U.S. patent application number 12/109560 was filed with the patent office on 2008-09-04 for implant stent with a retinoid for improved biocompatibility.
Invention is credited to Patrick M. Hughes, John S. Kent, Orest Olejnik.
Application Number | 20080213338 12/109560 |
Document ID | / |
Family ID | 25425169 |
Filed Date | 2008-09-04 |
United States Patent
Application |
20080213338 |
Kind Code |
A1 |
Olejnik; Orest ; et
al. |
September 4, 2008 |
IMPLANT STENT WITH A RETINOID FOR IMPROVED BIOCOMPATIBILITY
Abstract
An implant device is provided which incorporates a retinoid for
improving the biocompatibility of the device in tissue. The device
may be bioerodible for the purpose of systemically or locally
releasing a therapeutic agent in tissue or it may be a permanent
implant which includes a surface treated with a retinoid for
increasing the biocompatibility thereof.
Inventors: |
Olejnik; Orest; (Coto De
Caza, CA) ; Hughes; Patrick M.; (Aliso Viejo, CA)
; Kent; John S.; (Newport Beach, CA) |
Correspondence
Address: |
Walter A. Hackler
2372 S.E. Bristol, Ste. B.
Newport Beach
CA
92660
US
|
Family ID: |
25425169 |
Appl. No.: |
12/109560 |
Filed: |
April 25, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11066773 |
Feb 25, 2005 |
7384648 |
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12109560 |
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10853401 |
May 24, 2004 |
7179482 |
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11066773 |
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10396179 |
Mar 24, 2003 |
6743437 |
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10853401 |
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09982219 |
Oct 17, 2001 |
6537568 |
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10396179 |
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09587485 |
Jun 5, 2000 |
6306426 |
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09982219 |
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09356074 |
Jul 16, 1999 |
6110485 |
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09587485 |
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09150990 |
Sep 10, 1998 |
6074661 |
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09356074 |
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08908094 |
Aug 11, 1997 |
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09150990 |
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Current U.S.
Class: |
424/423 ;
514/356 |
Current CPC
Class: |
A61K 31/07 20130101;
A61L 2300/428 20130101; Y10S 514/955 20130101; A61K 31/455
20130101; A61K 9/0051 20130101; A61L 2300/602 20130101; C08L 67/04
20130101; A61L 27/54 20130101; A61K 31/192 20130101; A61L 2300/45
20130101; A61L 27/18 20130101; A61L 27/18 20130101 |
Class at
Publication: |
424/423 ;
514/356 |
International
Class: |
A61F 2/04 20060101
A61F002/04; A61K 31/455 20060101 A61K031/455 |
Claims
1. In an endovascular stent implantable in a blood vessel and
incorporating a therapeutic agent an improvement comprising a
retinoid, separate from said therapeutic agent, for improving
biocompatibility of the stent in said blood vessel.
2. The improvement according to claim 1 wherein said retinoid is
coated on the stent.
3. The improvement according to claim 1 wherein said retinoid is
bonded to the stent.
4. The device according to claim 1 wherein said retinoid comprises
a retinoid receptor agonist.
5. The device according to claim 1 wherein said therapeutic agent,
stent and retinoid are homogeneous.
6. The device according to claim 4 wherein said retinoid receptor
agonist comprises a naturally occurring retinoid.
7. The device according to claim 4 wherein said retinoid receptor
agonist is selected from a group consisting of Vitamin A (retinal),
Vitamin A aldehyde (retinal), Vitamin A acid (retinoic acid) and
their synthetic and natural congeners.
8. The device according to claim 4 wherein the retinoid receptor
agonist comprises
ethyl-6-[2-(4,4-dimethylthiochroman-6yl)ethyl]nicotinate.
9. The device according to claim 4 wherein retinoid receptor
comprises 6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic
acid.
10. The device according to claim 4 wherein the retinoid receptor
agonist comprises
p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2naphthyl)prop-
enyl]-benzoic acid.
Description
[0001] The present application is a continuation of U.S. Ser. No.
11/066,773, now U.S. Ser. No. ______ which is a continuation of
U.S. Ser. No. 10/853,401, now U.S. Pat. No. 7,179,482 which is a
continuation of U.S. Ser. No. 10/396,179, now U.S. Pat. No.
6,743,437 which is a continuation of U.S. Ser. No. 09/982,219,
filed Oct. 17, 2001, now U.S. Pat. No. 6,537,568 which is a
continuation of U.S. Ser. No. 09/587,485, filed Jun. 5, 2000, now
U.S. Pat. No. 6,306,426 which is a continuation-in-part of U.S.
Ser. No. 09/356,074 filed Jul. 16, 1999, now U.S. Pat. No.
6,110,485 which is a continuation of U.S. Ser. No. 09/150,990 filed
Sep. 10, 1998, now abandoned which is a continuation of U.S. Ser.
No. 08/908,094 filed Aug. 11, 1997, now abandoned. All of these
references are to be incorporated herewith in their entirety.
[0002] The present invention is generally related to implantable
devices and is more particularly directed to an implantable
prosthesis having improved biocompatibility. Still more
particularly, the present invention is directed to an implantable
device having improved biocompatibility while providing systemic
release of a therapeutic agent in tissue.
[0003] It should be appreciated that physiological compatibility
and biocompatibility are common problems for both implants for
providing a systemic, or local, release of the therapeutic agent
and for prosthesis, i.e., implants, utilized for functional or
cosmetic reasons, or both.
[0004] It should be appreciated that the term "biocompatible" in
the present application relates to a foreign object that can be
left in a human or animal body for an extended or an indefinite
period without causing any adverse physiological action.
[0005] The functional biocompatibility of an implant or device, is,
of course, determined by the chemical and surface properties of the
implant and its components. The general structure of a device,
including mechanical strength, elasticity, flexibility, fatigue
resistance, chemical inertness, impermeability to water, resistance
to acid, etc., all contribute to biocompatibility which, of course,
also depends upon the type of tissue into which the implant is to
be inserted. Most importantly, the surface of the implant in
contact with body tissues should also exhibit resistance to
immunological attack, cell adhesion, pannus formation, etc.
[0006] Undesirable properties which can result from tissue
interacting with the surface may significantly affect the
efficiency of the implant and be counteractive to the intended use
of the implant in certain medical devices, for example, sustained
or controlled drug release devices.
[0007] The use of a sustained, or controlled release system has a
well known advantage of providing an active agent at a relatively
constant level of concentration in tissue. Sustained drug release
systems have been utilized in a great number of applications
including drug release into the vitreous for endophthalmitis and
other vitreoretinal disorders with the use of antibiotics and a
fungal agent, antineoplastic drugs and anti-inflammatory
agents.
[0008] Unfortunately, in many instances, particularly where the
implant is intended to remain in contact with tissue for extended
periods of time, various problems associated with the physiological
and chemical stability and compatibility with respect to various of
the contacted tissues and biological fluids occurs. This is true
even though the implant may function properly in its sustained or
controlled release of the active agent.
[0009] For example, biomaterial such as a synthetic polymer, when
contacted with blood, rapidly forms an adsorbed protein layer.
Subsequently, conformational alterations and complexing of proteins
which may occur which activate defense mechanisms such as
coagulation, platelet adhesion, and aggregation, white cell
adhesion, etc.
[0010] In eye tissue, an implant may cause superficial
vascularization of the cornea with infiltration of granulation
tissue. Biodegradable polymers may cause mild foreign body
reactions which include inflammation in the vitreous.
[0011] Implanted biomaterials will cause a typical foreign body
reaction with fibrinous membrane formation. A fibrinous membrane
will surround and encapsulate the implant. Contraction of this
fibrous capsule can range from transient pain to serious sequelae
depending upon the location. Fibrinous infiltration of the vitreous
with a prominent inflammatory response can lead to traction retinal
detachment, disruption of the retinal pigmented epithelium or
breakdown of the blood retinal barrier. Tissue and organ adhesions
may develop as a result of the fibrinous inflammation. Intraocular
implants can also cause cataract formation. Iris-ciliary body
adhesions would seriously effect the homeostasis of ocular tension.
Implants, being foreign objects, may cause acute and chronic
inflammation. Tissue necrosis and scarring may result as well as
neovascularization. Biopolymers may often be antigenic and elicit
allergic or other adverse events. In the case of an implantable
material in the vasculature or heart thrombus formation and embolus
may occur.
SUMMARY OF THE INVENTION
[0012] In accordance with one embodiment of the present invention,
an implantable device is provided for systemic, or local, release
of a therapeutic agent in tissue. The device generally includes a
therapeutic agent along with a carrier sized for insertion into
tissue in which the systemic release of a therapeutic agent is
desired, the carrier including means for providing sustained or
controlled release of the therapeutic agent.
[0013] In addition, retinoid means, present in the carrier, is
provided for improving biocompatibility of the device in the
tissue.
[0014] As will be described in detail hereinafter, this
hereinbefore unrecognized property of a retinoid substantially
reduces or prevents undesirable attributes which can result from
tissue interacting with the surface of the implantable device.
[0015] More particularly, in accordance with the present invention,
the retinoid means may comprise a retinoid receptor agonist and the
therapeutic agent, carrier, and retinoid means, may be homogeneous.
This homogeneity provides for ease of manufacturing through the use
of simple extrusion techniques or injection molding.
[0016] Specifically, in accordance with this embodiment of the
present invention, the means for providing time release of the
therapeutic agent may comprise a biodegradable polymer, such as,
for example, a poly(lactic acid) and
poly(lactide-co-glycolide).
[0017] More particularly, in accordance with one embodiment of the
present invention, the carrier may be sized for implanting into a
sclera and the retinoid receptor agonist may be a retinoid acid,
for example, selected from the group of naturally occurring
retinoids such as Vitamin A (retinol), Vitamin A aldehyde
(retinal), Vitamin A acid (retinoic acid) and their synthetic and
natural congeners. These would include but not be limited to the
isomers all trans; 9-cis; 11-cis; 13-cis; 9,11-dicis, and
11,13-dicis as well as physiologically compatible ethers, esters,
amides and salts thereof. The 7,8-dihydro and 5,6-dihydro congeners
as well as etretinate are also acceptable for the invention.
[0018] Compounds that intrinsically or upon metabolism possess the
physiologic properties of retinoids are also included within the
scope of this invention. These would include synthetic and natural
retinoid compounds having affinity to nuclear retinoic acid
receptors (RARs) and retinoid X receptors (RXRs).
[0019] More particularly, the retinoid receptor agonist may be
ethyl-6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, or
6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic acid, or
p-[(E)-2-(5,6,7,8-tetrahydro-,5,5,8,8-tetramethyl-2-naphthyl)propenyl]-be-
nzoic acid.
[0020] Corresponding to the device of the present invention, a
method in accordance with the present invention for improving
biocompatibility of an implant in tissue generally includes the
steps of providing a therapeutic agent, providing a carrier sized
for insertion into tissue in which release of the therapeutic agent
is desired, incorporating a therapeutic agent into a carrier in a
manner enabling sustained or controlled release of the therapeutic
agent and incorporating a retinoid into the carrier in an amount
effective for improving biocompatibility of the carrier in the
tissue.
[0021] Many conditions and diseases are treatable with stents,
catheters, cannulae and other devices inserted into the esophagus,
trachea, colon, biliary tract, urinary tract and other locations in
the body, or with orthopedic devices, implants, or replacements. It
would be desirable to develop devices and methods for reliably
delivering suitable agents, drugs or bioactive materials directly
into a body portion during or following a medical procedure, so as
to treat or prevent such conditions and diseases, for example, to
prevent abrupt closure and/or restenosis of a body portion such as
a passage, lumen or blood vessel.
[0022] As a particular example, it would be desirable to have
devices and methods which can deliver an antithrombic or other
medication to the region of a blood vessel which has been treated
by PTA, or by another interventional technique such as atherectomy,
laser ablation, or the like. It would also be desirable that such
devices would deliver their agents over both the short term (that
is, the initial hours and days after treatment) and the long term
(the weeks and months after treatment). It would also be desirable
to provide precise control over the delivery rate fro the agents,
drugs or bioactive materials, and to limit systemic exposure to
them. This would be particularly advantageous in therapies
involving the delivery of a chemotherapeutic agent to a particular
organ or site through an intravenous catheter (which itself has the
advantage of reducing the amount of agent needed for successful
treatment), by preventing stenosis both along the catheter and at
the catheter tip. A wide variety of other therapies could be
similarly improved.
[0023] Another embodiment of the present invention includes an
implantable device, specifically a surgically implantable
prosthesis in combination with retinoid means for improving the
biocompatibility of the prosthesis. More specifically, the retinoid
means may be present in the form of a film on the prosthesis or,
alternatively, bonded to a surface of the prosthesis.
[0024] Other implants to be considered as part of the present
invention include biocompatible stents such as described in U.S.
Pat. Nos. 5,342,348 and 5,554,381, biocompatible bone pins such as
described in U.S. Pat. No. 4,851,005, biodegradable/biodegradable
joint prosthesis such as described in U.S. Pat. No. 6,007,580,
biodegradable birth control devices such as described in U.S. Pat.
No. 5,733,565, biodegradable implants for treatment of prostate
cancer or any biodegradable drug delivery system.
[0025] All of the hereinabove referenced patents are to be
incorporated herewith, including all drawings and specifications,
by this specific references thereto.
[0026] As hereinabove noted, the retinoid means may comprise a
retinoid selected from the group of naturally occurring retinoids
such as Vitamin A (retinol), Vitamin A aldehyde (retinal), Vitamin
A acid (retinoic acid) and their synthetic and natural congeners.
These would include but not be limited to the isomers all trans;
9-cis; 11-cis; 13-cis; 9,11-dicis, and 11,13-dicis as well as
physiologically compatible ethers, esters, amides and salts
thereof. The 7,8-dihydro and 5,6-dihydro congeners as well as
etretinate are also acceptable for the invention.
[0027] Compounds that intrinsically or upon metabolism possess the
physiologic properties of retinoids are also included within the
scope of this invention. These would include synthetic and natural
retinoid compounds having affinity to nuclear retinoic acid
receptors (RARs) and retinoid X receptors (RXRs).
[0028] Importantly, the present invention encompasses a method for
improving biocompatibility of a surgically implantable prosthesis
with the method comprising the step of combining a retinoid with
the prosthesis. More particularly, the step may include disposing a
film of retinoid on the prosthesis or, embedding retinoid, to the
surface of the prosthesis. The retinoid may comprise a retinoid, as
hereinabove noted, and be selected from the group of naturally
occurring retinoids such as Vitamin A (retinol), vitamin A aldehyde
(retinal), Vitamin A acid (retinoic acid) and their synthetic and
natural congeners. These would include but not be limited to the
isomers all trans; 9-cis; 11-cis; 13-cis; 9,11-dicis, and
11,13-dicis as well as physiologically compatible ethers, esters,
amides and salts thereof. The 7,8-dihydro and 5,6-dihydro congeners
as well as etretinate are also acceptable for the invention.
[0029] Compounds that intrinsically or upon metabolism possess the
physiologic properties of retinoids are also included within the
scope of this invention. These would include synthetic and natural
retinoid compounds having affinity to nuclear retinoic acid
receptors (RARs) and retinoid X receptors (RXRs).
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] The advantages and features of the present invention will be
better understood by the following description when considered in
conjunction with the accompanying drawings in which:
[0031] FIG. 1 is an implantable device in accordance with the one
embodiment of the present invention, specifically a retinal plug,
for providing local delivery to the intraocular tissues of a
therapeutic agent;
[0032] FIG. 2 is a diagram showing the positioning of the retinal
plug shown in FIG. 1 in an eye through the sclera and pars
plana;
[0033] FIG. 3 is a perspective view of an alternative embodiment in
accordance with the present invention, specifically a surgically
implantable prosthesis such as a cardiac valve component coated
with a film of retinoid;
[0034] FIG. 4 is a perspective view of a stent coated with a film
of retinoid;
[0035] FIG. 5 is a cross section view of a stud implant coated with
a film of retinoid;
[0036] FIG. 6 in a side view of a joint prosthesis incorporating a
retinoid in accordance with the present invention;
[0037] FIG. 7 is a drawing showing the encapsulation of a placebo
plug 28 days after insertion into the vitreous through sclera. The
plug is comprised of polylactic acid. The plug disappears during
the processing of the eye (A). The tissues surrounding the plug
were stained with PAS and show a fibrous capsule surrounding the
area (B) where the placebo was previously located. The capsule that
surrounded the polylactic acid plug shows a very prominent
inflammatory response with inflammatory cell infiltration (C);
and
[0038] FIG. 8 is a drawing showing the encapsulation of a retinoid
containing plug 28 days after insertion. The polylactic acid plug
contained 10% by weight of the retinoid 6-[(4,4-dimethyl
thiochroman-6-yl)ethynyl]nicotinic acid (AGN 190299). The plug
disappears in the processing of the eye (A). The tissues
surrounding the retinoid containing plug were stained with PAS. The
figure shows that the capsule surrounding the AGN190299 plug (B)
has very little fibrous inflammation (C).
DETAILED DESCRIPTION
[0039] Turning to FIGS. 1 and 2, there is shown an implantable
device 10 for providing systemic release of a therapeutic agent in
tissue. Device 10 is representative of a great number of devices
for systemic release of a therapeutic agent. This specific
embodiment 10 is a sterile, bioerodible plug for the intraocular
delivery of pharmaceutically active compounds. Placement of the
device 10 is illustrated in FIG. 2 as it may be inserted into an
eye 12 specifically, the sclera 14 proximate the lens 16 and iris
18 for release of the drug into the sclera, choroid, retina and
vitreous cavity. By way of example, the retinal plug, or device,
10, may have a weight of about 0.5 to about 10 milligrams, have a
diameter of about 0.5 and about 2 millimeters and a length of
between one and 12 millimeters. A hole 20 through a proximal end 22
of the device 10 enables a suture 24 to be used for securing the
device 10, as shown in FIG. 2, with a distal end 26 thereof
protruding into a vitreous cavity 30.
[0040] Any suitable therapeutic agent may be utilized. The
diversity of therapeutic agents that can be delivered by the
present invention is great and known to those skilled in the art.
Examples include but are not limited to antibiotics, antifungals
and antivirals such as erythromycin, tetracycline, aminoglycosides,
cephalosporins, quinolones, penicillins, sulfonamides,
ketoconazole, miconazole, acyclovir, ganciclovir, azidothymidine,
interferon; anticonvulsants such as phenyloin and valproic acid;
antidepressants such as amitriptyline and trazodone;
antiparkinsonism drugs; cardiovascular agents such as calcium
channel blockers, antiarythmics, beta blockers; antineoplastics
such as cisplatin and methotrexate, corticosteroids such as
dexamethasone, hydrocortisone, prednisolone, and triamcinolone;
NSAIDs such as ibuprofen, salicylates indomethacin, piroxicam;
Hormones such as progesterone, estrogen, testosterone; growth
factors; carbonic anhydrase inhibitors such as acetazolamide;
prostaglandins; antiangiogenic agents; neuroprotectants; other
drugs known to those skilled in the art to benefit from controlled
or sustained release from implantable devices or combinations
thereof.
[0041] These active agents may be incorporated into a bioerodible
polymer such as a poly ester, poly (ortho ester), poly
(phosphazine), poly (phosphate ester), poly-caprolactone, poly
(hydroxybutyric acid), natural polymer such as gelatin or collagen,
or a polymeric blend. In addition, the present invention may also
improve the biocompatibility of non-erodible polymeric
implants.
[0042] Importantly, a retinoid is incorporated into the device 10
for improving the biocompatibility thereof. All of the components
of the device 10 are extruded as a homogeneous system in the shape
of a plug.
[0043] The device 10 may be optimized to resist sclera and
choroidal erosion in order to prevent disintegration or
fragmentation of the plug 10 into the vitreous cavity 30. This may
be accomplished, as is well known in the art, by altering the
surface, finish of the plug 10, coating the plug with another
biodegradable semipermeable polymer, or the addition of another
polymer to the blend. Because the plug is a homogeneous system,
ease of manufacture is provided through simple extrusion techniques
or injection molding.
[0044] The mechanism and rate of drug release may be controlled by
the choice polymer, polymer molecular weight, polymer
crystallinity, copolymer ratios, processing conditions, surface
finish, geometry, excipient addition, and polymeric coatings, with
the drug being released from the device 10 by diffusion, erosion,
dissolution or osmosis.
[0045] The fabrication of various sclera plugs and the mechanism of
controlling the drug release is well known in the art as set forth
in numerous publications such as, for example, "Sclera Plug of
Biodegradable Polymers for Controlling Drug Release in Vitreous",
Mototane Hashizoe, Archopthalmol/Volume 112, page 1380-1384,
October, 1994; "VA New Vitreal Drug Delivery Systems Using an
Implantable Biodegradable Polymeric Device", Hideya Kimura et al,
Investigative Opthalmology and Visual Science, Volume 35, page
2815-2819, May, 1994, and U.S. Pat. No. 5,466,233, all of which are
incorporated herein in their entirety for the purpose of describing
sclera plug manufacture, use and mechanisms.
[0046] All of the active ingredients utilized in the plug device 10
are present in a therapeutic effective amount which is calculated
to achieve and maintain a therapeutic level in the vitreous cavity
and introduced by the vitreous plug. Naturally, the therapeutic
amount will vary with the potency of the active agent, the rate of
release by the plug device 10.
[0047] The amount of incorporated retinoid will depend on the
potency and receptor selectivity of the retinoid employed as well
as the release rate of the retinoid from the specific implant.
Typically, the amount of retinoid employed represents 0.001% to
50%, more typically from 0.01 to 20% Retinoic acid receptor
agonists have been utilized for preventing proliferation of retinal
pigment epithelium, see copending U.S. patent application Ser. No.
08/383,741, entitled "Method of Preventing Proliferation of Retinal
Pigment of Epithelium by Retinoic Acid Receptor Agonists", filed in
the name of Campochiaro and is to be incorporated herewith in its
entirety for describing the use of retinoic acid activity in the
vitreous cavity 30.
[0048] Importantly, it has been discovered that the use of
retinoids can improve the biocompatibility of the device 10 in
tissue. While the retinoid may be incorporated into the device as a
component of the homogeneous mass, as hereinabove described in
connection with the plug device 10, the retinoid may also be used
to advantage for improving biocompatibility when disposed as a film
40 on an implanted device 42 as shown in FIG. 3. The device 42 is a
component for a cardiac valve as is described in U.S. Pat. No.
5,370,684 which is to be incorporated herewith in its entirety in
describing typical implantable devices 42 suitable in combination
with the retinoid for improving biocompatibility thereof. In
addition, this patent is to be incorporated herein by the specific
reference thereto for the purpose of coating or embedding
techniques suitable for bonding the retinoid to the surface 44 of
the implant 42.
[0049] When applied as a film 40 or imbedded into a surface 44 of
the implant 42, the retinoid may be incorporated in amounts
depending on the potency and receptor selectivity of the retinoid
employed as well as the release rate of the retinoid from the
specific implant.
[0050] With reference to FIG. 4 there is shown an endovascular
stent 80 comprising a single helically wound strand 82 and a pair
of counter-wound filaments 84, 86. Coatings 90,92,96 respectively
disposed on the strand 82 and filaments 84, 86 improves the
biocompatibility of the stent 80 as hereinabove described in
connection with the implant 42 shown in FIG. 3. Alternatively, the
retinoid may be embedded into the strand 82 and filaments 84,
86.
[0051] The stent 80 may provide delivery of therapeutic and other
substances to a location within a patients' vascular system. (not
shown)
[0052] The endovascular stent comprises a tubular structure having
an initial diameter and being expandable from the initial diameter
to an enlarged diameter. The filaments 84, 86, providing a delivery
matrix, are interlaced with the tubular structure and expandable
therewith from the initial diameter to the enlarged diameter. A
bioactive substance is releasably contained within the filament 84,
86 of the delivery matrix, and is released from said matrix when
exposed to the conditions present in the vascular system.
[0053] The tubular structure may be composed of an elastic
material, such as an elastomer polymer, whereby the tubular
structure may be initially constrained to set initial diameter and
thereafter released to said enlarged diameter, Alternatively, the
tubular structure could be composed of a non-plastic material,
whereby the tubular structure may be expanded from the initial
diameter to the typically using a balloon dilatation catheter.
[0054] The various specific designs for the tubular structure
exist, including a helical structure where the filament of the
delivery matrix is counter woven with a helical strand of the
tubular structure, a helical structure where the filament is
laminated to a helically wound strand of the tubular structure, and
a perforated cylinder where the filament of the delivery matrixes
interwoven through perforations in the cylinder.
[0055] The filaments 84,86 of the delivery matrix may be porous and
substantially non-erodible, where the bioactive substance is
absorbed or impregnated therein and released over time.
Alternatively, the filament will be composed of the material which
is erodible within the vascular environment, where the bioactive
substance is contained or dispersed in the filament and released as
the filament material erodes. When an erodible material is used,
the retinoid in incorporated therein as hereinabove described.
[0056] With reference to FIG. 5 there is shown in sectional side
elevation, a surgical implant kit 100 including a stud 102 disposed
within a hole 104 drilled into a bone 106 with a pin 108 driven
into a passage 110 through the stud 102. A retinoid coating 114
provides biocompatibility as hereinabove discussed.
[0057] Turning to FIG. 6, there is shown a joint prosthesis 120
including a fibrous spacer 122 held in position between bones
126,128 to be joined by rigid fixation pins 130,132.
[0058] The spacer 122 may include a biodegradable polymer,
co-polymermixture and/or composite such as described in U.S. Pat.
No. 6,007,580 and including a retinoid as herein described to
improve biocompatibility.
[0059] Typically, the amount of retinoid employed represents 0.001%
to 50%, more typically from 0.01 to 20%.
[0060] The retinoid may be either naturally occurring or a
synthetic retinoid such as a retinoic acid receptor (RAR)
agonist.
[0061] Naturally occurring retinoids suitable for use in the
present invention includes naturally occurring retinoids such as
Vitamin A (retinol), Vitamin A aldehyde (retinal), Vitamin A acid
(retinoic acid) and their synthetic and natural congeners. These
would include but not be limited to the isomers all trans; 9-cis;
11-cis; 13-cis; 9,11-dicis, and 11,13-dicis as well as
physiologically compatible ethers, esters, amides and salts
thereof. the 7,8-dihydro and 5,6-dihydro congeners as well as
etretinate are also acceptable for the invention.
[0062] Compounds that intrinsically or upon metabolism possess the
physiologic properties of retinoids are also included within the
scope of this invention. These would include synthetic and natural
retinoid compounds having affinity to nuclear retinoic acid
receptors (RARs) and retinoid X receptors (RXRs).
[0063] Other synthetically prepared retinoids are also well known
in the art. For example, see U.S. Pat. No. 5,234,926 which is
incorporated here by reference thereto in its entirety which
discloses methods of synthesizing disubstituted acetylenes bearing
heteroaeromatic and heterobicyclic groups with a selective activity
as RAR agonists. U.S. Pat. No. 4,326,055 is incorporated herewith
by reference thereto in its entirety for disclosing methods for
synthesizing 5,6,7,8-tetrahydro naphthal and indanyl stilbene
derivatives with retinoid-like activity.
[0064] Examples of synthetic agonists suitable for use in the
practice of this invention are ethyl
6-[2-(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate (Compound
168) and 6-[2-(4,4-dimethylchroman-6-yl)ethynyl]nicotinic acid
(Compound 299), whose synthesis is disclosed in U.S. Pat. No.
5,234,926 as Examples 6 and 24, respectively; and
p-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)propenyl]-ben-
zoic acid (Compound 183), whose synthesis is disclosed in U.S. Pat.
Nos. 4,326,055, and
2-[(E)-2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthaleen-2-yl)propen-
-1-yl]thiophene-4-carboxylic acid (Compound 701), whose synthesis
is disclosed in U.S. Pat. No. 5,324,840, Example 11.
[0065] Alternatively, the sclera plug 10, while being generally
homogeneous, may include a film 50 of retinoid thereon in order to
improve biocompatibility in a manner similar to the improved
biocompatibility of a non-bioerodible device 42 such as shown in
FIG. 3.
[0066] Accompanying the hereinabove described devices is a method
in accordance with the present invention for improving the
biocompatibility of an implant in tissue which includes the step of
providing a therapeutic agent, providing a carrier sized for
insertion into the tissue in which the release of a therapeutic
agent is desired, incorporating the therapeutic agent into a
carrier in a manner enabling the time released of the therapeutic
agent and incorporating the retinoid into the carrier in an amount
effective for improving the biocompatibility of a carrier in the
tissue. This method, of course, corresponds to the device 10 shown
in FIGS. 1 and 2.
[0067] Correspondingly, a method in accordance with the present
invention relating to the device 42 shown in FIG. 3 include
combining the retinoid 40 with the prosthesis 42. This method may
include the deposition of a film 40 on the prosthesis 42 or
imbedding the retinoid into surface 44 of the prosthesis. All of
the hereinabove recited retinoids may be used in accordance with
the method of the present invention.
[0068] The following example illustrates the effectiveness of the
method and devices of the present invention. It should be
appreciated that the example is set forth herein for the purpose of
illustration only and is not to be regarded as limiting to any of
the specific materials or methods disclosed.
EXAMPLE 1
[0069] An implantable device 10 was prepared as follows:
[0070] Retinal plugs were manufactured from poly(D,L)lactic acid
(PLA) with an intrinsic viscosity of 0.6 DL/G. The retinoid
6-[(4,4-dimethyl thiochroman-6-yl)ethynl]nicotinic acid (AGN190299)
was mixed with polymer in a three-dimensional mixer. The mixture
was then extruded at 85.degree. C. into a homogeneous rod. The
retinoid was incorporated into the polymeric plug at a
concentration of 10%. The extruded plug was then cut to a length of
3.0 mm and had a diameter of 1.5 mm. A 0.5 mm hole was drilled into
the distal end of the plug to allow for suture fixation to the
sclera. Placebo plugs containing no retinoid were also manufactured
to the same dimensions. The average weight of the plugs was 8 mg.
All plugs were sterilized by gamma irradiation at l Mrad.
[0071] The plugs were then implanted into pigmented rabbits as
shown in FIG. 2. The rabbit eyes were vitrectomized and the retinal
plugs with or without incorporated retinoid were inserted through a
sclerotomy 3 mm posterior to the corneoscleral limbus. The plugs
were then fixated with the suture used to close the sclerotomy. An
intravitreal injection of 500,000 human RPE cells was given to
simulate traction retinal detachment. The rabbits were sacrificed
at 28 days and histopathology was done.
[0072] These observed results are shown in FIG. 7 for the placebo
plug and in FIG. 8 for the plug 10 including the retinoid as
hereinabove described.
[0073] FIG. 7 is a drawing showing the encapsulation of a placebo
plug 28 days after insertion into the vitreous through the sclera.
The plug is comprised of polylactic acid. The plug disappears
during the processing of the eye (A). The tissues surrounding the
plug were stained with PAS and show a fibrous capsule surrounding
the area (B) where the placebo was previously located. The capsule
that surrounded the polylactic acid plug shows a very prominent
inflammatory response with inflammatory cell infiltration (C).
[0074] FIG. 8 is a drawing showing the encapsulation of a retinoid
containing plug 28 days after insertion. The polylactic acid plug
contain 10% by weight of the retinoid 6-[(4,4-dimethyl
thiochroman-6-yl)ethynyl]nicotinic acid (AGN190299). The plug
disappears in the processing of the eye (A). The tissues
surrounding the retinoid containing plug were stained with PAS. The
figure shows that the capsule surrounding the AGN190299 plug (B)
has very little fibrous inflammation (C).
[0075] Although there has been hereinabove described a particular
arrangement of implantable devices and methods in accordance with
the present invention, for the purpose of illustrating the manner
in which the invention may be used to advantage, it should be
appreciated that the invention is not limited thereto. Accordingly,
any and all modifications, variations or equivalent arrangements
which may occur to those skilled in the art, should be considered
to be within the scope of the present invention as defined in the
appended claims.
* * * * *