Note: Descriptions are shown in the official language in which they were submitted.
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203-396 (1?69)
nIOA13SORI~BI,E l~LENDS Ol; A ~IOAl~SORBA13Ll:
COPOLYMER AND A rOLY(O~YYALl~YLEl~E)
I;IE:LD Oli TIIE INVr,NT~ON
This invention relates generally to novel bioabsorbable compositions.
More particularly, this invention relates to new bioabsorbable polymer blends useful
for coating medical devices.
~J~CKGROIJN~ O~ TIII~ INYI;,NTION
Bioabsorbable coa~ings are applied to a wide range of medical devices
for a variety of reasons. The natllre of the medical device used as the substrate for
the coating wilt normally determine which particular characteristics are desired in the
coating. For example, implantable porous prostheses for use as bone or other hard
tissue replacements are usually formecl from polymeric beads or parlic]es having a
biologically compatible, hydropllilic coating. The hydrophilic coating on the particles
facilitates infllsioll of body fluids into the pores of the implant, ~hereby faci1itating the
ingrowth of tissue into the pores of the implant. Such prostheses are described in
U.S. Patent Nos. 4,728,570; 4,535,485; 4,547,327; and 4,536,158.
As another example, synthetic vascular grafts made from tubes of
fabric rnay be manufactured from yarns coated with a hydrophilic coating. In
addition, a surface of the fabric may be coated with an absorbable coating to
temporarily render the olllerwise porous fabric impervious to blood and~or other body
fluids. It is desirable that ~he fluids-occlllcling coa~ing exhibit sufrlcient elasticity to
accommodate the alternate elongation ancl contraction which llle tubular fabric
prothesis llndergoes when implanted in the body. Such tubular fabric protheses are
described in U.S. Palelll No. 4,990,158.
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In certain applications, a medical device may advantageously include a
hydrophobic coating. ~Iydropl~obic coatings provi~le desirable handling
characteristics, allowing easy and accurate positioning of the device, better holding of
knots, and decreased slipping in the gloved hands of surgeons. Additional1y, medicat
devices with hydrophobic coatings may provide improved tissue retaining properties,
for example, where it is desired to hold tissue together.
Copolymers of glycolide and trimethylene carbonate (also referred to as
1,3-dioxan-2-one) have been used to fabricate bioabsorbable medical devices or
surgical articles. See for example, U.S. Patent Nos. 4,243,775; ~,300,565;
4,429,030; 4,633,873; and 4,719,917. ~dditionally, glycolide-trimethylene carbonate
(GTMC) polymers have been applied to sutures and other surgical articles as a
bioabsorbable coating. Sce U.S. Patent Nos. 4,705,820 and 4,7~8,979. GTMC
polymers have also been formed into filaments and braided witll non-absorbable
components (see U.S. Patent No. 4,792,336) and used to coat or encapsulate a woven
mesh or other textile structllres formed by filaments of non~absorbable polymers (see
Europem Patent ~pplication No. 0334046).
U.S. Patent No. 4,452,973 describes poly(glycolic
acid)/poly(oxyalkylene) AB~ triblock copolymers useflll as absorbable sutures.
SUMMAR~ OF T~TE INVENTTON
It has now been found tllat blends of poly(oxyalkylene) with a
bioabsorbable copolymer having soft segments are llseful as bioabsorbable
compositions, sucll as, for example bioabsorbable coatings for medical drvices.
Tllese blends provide coatings wllicl- have good elastic, durability and llydropllilic
and/or hydrophobic properties as required ror a particular end use. The soft segments
of the copolymer may be forrned by incorporating into tlle copolymer a monomer
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selected from the group consisting of trimethylene carbonate, dioxanone,
caprolactone, a]ky]ene oxalates, hytiroxybutyrates, esteramides, hydroxyva]erates,
urcthanes, hexamethy]ene carbonate and mixtllres thereof. The blend optiona]]y
5 includes a medico-surgica]ly usefill substance, such as, for examp]e, an
antithrombogenic substance.
DESCRIPrlON Oli' PRr,lir,RRr,D r,MnODIMr,NTS
The compositions of the present invention comprise polymer blends
containing or physical mixtures Or: (a) a bioabsorbable copolymer having soft
segments; and (b) poly(oxyalkylene).
Bioabsorbable copolymers suitable for preparing the blends of this
invention contain onc or more comonomer which provide soft segments. ~or
example, soft segments may be incorporated into polymers of glycolide, lactide or
glycolide lactide copolymers by incorporatillg trimethylene carbonate as a comonomer
during polymerization. Other comonomers suitable for generating soft segments
include dioxanone, caprolactone, alkylene oxalates, hydroxyblltyrates, esteramides,
20 hydroxyvalerates, llrethanes, hexamethylene carbonate and mixtures thereof.
Trimethylene carbonate, dioxanone and caprolactone are the preferred comonomers.These comonomers may be present in an amount up to 75 mole percent, and
preferably between abollt 65 mole percent.
The bioabsorbable copolymer used in the present invention may be
formed by copolymerizing one or morc Or Ihe aforementioned sof~ segment
comonomers with one or more monomers known to produce a bioabsorbable polymer,
such as, for example, glycolide or lactide. ~referred bioabsorbable copolymer
include copolymers of glycolide and trimethylene carbonate.
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Glycolide-trimethylene carbonate copolymers employed in particularly
usefl11 ernbodiments of the present invenlion may contain up to about 50 mole percent
glycolide and llp to abollt 75 mole percent trimethylene carbonate. A preferred
5 copolymer is glycolide/trimethylene carbonate (GTMC) copolymer containing about
35 mole percent glycolide and about 65 mole percent trimethylene carbonate.
Polyoxyalkylenes usefill in this invention incl~lde those which are
hydrophilic in nature, such as, for example, polyethylene oxide, poly(oxyethylene- !
l O oxypropylene) copolymers and block copolymers of polyoxyethylene and
polyoxypropylene commercially available under the tradename Pluronic.
Hydrophobic polyethers may also be used in the present blends. Sllitable hydrophobic
polyethers include polypropylene oxide, polypentylene oxide and poly-1,4-butane diol.
Polyelhylene oxide tPEO) polymers suitable for llse in this invention
are commercially available in a wide variety of molecular weights. Preferred
polyethylene oxide polymers are those having a molecular weight from about 400 to
about 20,000. Most preferred is a polyetllylene oxide with a molecular weight of8000. Generally, as the amolmt of polyethylene oxide in the blend is increased, the
20 hydrophylicity of the blend will increase. The polymer blends may include
poly(oxyalkylene) in an amount up to about 50 percent based on the total weight of
the blend. Preferably, the blend will contain between abollt 10 and 20 percent
polyalkylene oxide based on the total weight of the blend.
The compositions of the present invention may be formulated to possess
a desired set of characteristics depending on the application in which tl~e compositions
are to be used. I~or example, the hydrophobic or hydropllilic natllre of the
composition may be adjusted by the choice of polyalkylene oxide or mixture of
polyalkylene oxides. ~ balancc of hydropllilic and hydropllobic characteristics are
achievable by thc compositions Or tl~e present inventiom ~s another examplc, the rate
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at which the composition bioabsorbs may be adjllsted by varying the amounts of
glycolide and trimethylene carbonate in the copolymer.
Otller components may be included in the compositions of this
5 invention sucll that tlle coating compositions are employed as a carrier for one or
more medico-surgically usefill subs~ances, e.g., those which accelerate or otherwise
beneficially modify the healing process ~vhen applied to a wound or surgical siie. In
general, any biologically active material which is sol~lble in and otherwise compatible
10 with the selected coating composition can be incorporated therein in therapeutically
useful annollnts. I~or example, a therape~ltic agent may be chosen for its antimicrobial
properties, capability for promoting wound repair and/or tissue growth or for specific
indica~ions sucll as thrombolysis. Antimicrobial agents such as broad spectmm
antibio~ics (gentamycin sulpllate, erytllromycin or derivatized glycopeptides) which are
slowly released in~o the ~issue can be applied in tl-is manner to aid in combating
clinical and sub-clinical infections in a surgical or trauma wound site. To promote
wound repair and/or tiss~le growth, one or several growtll promoting factors can be
added to the coating, e.g., fibroblast growth ractor, bone growth factor, epidermal
20 growth factor, plalelet derived growtll factor, macrophage derived growth factor,
alveolar derived growth factor, monocy~e derived growth factor, magainin, and soforth. Some therapeutic indications are: gTycerol with tissue or kidney plasminogen
activator to cause tllrombolysis, s~lperoxide dismlltase to scavenge tissue damaging
25 free radicals, tumor necrosis factor for cancer therapy or colony stimulating factor
and interferon, interlellkin-2 or otl1er Iymphokine to enhance the immune system.
Other examples Or materia]s whicll may be addetl to the blends of tllis invention
inclllde antitllroml)ogellic agents (sllch as heparin, hirlldin and prostaglandins),
30 pharmaco10gically iac~ive agents, anti-coagulants, osteogenic factors, anti-filngals,
imm~mosuppressive agcnts, anti-inrlamlllatory agents, preservatives, saccharides,
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diagnostic agents, antihistamines, hormones, enzymes, peptides ancltor steroids. The
amount of each additional component added ~ill depend on the particlllar nature of
the component and the purpose for aclding the component. Typically, however, thes amount of each optiona1 component will be below about 10% by weight of the toka
weight of the blend.
The phrase "total weight Or the blend" is intende(l to include ~he weight
of GTMC and poly(oxyalkylene) and any additional ingredients included in the blend,
10 but is intended to exclude the weight of the solvent, if any, employed in mixing or
applying the blend.
The preparation and application of the polymer blends of the present
invention may be accomplished by any suitable melhod which provides a substantially
homogenous mixture of the two principal polymer components (i.e., GTMC and
poly(oxyalkylene)). For example, tlle bioabsorbable copolymer and poly(oxyalkylene)
may be melt blended. Preferably, the components of the blends are dissolved in asolvent and mixed to providc a substantially homogenolls solution. Tlle solution is
applied to a substrate such as a medical device, and the solvent is removed, such as
20 for example, by evaporation.
More particul~rly, in forming the solution it is preferred to first
dissolve the GTMC polymer in just enougll solvent to dissolve the polymer with
stirring. Then the poly(oxyalkylene) is slowly added with continlled stirring. If
2~; necessary, adclitional amounts of solvent may be added to efrectuate complete
dissolving of the poly(oxyalkylene).
The compositions of this invention form absorbable rllms having good
durability, elastic and hydrophilic or hydropl1obic properties. They may be used for
30 surface coating and/or encapsul;lting and may act to r~ll voids or interstices in medical
dcvices, sucll as, ror example, vascnlar grart ma~crials or beacls used to form
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orthopedic or dental implants. The coating composi~ions may be applied to
absorbable or non-absorbable substrates.
5 EXAMPLE
Corolvmcr rlcparation
A copolymer of glycolide and trimetl)ylene carbonate was prepared by
melt phase ring opening copolymerization of 28.42 grams (35 mole percent) glycolide
O and 46.41 grams (65 mole percent) trimelhylene carbonate in the presence of stannous
octoate (1.9 cc of .2 gms Or stannous octoate ~lissolved in 25 cc of ether) in an
appropriate reaction vessel at 1600C for 12 hollrs. After polymerization the vessel
was allowed to cool to room temperature. The polymer was then removed from the
vessel, dried in vacuum and kept dry until used.
I'olvmcr l~lcnd Prc~ar:ltio
22.5 grams of dried poly (glycolide-co-trimethylene carbonate) was
placed into a round bottom flask and dissolved in about 200 ml of methylene chloride.
20 Polyethylene oxide (2.5 gms; molecular weigllt 8000) was slowly adlled to this
solution wllile stirring. After complete addition of polyethylene oxide, stirring of the
mixture was conlinued for 16 hours. Arter tl-orougll mixing, the solution mixture was
poured into a dish and lhe excess solvent was evaporated. The thick film formed was
5 dried well under vacullm (24 hours at room temperature) and stored dry. The
resulting material contained 90% GTMC copolymer and 10% PEO.
Coatin~ Onto Yn.sclllar Grnrt Tul)cs
A polymcr blend was prepared as described above containing 20
percent polyethylene oxide based on tl-c total weight of lhe blend. A 5% sollltion of
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tlle blend in methylene chloridc was applied to a Iengtll of a vascular graft tube
having a diameter of 2-3 mm by dipping the tube into the solution and evaporating off
the solvent. The vascular graft tube was woven from filaments of both absorbable5 and non-absorbable materials; namely, filaments of poly(glycolide/lactide) andfilaments of Hytrel 5556 (an elastomer commercially available from E. I. duPont de
Nemours ~ Co., Delaware). Irt vitro tesling suggests that the blend of this Example
would begin to absorb in about 2-3 hollrs after implantation into a mammalian body.
It is not intended to limit the present invention to the specific
embodiments described above. It is recognized that changes may be made in the
coating compositions specifically described herein without departing from the scope
and teaching of the instant invention, and it is intended to encompass all other
embodiments, alternatives an(l modifilcalions consistent with the invention.
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