
in a 37 deg.C. incubator.
[0057] The PBS was thereafter replaced at 1, 2, 4, 5, 7, 11, 15,
21, 25, and 30 days, and each aliquot was frozen until subsequent
analysis by HPLC. The release profiles for rifampin and minocycline
are summarized below in Tables 3 and 4, respectively.
3TABLE 3 RELEASE OF RIFAMPIN (mg) OVER 30 DAYS Cuff Felt Day Cuff
(methanol Felt (methanol collected (U.S. 5,624,704) only) (U.S.
5,624,704) only) 0 14.0 14.6 10.6 5.85 1 22.1 19.9 12.7 13.5 2 13.4
13.1 2.16 5.63 4 5.37 10.1 0.66 1.31 5 0.72 2.45 0.25 0.12 7 0.29
0.59 0.16 0.02 11 0.25 0.20 0.08 0.01 15 0.20 0.06 0.04 -- 21 0.17
0.02 0.02 -- 25 0.13 0.02 0.01 -- 30 0.07 0.01 -- -- Avg. Total
56.51 60.49 53.25 26.44
[0058]
4TABLE 4 RELEASE OF MINOYCLINE (mg) OVER 30 DAYS Cuff Felt Day Cuff
(methanol Felt (methanol collected (U.S. 5,624,704) only) (U.S.
5,624,704) only) 0 11.6 15.8 8.25 4.8 1 7.43 8.70 3.53 0.75 2 2.18
1.13 0.33 0.1 4 0.92 1.01 0.11 0.02 5 0.15 0.09 0.05 -- 7 0.05 0.06
0.05 -- 11 0.05 0.03 0.02 -- 15 0.04 0.02 -- -- 21 0.08 -- -- -- 25
0.02 -- -- -- 30 0.01 -- -- -- Avg. Total 22.1 25.3 24.7 11.9
[0059] From the above examples, it is apparent that minocylcine and
rifampin can be incorporated into medical devices according to the
method of this invention without the need to include the
penetrating agents and/or alkalinizing agents taught by U.S. Pat.
No. 5,624,704 as necessary for effective antimicrobial agent
incorporation. Moreover, the devices exhibited clinically desirable
antimicrobial agent release characteristics.
EXAMPLE 4
Inhibition of Device Colonization and Infection in Vivo
[0060] Samples of polyethylene terepthalate fabric (DTH-2, Vascutek
Inc., Renfrewshire, Scottland) were sewn around
polytetrafluoroethylene felt (CR Bard Inc., Haverhill, Mass.) using
silicone-treated, non-absorbable, braided polyester 4.0 sutures
(Davis and Geck Inc., St.Louis, Mo.). Some of these sample
assemblies were treated according to U.S. Pat. No. 5,624,704 by
contacting them with a solution comprised of 40 mg/ml rifampicin,
25 mg/ml minocycline, and 1 mg/ml sodium hydroxide in 20% (v/v)
methanol in butyl acetate. Other sample assemblies were treated
with 40 mg/ml rifampicin and 25 mg/ml minocycline dissolved in
methanol only. The samples were incubated in these solutions for
approximately 1.5 hours at about 45 deg.C. After incubation, the
samples were removed from their respective solutions and air-dried
overnight.
[0061] The treated samples were inoculated with approximately
10.sup.5 CFU Staphylococcus aureus (P1 strain, a mutant of ATCC
25923), and implanted subcutaneously into rabbits. The samples were
retrieved from the animals after one week after implantation.
Device colonization was evaluated by culturing the retrieved device
by rolling and/or dragging each side of the device on chocolate
agar plates (BBL Media, Becton Dickinson Microbiology Systems,
Cockeysvile, Md.). Device-related infection was evaluated by
inoculating blood samples taken at the time of device retrieval on
chocolate agar plates. Bacterial growth was assessed after
incubating the plates for 48 hours at 37 deg.C. The results of
these experiments are summarized in Table 5 below.
5 TABLE 5 U.S. Pat. Untreated No. 5,624,704 Methanol only Device
Colonization 25/31 2/30 1/34 Device-related 25/31 0/30 0/34
Infection
[0062] These results demonstrate the in vivo efficacy of medical
devices treated in accordance with this invention. In particular,
protection from device colonization and device-related infection
was comparable, if not improved, relative to a group of samples
treated according to U.S. Pat. No. 5,624,704.The particular
embodiments disclosed above are illustrative only, as the invention
may be modified and practiced in different but equivalent manners
apparent to those skilled in the art having the benefit of the
teachings herein. Furthermore, no limitations are intended to the
details of construction or design herein shown, other than as
described in the claims below. It is therefore evident that the
particular embodiments disclosed above may be altered or modified
and all such variations are considered within the scope and spirit
of the invention. Accordingly, the protection sought herein is as
set forth in the claims below.
* * * * *