U.S. patent application number 14/528071 was filed with the patent office on 2015-02-19 for medical device with inflammatory response-reducing coating.
The applicant listed for this patent is Sofradim Production. Invention is credited to Philippe Gravagna, Sebastien Ladet.
Application Number | 20150050417 14/528071 |
Document ID | / |
Family ID | 42246167 |
Filed Date | 2015-02-19 |
United States Patent
Application |
20150050417 |
Kind Code |
A1 |
Ladet; Sebastien ; et
al. |
February 19, 2015 |
MEDICAL DEVICE WITH INFLAMMATORY RESPONSE-REDUCING COATING
Abstract
Implantable non-bioabsorbable medical devices have an
amphiphilic coating for reducing the inflammatory response to the
device after implantation.
Inventors: |
Ladet; Sebastien; (Caluire
& Cuire, FR) ; Gravagna; Philippe; (Irigny,
FR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Sofradim Production |
Trevoux |
|
FR |
|
|
Family ID: |
42246167 |
Appl. No.: |
14/528071 |
Filed: |
October 30, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12708861 |
Feb 19, 2010 |
8877170 |
|
|
14528071 |
|
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61154385 |
Feb 21, 2009 |
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Current U.S.
Class: |
427/2.31 ;
427/2.1 |
Current CPC
Class: |
A61L 31/16 20130101;
A61L 2300/606 20130101; A61L 17/005 20130101; A61L 2300/252
20130101; A61L 31/10 20130101; A61L 2400/18 20130101; A61L 2300/256
20130101; A61L 2300/406 20130101; A61L 2300/414 20130101; A61L
2420/02 20130101; A61L 2300/43 20130101; A61L 17/145 20130101; A61L
2300/41 20130101 |
Class at
Publication: |
427/2.31 ;
427/2.1 |
International
Class: |
A61L 31/10 20060101
A61L031/10 |
Claims
1-2. (canceled)
3. A method of providing a medical device with an amphiphilic
coating comprising functionalizing at least a portion of a surface
of a non-bioabsorbable polymeric medical device with a first click
reactive member and reacting the surface of the non-bioabsorbable
polymeric medical device functionalized with the first click
reactive member with an amphiphilic compound having a hydrophobic
portion and a hydrophilic portion, the hydrophobic portion
functionalized with a second click reactive member that is
complimentary to the first click reactive member, wherein the
hydrophobic portion of the amphiphilic compound is covalently
bonded to the surface of the non-bioabsorbable polymeric medical
device via a click chemistry reaction.
4. The method of claim 3, wherein the non-bioabsorbable polymeric
medical device comprises a material selected from the group
consisting of polyethylene terephthalate, polypropylene,
polytetrafluoroethylene, nylons, polyamides, polyurethanes,
silicones, ultra high molecular weight polyethylene, polybutesters,
polyaryletherketone, copolymers and combinations thereof.
5. The method of claim 3, wherein the non-bioabsorbable polymeric
medical device comprises polyethylene terephthalate.
6. The method of claim 3, wherein the non-bioabsorbable polymeric
medical device comprises polypropylene.
7. The method of claim 3, wherein the hydrophilic portion of the
amphiphilic compound comprises a material selected from the group
consisting of polyamides, polyethylene oxide, hydrophilic
polyurethanes, polylactones, polyimides, polylactams,
poly-vinyl-pyrrolidone, polyvinyl alcohols, polyacrylic acid,
polymethacrylic acid, poly(hydroxyethyl methacrylate), gelatin,
dextran, chitosan, hyaluronic acid, alginate, chondroitin sulfate,
mixtures and combinations thereof.
8. The method of claim 3, wherein the hydrophobic portion of the
amphiphilic compound comprises a material selected from the group
consisting of polyethylene, polypropylene, hydrophobic
polyurethanes, polyacrylates, polymethacrylates, fluoropolymers,
polycaprolactone, polylactide, polyglycolide, phospholipids,
polyureas, poly(ethylene/-vinyl acetate), polyvinylchloride,
polyesters, polyamides, polycarbonate, polystyrenes,
polytetrafluoroethylene, silicones, siloxanes, fatty acids,
chitosan having high degrees of acetylation and mixtures and
combinations thereof.
9. The method of claim 3, wherein the hydrophobic portion of the
amphiphilic compound is derived from a fatty acid.
10. The method of claim 9, wherein the fatty acid is selected from
the group consisting of butanoic acid, pentanoic acid, hexanoic
acid, octanoic acid, nonanoic acid, decanoic acid, dodecanoic acid,
tetradecanoic acid, hexadecanoic acid, heptadecanoic acid,
octadecanoic acid, eicosanoic acid, docosanoic acid, tetracosanoic
acid, hexacosanoic acid, heptacosanoic acid, and octacosanoic
acid.
11. The method of claim 3, wherein the hydrophobic portion of the
amphiphilic compound comprises a material selected from the group
consisting of polycaprolactone, polylactide, polyglycolide, and
mixtures and combinations thereof.
12. The method of claim 3, wherein the first click reactive member
comprises an alkyne and the second complimentary click reactive
member comprises an azide.
13. The method of claim 3, wherein the first click reactive member
comprises an azide and the second complimentary click reactive
member comprises an alkyne.
14. The method of claim 3, wherein the medical device is a
monofilament.
15. The method of claim 3, wherein the medical device is a
multifilament.
16. The method of claim 3, wherein the medical device is a surgical
mesh.
17. The method of claim 3, wherein the hydrophilic portion of the
amphiphilic compound is positioned away from the substrate and
provides an environment favorable for cellular attachment.
18. The method of claim 17, wherein the hydrophobic portion of the
amphiphilic compound prevents cellular migration nearest the
substrate thereby reducing an inflammatory response and improving
the long term performance of the device.
19. The method of claim 3, wherein reacting the surface of the
non-bioabsorbable polymeric medical device with the amphiphilic
compound further comprises adding a catalyst.
20. The method of claim 19, wherein the catalyst is selected from
the group consisting of a pH modifier, a metal catalyst, heat, and
UV radiation.
21. The method of claim 19, wherein the catalyst is a metal
catalyst.
22. The method of claim 3, wherein the click chemistry reactions is
selected from the group consisting of Huisgen cycloaddition,
Diels-Alder reactions, thiol-alkene reactions, and maleimide-thiol
reactions.
23. A method of providing a medical device with an amphiphilic
coating comprising functionalizing at least a portion of a surface
of a non-bioabsorbable polymeric medical device with a first click
reactive member and reacting the surface of the non-bioabsorbable
polymeric medical device functionalized with the first click
reactive member with an amphiphilic compound having a hydrophobic
polymer comprising a fatty acid and a hydrophilic polymer, the
hydrophobic polymer functionalized with a second click reactive
member that is complimentary to the first click reactive member,
wherein the hydrophobic polymer of the amphiphilic compound is
covalently bonded to the surface of the non-bioabsorbable polymeric
medical device via a Huisgen cycloaddition reaction between the
first and second click reactive members and the medical device is a
fiber.
Description
RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Patent Application No. 61/154,385 filed Feb. 21, 2009.
BACKGROUND
[0002] 1. Technical Field
[0003] The present disclosure relates to methods of making
implantable medical devices having a coating that reduces
inflammatory response to the implantable medical device.
[0004] 2. Background of Related Art
[0005] Implantable medical devices are formed from a variety of
different biodegradable and non-biodegradable materials.
Non-biodegradable devices offer increased strength and support
however, the permanency of these devices can induce inflammatory
responses over the short and long term which affects the durability
of the repair. Regarding long term performances non-absorbable
polymer devices can induce chronic inflammatory responses which
increase the risk of infection.
[0006] Accordingly, it would be beneficial to provide a medical
device which includes a coating that reduces inflammatory response
to the device.
SUMMARY
[0007] Implantable medical devices are described herein which
include a non-bioabsorbable polymeric substrate having a surface to
which a inflammatory response-reducing coating is attached. The
inflammatory response-reducing coating includes an amphiphilic
compound--that is, a compound having a hydrophilic portion and a
hydrophobic portion. The hydrophobic portion of the amphiphilic
compound is functionalized with a reactive member that reacts with
a reactive member on a functionalized surface of the bioabsorbable
polymeric substrate. In this manner, the hydrophobic portion of the
amphiphilic compound is covalently bound to a surface of the
implantable medical device.
[0008] Methods of making such medical devices are described herein
which include reacting a functionalized surface of the
non-bioabsorbable polymeric substrate with an amphiphilic compound
having a functionalized hydrophobic portion. In embodiments, the
surface of the non-bioabsorbable polymeric substrate and the
hydrophobic portion of the amphiphilic compound are functionalized
with reactive members involved in click chemistry.
BRIEF DESCRIPTION OF THE DRAWINGS
[0009] FIG. 1 schematically illustrates a medical device in
accordance with an embodiment described herein.
[0010] FIG. 2 schematically illustrates the effect of implantation
on the embodiment of FIG. 1.
[0011] FIG. 3 schematically illustrates a medical device having an
activated surface and an activated amphiphilic compound.
[0012] FIG. 4 schematically illustrates the medical device shown in
FIG. 3 having the amphiphilic compound covalently bonded
thereto.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0013] Implantable medical devices in accordance with the present
disclosure include a non-bioabsorbable polymeric substrate having a
surface to which a inflammatory response-reducing coating
containing an amphiphilic compound is covalently bound. At least a
portion of a surface of the non-bioabsorbable polymeric substrate
is functionalized with a first reactive member and the hydrophobic
portion of the amphiphilic compound is functionalized with a second
reactive member that is reactive with the first reactive member on
the surface of the non-bioabsorbable polymeric substrate. The first
and second reactive members react to covalently bond the
hydrophobic portion of the amphiphilic compound to the surface of
the non-bioabsorbable polymeric substrate.
[0014] Turning now to FIG. 1, medical device 10, has a
non-bioabsorbable polymeric substrate shown as a single fiber or
monofilament 15 having coating 20 that includes an amphiphilic
compound having hydrophilic portion 30 and hydrophobic portion 40
wherein hydrophobic portion 40 is covalently attached to substrate
15. Hydrophilic portion 30 of amphiphilic coating 20 is positioned
away from substrate 15 and provides an environment favorable for
cellular attachment and infiltration. Hydrophobic portion 40 is
positioned nearest substrate 15 and provides a barrier preventing
water diffusion and also cell attraction to substrate 15, thereby
retarding the degradation of medical device 10 and increasing the
in vivo persistence of medical device 10.
[0015] As shown in FIG. 2, hydrophobic portion 40 of amphiphilic
compound 20 collapses along the surface of substrate 15 following
implantation and prevents cellular migration during the early
stages of the healing process and thereby reducing any inflammatory
response. By limiting the inflammatory response during the early
phases of the healing process, the long term performance of the
implant is improved.
The Polymeric Substrate
[0016] The substrate of the medical devices described herein may be
made from any non-bioabsorbable polymer. The non-bioabsorbable
polymer may be a homopolymer or a copolymer, including random
copolymer, block copolymer, or graft copolymer. The
non-bioabsorbable polymer may be a linear polymer, a branched
polymer, or a dendrimer. The non-bioabsorbable polymers may be of
natural or synthetic origin. Examples of suitable non-bioabsorbable
polymers include, but are not limited to fluorinated polymers (e.g.
fluoroethylenes, propylenes, fluoroPEGs), polyolefins such as
polyethylene, polyesters such as poly ethylene terepththalate
(PET), polypropylene, cellulose, polytetrafluoroethylene (PTFE),
nylons, polyamides, polyurethanes, silicones, ultra high molecular
weight polyethylene (UHMWPE), polybutesters, polyaryletherketone,
copolymers and combinations thereof.
[0017] The non-bioabsorbable polymeric substrate may be fabricated
into any desired physical form. The polymeric substrate may be
fabricated for example, by spinning, casting, molding or any other
fabrication technique known to those skilled in the art. The
polymeric substrate may be made into any shape, such as, for
example, a fiber, sheet, rod, staple, clip, needle, tube, foam, or
any other configuration suitable for a medical device. Where the
polymeric substrate is in the form of a fiber, the fiber may be
formed into a textile using any known technique including, but not
limited to, knitting, weaving, tatting and the like. It is further
contemplated that the polymeric substrate may be a non-woven
fibrous structure.
[0018] The present non-bioabsorbable polymeric substrate having a
coating containing an amphiphilic compound may be used as any
medical device suitable for implantation. Some non-limiting
examples include monofilaments, multifilaments, surgical meshes,
ligatures, sutures, staples, patches, slings, foams, pellicles,
films, barriers, and the like.
The Amphiphilic Compound
[0019] The amphiphilic compound includes at least one portion which
is hydrophilic and at least one portion which is hydrophobic. The
terms "hydrophilic" and "hydrophobic" are generally defined in
terms of a partition coefficient P, which is the ratio of the
equilibrium concentration of a compound in an organic phase to that
in an aqueous phase. A hydrophilic compound has a log P value less
than 1.0, typically less than about -0.5, where P is the partition
coefficient of the compound between octanol and water, while
hydrophobic compounds will generally have a log P greater than
about 3.0, typically greater than about 5.0.
[0020] The amphiphilic compound may be linear, branched, block or
graft copolymers. The hydrophilic portions are derived from
hydrophilic polymers or compounds selected from the member
consisting of polyamides, polyethylene oxide, hydrophilic
polyurethanes, polylactones, polyimides, polylactams,
poly-vinyl-pyrrolidone, polyvinyl alcohols, polyacrylic acid,
polymethacrylic acid, poly(hydroxyethyl methacrylate), gelatin,
dextran, oligosaccharides, such as chitosan, hyaluronic acid,
alginate, chondroitin sulfate, mixtures and combinations thereof.
The hydrophobic portions are derived from hydrophobic polymers or
compounds selected from the member consisting of polyethylene,
polypropylene, hydrophobic polyurethanes, polyacrylates,
polymethacrylates, fluoropolymers, polycaprolactone, polylactide,
polyglycolide, phospholipids, and polyureas, poly(ethylene/-vinyl
acetate), polyvinylchloride, polyesters, polyamides, polycarbonate,
polystyrenes, polytetrafluoroethylene, silicones, siloxanes, fatty
acids, and chitosan having high degrees of acetylation and mixtures
and combinations thereof. The amphiphilic compound may include any
biocompatible combination of hydrophilic and hydrophobic
portions.
[0021] In embodiments, the amphiphilic compound may include a
hydrophobic portion derived from a fatty acid, some non-limiting
examples include saturated fatty acids, monoenoic fatty acids,
polyenoic fatty acids, methylene-interrupted
polymethylene-interrupted, conjugated, allenic acids, cumulenic
acids, acetylenic fatty acids, hydroxy fatty acids, dicarboxylic
acids, fatty acid carbonates, divinyl ether fatty acids, sulfur
containing fatty acids, fatty acid amides, methoxy and acetoxy
fatty acids, keto fatty acids, aldehydic fatty acids, halogenated
fatty acids (F, Cl, Br), nitrated fatty acids, arsenic containing
fatty acids, branched-chain fatty acids, mono or multibranched
chain fatty acids, branched methoxy fatty acids, branched hydroxy
fatty acids, ring containing fatty acids, cyclopropane acids,
cyclobutane acids, cyclopentenyl acids, furanoid acids, cyclohexyl
acids, phenylalkanoic acids, epoxy acids, cyclic fatty peroxides,
lipoic acids and combinations thereof. Examples of saturated fatty
acids include butanoic, pentanoic, hexanoic, octanoic, nonanoic,
decanoic, dodecanoic, tetradecanoic, hexadecanoic, heptadecanoic,
octadecanoic, eicosanoic, docosanoic, tetracosanoic, hexacosanoic,
heptacosanoic, and octacosanoic. In embodiments, the fatty acid may
include one of the following formulas: C.sub.6H.sub.11O,
C.sub.10H.sub.19O, C.sub.16H.sub.31O, C.sub.22H.sub.43O. The
amphiphilic compound may also includes a hydrophilic portion
derived from an oligosaccharide such as chitosan, hyaluronic acid,
alginates or chondroitin sulfate.
[0022] Chitosan is a natural polysaccharide comprising copolymers
of glucosamine and N-acetylglucosamine, and can be obtained by the
partial acetylation of chitin, from crustacean shells, the second
most abundant natural polymer after cellulose. The process of
acetylation involves the removal of acetyl members from the
molecular chain of chitin, leaving behind a complete amino member
(--NH.sub.2) and chitosan versatility depends mainly on this high
degree chemical reactive amino members. As the degree of
acetylation increases, the more hydrophobic the chitosan becomes.
Conversely, as the degree of acetylation decreases, the more
hydrophilic the chitosan becomes. Thus, in some embodiments,
chitosan oligmers displaying different degrees of acetylation may
be combined to form an amphiphilic compound. Moreover, in some
embodiments in which more than one oligosaccharide may be utilized
to form the amphiphilic compound, the degree of acetylation of the
chitosan oligomers may be altered depending ion the hydrophilicity
of the other oligosaccharides. For instance, the amphiphilic
compound may include a hydrophilic portion derived from a chitosan
oligomer having a low degree of acetylation, ranging from about 0
to about 50%, and a hydrophobic portion derived from a chitosan
oligomer having a higher degree of acetylation, greater than about
50%. Alternatively, the amphiphilic compound may be formed under a
raised pH, greater than 7.5, such that the compound includes a
hydrophobic portion derived from a chitosan oligomer having a low
degree of acetylation, ranging from about 0 to about 50%, and a
hydrophilic portion derived from a hyaluronic acid oligomer or
alginate oligomer which under the raised pH conditions displays a
negative charge. Under the raised pH conditions, the chitosan
oligomer having a low degree of acetylation displays a positive
charge and becomes more hydrophilic.
[0023] In still other embodiments, a fatty acid hydrophobic portion
may be combined with a hydrophilic drug. Some non-limiting examples
of hydrophilic drugs include oxytocin, vasopressin,
adrenocorticotrophic hormone (ACTH), epidermal growth factor (EGF),
transforming growth factor antagonists, prolactin, luliberin or
luteinizing hormone releasing hormone (LH-RH), LH-RH agonists or
antagonists, growth hormone, growth hormone releasing factor,
insulin, somatostatin, bombesin antagonists, glucagon, interferon,
gastrin, tetragastrin, pentagastrin, urogastrone, secretin,
calcitonin, enkephalins, endorphins, angiotensins, renin,
bradykinin, bacitracins, polymyzins, colistins, tyrocidin,
gramicidines, and synthetic analogues and modifications and
pharmaceutically-active fragments thereof, monoclonal antibodies
and soluble vaccines.
Coating the Polymer Substrate with the Amphiphilic Compound
[0024] In order to covalently bond the amphiphilic compound to the
surface of the non-bioabsorbable polymeric substrate, the surface
of the non-bioabsorbable polymeric substrate is functionalized with
a first reactive member and the hydrophobic portion of the
amphiphilic compound is functionalized with a second reactive
member. The first and second reactive members are complementary. By
"complementary" it is meant that the first and second reactive
members are able to specifically interact together to covalently
bond the amphiphilic compound to the functionalized polymer.
[0025] In embodiments, the surface of the non-bioabsorbable
polymeric substrate and the hydrophobic portion of the amphiphilic
compound are functionalized with electrophilic or nucleophilic
functional members, such that, for example, a nucleophilic
functional member on the surface of the non-bioabsorbable polymeric
substrate may react with an electrophilic functional member on the
hydrophobic portion of the amphiphilic compound to form a covalent
bond.
[0026] Virtually any nucleophilic member can be used to
functionalize the surface of the non-bioabsorbable polymeric
substrate, so long as reaction can occur with the electrophilic
member on the hydrophobic portion of the amphiphilic compound.
Analogously, virtually any electrophilic member can be used to
functionalize the hydrophobic portion of the amphiphilic compound,
so long as reaction can take place with the nucleophilic member on
the surface of the non-bioabsorbable polymeric substrate. The only
limitation is a practical one, in that reaction between the
complementary members should be fairly rapid and take place
automatically upon admixture with an aqueous medium, without need
for heat or potentially toxic or non-non-bioabsorbable reaction
catalysts or other chemical reagents. It is also preferred although
not essential that reaction occur without need for ultraviolet or
other radiation. In embodiments, the reactions the complementary
members should be complete in under 60 minutes, in embodiments
under 30 minutes, in yet other embodiments, the reaction occurs in
about 5 to 15 minutes or less.
[0027] Non-limiting examples of nucleophilic members include, but
are not limited to, --NH.sub.2, --NHR, --N(R).sub.2, --SH, --OH,
--COOH, --C.sub.6H.sub.4--OH, --PH.sub.2, --PHR, --P(R).sub.2,
--NH--NH.sub.2, --CO--NH--NH.sub.2, --C.sub.5H.sub.4N, etc. wherein
R is hydrocarbyl, typically C.sub.1-C.sub.4 alkyl or monocyclic
aryl. Organometallic moieties are also useful nucleophilic members
for the purposes of this disclosure, particularly those that act as
carbanion donors. Examples of organometallic moieties include:
Grignard functionalities --RMgHal wherein R is a carbon atom
(substituted or unsubstituted), and Hal is halo, typically bromo,
iodo or chloro; and lithium-containing functionalities, typically
alkyllithium members; sodium-containing functionalities.
[0028] It will be appreciated by those of ordinary skill in the art
that certain nucleophilic members must be activated with a base so
as to be capable of reaction with an electrophile. For example,
when there are nucleophilic sulfhydryl and hydroxyl members on the
surface of the non-bioabsorbable polymeric substrate, the
composition must be admixed with an aqueous base in order to remove
a proton and provide an --S.sup.- or --O.sup.- species to enable
reaction with an electrophile. Unless it is desirable for the base
to participate in the reaction, a non-nucleophilic base is used. In
some embodiments, the base may be present as a component of a
buffer solution.
[0029] The selection of electrophilic members provided on the
hydrophobic portion of the amphiphilic compound is made so that
reaction is possible with the specific nucleophilic members on the
surface of the non-bioabsorbable polymeric substrate. Thus, when
the surface of the non-bioabsorbable polymeric substrate is
functionalized with amino members, the hydrophobic portion of the
amphiphilic compound is functionalized with members selected so as
to react with amino members. Analogously, when the surface of the
non-bioabsorbable polymeric substrate is functionalized with
sulhydryl moieties, the corresponding electrophilic members are
sulfhydryl-reactive members, and the like.
[0030] By way of example, when the surface of the non-bioabsorbable
polymeric substrate is functionalized with amino members (generally
although not necessarily primary amino members), the electrophilic
members present on the hydrophobic portion of the amphiphilic
compound are amino reactive members such as, but not limited to:
(1) carboxylic acid esters, including cyclic esters and "activated"
esters; (2) acid chloride members (--CO--Cl); (3) anhydrides
(--(CO)--O--(CO)--R); (4) ketones and aldehydes, including
.alpha.,.beta.-unsaturated aldehydes and ketones such as
--CH.dbd.CH--CH.dbd.O and --CH.dbd.CH--C(CH.sub.3).dbd.O; (5)
halides; (6) isocyanate (--N.dbd.C.dbd.O); (7) isothiocyanate
(--N.dbd.C.dbd.S); (8) epoxides; (9) activated hydroxyl members
(e.g., activated with conventional activating agents such as
carbonyldiimidazole or sulfonyl chloride); and (10) olefins,
including conjugated olefins, such as ethenesulfonyl
(--SO.sub.2CH.dbd.CH.sub.2) and analogous functional members,
including acrylate (--CO.sub.2--C.dbd.CH.sub.2), methacrylate
(--CO.sub.2--C(CH.sub.3).dbd.CH.sub.2)), ethyl acrylate
(--CO.sub.2--C(CH.sub.2CH.sub.3).dbd.CH.sub.2), and ethyleneimino
(--CH.dbd.CH--C.dbd.NH). Since a carboxylic acid member per se is
not susceptible to reaction with a nucleophilic amine, components
containing carboxylic acid members must be activated so as to be
amine-reactive. Activation may be accomplished in a variety of
ways, but often involves reaction with a suitable
hydroxyl-containing compound in the presence of a dehydrating agent
such as dicyclohexylcarbodiimide (DCC) or dicyclohexylurea (DHU).
For example, a carboxylic acid can be reacted with an
alkoxy-substituted N-hydroxy-succinimide or
N-hydroxysulfosuccinimide in the presence of DCC to form reactive
electrophilic members, the N-hydroxysuccinimide ester and the
N-hydroxysulfosuccinimide ester, respectively. Carboxylic acids may
also be activated by reaction with an acyl halide such as an acyl
chloride (e.g., acetyl chloride), to provide a reactive anhydride
member. In a further example, a carboxylic acid may be converted to
an acid chloride member using, e.g., thionyl chloride or an acyl
chloride capable of an exchange reaction. Specific reagents and
procedures used to carry out such activation reactions will be
known to those of ordinary skill in the art and are described in
the pertinent texts and literature.
[0031] Analogously, when the surface of the non-bioabsorbable
polymeric substrate is functionalized with sulfhydryl, the
electrophilic members present on the hydrophobic portion of the
amphiphilic compound are members that react with a sulfhydryl
moiety. Such reactive members include those that form thioester
linkages upon reaction with a sulfhydryl member, such as those
described in PCT Publication No. WO 00/62827 to Wallace et al. As
explained in detail therein, such "sulfhydryl reactive" members
include, but are not limited to: mixed anhydrides; ester
derivatives of phosphorus; ester derivatives of p-nitrophenol,
p-nitrothiophenol and pentafluorophenol; esters of substituted
hydroxylamines, including N-hydroxyphthalimide esters,
N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and
N-hydroxyglutarinide esters; esters of 1-hydroxybenzotriazole;
3-hydroxy-3,4-dihydro-benzotriazin-4-one;
3-hydroxy-3,4-dihydro-quinazoline-4-one; carbonylimidazole
derivatives; acid chlorides; ketenes; and isocyanates. With these
sulfhydryl reactive members, auxiliary reagents can also be used to
facilitate bond formation, e.g.,
1-ethyl-3-[3-dimethylaminopropyl]carbodiimide can be used to
facilitate coupling of sulfhydryl members to carboxyl-containing
members.
[0032] In addition to the sulfhydryl reactive members that form
thioester linkages, various other sulfydryl reactive
functionalities can be utilized that form other types of linkages.
For example, compounds that contain methyl imidate derivatives form
imido-thioester linkages with sulfhydryl members. Alternatively,
sulthydryl reactive members can be employed that form disulfide
bonds with sulthydryl members, such members generally have the
structure --S--S--Ar where Ar is a substituted or unsubstituted
nitrogen-containing heteroaromatic moiety or a non-heterocyclic
aromatic member substituted with an electron-withdrawing moiety,
such that Ar may be, for example, 4-pyridinyl, o-nitrophenyl,
m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2-nitro-4-benzoic
acid, 2-nitro-4-pyridinyl, etc. In such instances, auxiliary
reagents, i.e., mild oxidizing agents such as hydrogen peroxide,
can be used to facilitate disulfide bond formation.
[0033] Yet another class of sulfhydryl reactive members forms
thioether bonds with sulfhydryl members. Such members include,
inter alia, maleimido, substituted maleimido, haloalkyl, epoxy,
imino, and aziridino, as well as olefins (including conjugated
olefins) such as ethenesulfonyl, etheneimino, acrylate,
methacrylate, and (.alpha.,.beta.-unsaturated aldehydes and
ketones.
[0034] When the surface of the non-bioabsorbable polymeric
substrate is functionalized with --OH, the electrophilic functional
members on the hydrophobic portion of the amphiphilic compound must
react with hydroxyl members. The hydroxyl member may be activated
as described above with respect to carboxylic acid members, or it
may react directly in the presence of base with a sufficiently
reactive electrophile such as an epoxide member, an aziridine
member, an acyl halide or an anhydride.
[0035] When the surface of the non-bioabsorbable polymeric
substrate is functionalized with an organometallic nucleophile such
as a Grignard functionality or an alkyllithium member, suitable
electrophilic functional members for reaction therewith are those
containing carbonyl members, including, by way of example, ketones
and aldehydes.
[0036] It will also be appreciated that certain functional members
can react as nucleophiles or as electrophiles, depending on the
selected reaction partner and/or the reaction conditions. For
example, a carboxylic acid member can act as a nucleophile in the
presence of a fairly strong base, but generally acts as an
electrophile allowing nucleophilic attack at the carbonyl carbon
and concomitant replacement of the hydroxyl member with the
incoming nucleophile.
[0037] Table 1, below illustrates, solely by way of example,
representative complementary pairs of electrophilic and
nucleophilic functional members that may be employed in
functionalizing the non-bioabsorbable polymeric substrate (e.g.,
R.sub.1 in Table 1) and the hydrophobic portion of the amphiphilic
compound (e.g., R.sub.2 in Table 1).
TABLE-US-00001 TABLE 1 REPRESENTATIVE NUCLEOPHILIC REPRESENTATIVE
COMPONENT ELECTROPHILIC COMPONENT (A, FN.sub.NU) (B, FN.sub.EL)
RESULTING LINKAGE R.sup.1--NH.sub.2
R.sup.2--O--(CO)--O--N(COCH.sub.2) R.sup.1--NH--(CO)--O--R.sup.2
(succinimidyl carbonate terminus) R.sup.1--SH
R.sup.2--O--(CO)--O--N(COCH.sub.2) R.sup.1--S--(CO)--O--R.sup.2
R.sup.1--OH R.sup.2--O--(CO)--O--N(COCH.sub.2)
R.sup.1--S--(CO)--R.sup.2 R.sup.1--NH.sub.2
R.sup.2--O(CO)--CH.dbd.CH.sub.2
R.sup.1--NH--CH.sub.2CH.sub.2--(CO)--O--R.sup.2 (acrylate terminus)
R.sup.1--SH R.sup.2--O--(CO)--CH.dbd.CH.sub.2
R.sup.1--S--CH.sub.2CH.sub.2--(CO)--O--R.sup.2 R.sup.1--OH
R.sup.2--O--(CO)--CH.dbd.CH.sub.2
R.sup.1--O--CH.sub.2CH.sub.2--(CO)--O--R.sup.2 R.sup.1--NH.sub.2
R.sup.2--O(CO)--(CH.sub.2).sub.3--CO.sub.2N(COCH.sub.2)
R.sup.1--NH--(CO)--(CH.sub.2).sub.3--(CO)--OR.sup.2 (succinimidyl
glutarate terminus) R.sup.1--SH
R.sup.2--O(CO)--(CH.sub.2).sub.3--CO.sub.2--N(COCH.sub.2)
R.sup.1--S--(CO)--(CH.sub.2).sub.3--(CO)--OR.sup.2 R.sup.1--OH
R.sup.2--O(CO)--(CH.sub.2).sub.3--CO.sub.2--N(COCH.sub.2)
R.sup.1--O--(CO)--(CH.sub.2).sub.3--(CO)--OR.sup.2
R.sup.1--NH.sub.2 R.sup.2--O--CH.sub.2--CO.sub.2--N(COCH.sub.2)
R.sup.1--NH--(CO)--CH.sub.2--OR.sup.2 (succinimidyl acetate
terminus) R.sup.1--SH R.sup.2--O--CH.sub.2--CO.sub.2--N(COCH.sub.2)
R.sup.1--S--(CO)--CH.sub.2--OR.sup.2 R.sup.1--OH
R.sup.2--O--CH.sub.2--CO.sub.2--N(COCH.sub.2)
R.sup.1--O--(CO)--CH.sub.2--OR.sup.2 R.sup.1--NH.sub.2
R.sup.2--O--NH(CO)--(CH.sub.2).sub.2--CO.sub.2--
R.sup.1--NH--(CO)--(CH.sub.2).sub.2--(CO)--NH--OR.sup.2
N(COCH.sub.2) (succinimidyl succinamide terminus) R.sup.1--SH
R.sup.2--O--NH(CO)--(CH.sub.2).sub.2--CO.sub.2--
R.sup.1--S--(CO)--(CH.sub.2).sub.2--(CO)--NH--OR.sup.2
N(COCH.sub.2) R.sup.1--OH
R.sup.2--O--NH(CO)--(CH.sub.2).sub.2--CO.sub.2--
R.sup.1--O--(CO)--(CH.sub.2).sub.2--(CO)--NH--OR.sup.2
N(COCH.sub.2) R.sup.1--NH.sub.2 R.sup.2--O--(CH.sub.2).sub.2--CHO
R.sup.1--NH--(CO)--(CH.sub.2).sub.2--OR.sup.2 (propionaldehyde
terminus) R.sup.1--NH.sub.2 ##STR00001## (glycidyl ether terminus)
R.sup.1--NH--CH.sub.2--CH(OH)--CH.sub.2--OR.sup.2 and
R.sup.1--N[CH.sub.2--CH(OH)--CH.sub.2--OR.sup.2].sub.2
R.sup.1--NH.sub.2 R.sup.2--O--(CH.sub.2).sub.2--N.dbd.C.dbd.O
R.sup.1--NH--(CO)--NH--CH.sub.2--OR.sup.2 (isocyanate terminus)
R.sup.1--NH.sub.2 R.sup.2--SO.sub.2--CH.dbd.CH.sub.2
R.sup.1--NH--CH.sub.2CH.sub.2--SO.sub.2--R.sup.2 (vinyl sulfone
terminus) R.sup.1--SH R.sup.2--SO.sub.2--CH.dbd.CH.sub.2
R.sup.1--S--CH.sub.2CH.sub.2--SO.sub.2--R.sup.2
[0038] In embodiments, the surface of the non-bioabsorbable
polymeric substrate is functionalized with a first click-reactive
member and the hydrophobic portion of the amphiphilic compound is
functionalized with a second click-reactive member complementary to
the first click-reactive member. The "click-reactive members" are
meant to include those reactive members used in the processes known
to those skilled in the art as Click chemistry.
[0039] Click chemistry refers to a collection of reactive members
having a high chemical potential energy capable of producing highly
selective, high yield reactions. The reactive members react to form
extremely reliable molecular connections in most solvents,
including physiologic fluids, and often do not interfere with other
reagents and reactions. Examples of click chemistry reactions
include Huisgen cycloaddition, Diels-Alder reactions, thiol-alkene
reactions, and maleimide-thiol reactions.
[0040] Huisgen cycloaddition is the reaction of a dipolarophile
with a 1,3-dipolar compound that leads to 5-membered
(hetero)cycles. Examples of dipolarophiles are alkenes and alkynes
and molecules that possess related heteroatom functional groups
(such as carbonyls and nitriles). 1,3-Dipolar compounds contain one
or more heteroatoms and can be described as having at least one
mesomeric structure that represents a charged dipole. They include
nitril oxides, azides, and diazoalkanes. Metal catalyzed click
chemistry is an extremely efficient variant of the Huisgen
1,3-dipolar cycloaddition reaction between alkyl-aryly-sulfonyl
azides, C--N triple bonds and C--C triple bonds which is
well-suited herein. The results of these reactions are 1,2
oxazoles, 1,2,3 triazoles or tetrazoles. For example, 1,2,3
triazoles are formed by a copper catalyzed Huisgen reaction between
alkynes and alkyl/aryl azides. Metal catalyzed Huisgen reactions
proceed at ambient temperature, are not sensitive to solvents,
i.e., nonpolar, polar, semipolar, and are highly tolerant of
functional groups. Non-metal Huisgen reactions (also referred to as
strain promoted cycloaddition) involving use of a substituted
cyclooctyne, which possesses ring strain and electron-withdrawing
substituents such as fluorine, that together promote a [3+2]
dipolar cycloaddition with azides are especially well-suited for
use herein due to low toxicity as compared to the metal catalyzed
reactions. Examples include DIFO and DIMAC. Reaction of the alkynes
and azides is very specific and essentially inert against the
chemical environment of biological tissues. One reaction scheme may
be represented as:
##STR00002##
where R and R' are a polymeric substrate or a amphiphilic
compound.
[0041] The Diels-Alder reaction combines a diene (a molecule with
two alternating double bonds) and a dienophile (an alkene) to make
rings and bicyclic compounds. Examples include:
##STR00003##
[0042] The thiol-alkene (thiol-ene) reaction is a hydrothiolation,
i.e., addition of RS--H across a C.dbd.C bond. The thiol-ene
reaction proceeds via a free-radical chain mechanism. Initiation
occurs by radical formation upon UV excitation of a photoinitiator
or the thiol itself. Thiol-ene systems form ground state charge
transfer complexes and therefore photopolymerize even in the
absence of initiators in reasonable polymerization times. However,
the addition of UV light increases the speed at which the reaction
proceeds. The wavelength of the light can be modulated as needed,
depending upon the size and nature of the constituents attached to
the thiol or alkene. A general thiol-ene coupling reaction
mechanism is represented below:
##STR00004##
[0043] In embodiments, the surface of the non-bioabsorbable
polymeric substrate and the hydrophobic portion of the amphiphilic
compound are functionalized to include a first click-reactive
member which is an alkyne and a second click-reactive member which
is an azide, respectively. In embodiments, the surface of the
non-bioabsorbable polymeric substrate and the hydrophobic portion
of the amphiphilic compound are functionalized to include a first
click-reactive member which is an azide and a second click-reactive
member which is an alkyne, respectively.
[0044] The first and second click-reactive members are intended to
react and covalently bond the amphiphilic compound to the
functionalized surface of the non-bioabsorbable polymeric substrate
at a physiologic pH. However, in some embodiments, the first and
second click-reactive members may react quicker or more completely
following the addition of a catalyst, such as a pH modifier, a
metal ion catalyst or the introduction of heat or radiation. In
embodiments, the addition of UV radiation may enhance the formation
of a covalent bond between the first and second click-reactive
members. In embodiments, the addition of a metal catalyst, e.g.,
transition metal ions such as copper ions, may assist with the
formation of a covalent bond between the first and second
click-reactive members.
[0045] As shown in FIG. 3, non-bioabsorbable polymeric substrate 15
includes first reactive functional members, in this case azide
members 12. An amphiphilic compound having hydrophilic portion 30
and hydrophobic portion 40 wherein hydrophobic portion 40 includes
second reactive members, in this case alkyne members 42 are
contacted with substrate 15 in solution under suitable reaction
conditions. As those skilled in the art will recognize, reaction
times between the azide and alkyne members can be reduced from
about 24 hours at room temperature to mere seconds at room
temperature by the presence of transition metal ions, such as
copper ions.
[0046] As shown in FIG. 4, after reaction non-bioabsorbable
polymeric substrate 15 includes a coating of the amphiphilic
compound having hydrophilic portion 30 extending away from
substrate 15 and hydrophobic portion 40 covalently bound to
substrate 15 via a triazole linkage 50.
Functionalizing the Substrate and Amphiphilic Compound
[0047] The first and second reactive members may be positioned on
the non-bioabsorbable polymeric substrate and amphiphilic compound
using any variety of suitable chemical processes. With respect to
the first reactive members on the non-bioabsorbable polymeric
substrate, it is contemplated that a plurality of first reactive
members may be present and may be terminally located, or
alternatively located along the length of the polymer chain.
[0048] For example, the monomers from which the non-bioabsorbable
polymeric substrate is made can be functionalized so that the
reactive members appear along the length of the non-bioabsorbable
polymer. In such embodiments, the monomers can be initially
functionalized with a member such as a halogen to provide a
reactive site at which the desired first reactive member can be
attached after polymerization. For example, the halogenated polymer
can be reacted with sodium azide to provide azide groups along the
polymer chain or with propagyl alcohol to provide alkyne groups
along the polymer chain. Alternatively, a pre-formed
non-bioabsorbable polyester can be halogenated by reaction with a
non-nucleophilic strong base, such as lithium diisopropylamide,
followed by electrophilic substitution with iodine chloride. The
halogenated polyester is then reacted with sodium azide or propagyl
alcohol to provide azide or alkyne groups, respectively.
[0049] In other embodiments, the non-bioabsorbable polymeric
substrate is functionalized after it has been fabricated into the
desired form. For example, non-bioabsorbable polymeric fibers can
be functionalized after the spinning process. In embodiments, the
fibers are surface treated and then activated with the first
reactive member (optionally with a coupling agent (e.g., a silane
coupling agent) being used). Surface activation of
non-bioabsorbable and biocompatible aliphatic polyesters can be
achieved by acid or base hydrolysis, treatment by means of cold
plasma, by chemical reactions or electromagnetic radiations. It is
contemplated that such surface activation can be performed before
or after the fibers are made into a textile structure.
[0050] Hydrolysis can be conducted in the presence of an aqueous
solution of a base or an acid to accelerate surface reaction,
inasmuch as excessively long processes of activation can induce a
reduction in molecular weight and thus in the mechanical properties
of the material. Suitable bases for obtaining watery solutions
suited to the aim are, for example, strong alkalis, such as LiOH,
Ba(OH).sub.2, Mg(OH).sub.2, NaOH, KOH, Na.sub.2CO.sub.3,
Ca(OH).sub.2 and the weak bases, such as for example NH.sub.4OH and
the ammines such as methylamine, ethylamine, diethylamine and
dimethylamine. Acids suitable for surface hydrolysis treatments can
be chosen, for example, from among HCl, HClO.sub.3, HClO.sub.4,
H.sub.2SO.sub.3, H.sub.2SO.sub.4, H.sub.3PO.sub.3, H.sub.3PO.sub.4,
HI, HIO.sub.3, HBr, lactic acid, glicolic acid. Surface activation
by means of hydrolysis can be conducted at temperatures preferably
comprised between 0 degrees Celsius and the material softening
temperature. Plasma treatment can be carried out both in the
presence of a reactive gas, for example air, Ar, O.sub.2 with the
formation of surface activation of oxygenate type, such as --OH,
--CHO, --COOH.
[0051] Surface treatment, whether hydrolytic or with plasma, can
remain unaltered or can be followed by further chemical
modifications to provide the first reactive members on the
non-bioabsorbable polymeric substrate. Thus, for example, the COONa
members generated by a base hydrolysis can be subsequently
converted into COOH members by treatment with strong mineral acids.
Further, the surface freeing of alcoholic members by means of a
hydrolysis process can be followed by reaction by means of the
addition of a compound provided with functional member or members
able to react with surface alcoholic members, such as for example
by means of the addition of an anhydride such as succinic
anhydride, with the conversion of --OH members into
--O--CO--CH.sub.2--CH.sub.2--COOH members. Suitable surface
activation techniques are disclosed in U.S. Pat. No. 6,107,453, the
entire disclosure of which is incorporated herein by this
reference.
[0052] With respect to the hydrophobic portion of the amphiphilic
compound, it is contemplated that one or more than one second
reactive members can be provided thereon. The process used to
incorporate the second reactive members on the hydrophobic portion
of the amphiphilic compound will be chosen based upon the nature of
the hydrophobic portion.
[0053] For example, where the hydrophobic portion is based on a
fatty acid, the second reactive members can be attached using the
following synthetic route:
##STR00005## ##STR00006##
[0054] In embodiments, the acids used to introduce the acyl chains
(10d) may be dicarboxylic acid fatty acids which provide for the
synthesis of di-azide compounds.
[0055] In other embodiments where the hydrophobic portion is based
on a hydrophobic peptide, N-propargyl maleimide can be used to
attach alkyne group (the second reactive members) on to the protein
using to the thiol group as shown below:
##STR00007##
[0056] In other embodiments where the hydrophobic portion is based
on a hydrophobic peptide azide groups may be provided by conversion
of the amino acid methyl ester to the corresponding azide via a
Cu(II)-catalyzed diazotransfer reaction using triflic azide as
shown in the following reaction scheme:
##STR00008##
[0057] In yet other embodiments where the hydrophobic portion is
based on an oligosaccharide, the second reactive members can be
attached using the following reaction scheme as described in detail
in Zhang et al., Helvetica Chimica Acta--Vol. 91 pages
608-617(2008):
##STR00009##
[0058] In embodiments, a plurality of different reactive members
may be positioned on each of the non-bioabsorbable polymeric
substrate and amphiphilic compound.
[0059] Various modifications and variations of the polymers,
amphiphilic compounds, medical devices, click-reactive members and
processes described herein will be apparent to those skilled in the
art from the foregoing detailed description. Such modifications and
variations are intended to come within the scope of the following
claims.
* * * * *