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Patent 2092646 Summary

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(12) Patent Application: (11) CA 2092646
(54) English Title: BIOABSORBABLE BLENDS OF A BIOABSORBABLE COPOLYMER AND A POLY(OXYALKYLENE)
(54) French Title: MELANGES BIOABSORBABLES D'UN COPOLYMERE BIOABSORBABLE ET D'UN POLY(OXYALKYLENE)
Status: Dead
Bibliographic Data
(51) International Patent Classification (IPC):
  • C08L 71/02 (2006.01)
  • A61L 27/00 (2006.01)
  • A61L 27/26 (2006.01)
  • A61L 27/34 (2006.01)
  • A61L 33/00 (2006.01)
  • C08L 67/04 (2006.01)
  • C08L 69/00 (2006.01)
  • C08L 101/00 (2006.01)
  • C09D 169/00 (2006.01)
(72) Inventors :
  • MUTH, ROSS R. (United States of America)
  • TOTAKURA, NAGABHUSHANAM (United States of America)
(73) Owners :
  • UNITED STATES SURGICAL CORPORATION (United States of America)
(71) Applicants :
(74) Agent: OSLER, HOSKIN & HARCOURT LLP
(74) Associate agent:
(45) Issued:
(22) Filed Date: 1993-03-12
(41) Open to Public Inspection: 1993-09-26
Availability of licence: N/A
(25) Language of filing: English

Patent Cooperation Treaty (PCT): No

(30) Application Priority Data:
Application No. Country/Territory Date
07/857,616 United States of America 1992-03-25

Abstracts

English Abstract






ABSTRACT
Bioabsorbable compositions useful for coating medical devices include a
blend or physical mixture of a poly(oxyalkylene), such as polyethylene oxide, and a
bioabsorbable copolymer having soft segments, such as glycolide-trimethylene
carbonate copolymer.


Claims

Note: Claims are shown in the official language in which they were submitted.



-9-


THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:




1. A bioabsorbable composition comprising a mixture of:
a bioabsorbable copolymer having soft segments; and
a poly(oxyalkylene).

2. A composition according to claim 1 wherein said soft segments
are provided in said copolymer by one or more comonomers selected from the groupconsisting of trimethlylene carbonate, dioxanone, coprolactones, alky1ene oxylates,
hydroxybutyrates, esteramides, hydroxyvalerates, urethanes, hexamethylene
carbonate, and mixtures thereof.

3. A composition according to claim 1 wherein said soft segment
comonomer is present in said copolymer in an amount of up to about 75 mole %.

4. A composition according to claim 1 wherein said soft segment
comonomer is present in said copolymer in an amount of about 65%.

5. A composition according to claim 1 wherein said
poly(oxyalkylene) is present in the mixture in an amount less than about 30 percent
based on the weight of the total mixture.

6. A composition according to claim 2 wherein said copolymer
comprises one or more monomers selected from the group consisting of glycolide and
lactide.





- 10 -


7. A composition according to claim 1 further comprising an
effective amount of a medico-surgically useful substance.

8. A composition according to claim 1 wherein said medico-
surgically useful substance is an antithrombogenic agent.

9. A composition according to claim 8 wherein said
antithrombogenic agent is selected from the group consisting of heparin, hirudin and
prostaglandins.

10. A bioabsorbable composition comprising a mixture of:
a copolymer of glycolide and trimethylene carbonate; and
a poly(oxyalkylene).

11. A composition according to claim 10 wherein said
poly(oxyalkylene) is present in the mixture in an amount less than about 30 percent
based on the weight of the total mixtures.

12. A composition according to claim 10 wherein the copolymer
comprises:
glycolide in an amount up to about 50 mole percent; and
trimethylene carbonate in an amount up to about 75 mole
percent.



-11-


13. A composition according to claim 10 wherein said copolymer
comprises about 35 mole percent glycolide and about 65 percent mole trimethylenecarbonate.

14. A composition according to claim 10 wherein said
poly(oxyalkylene) is present in an amount from about 10 percent to about 20 percent
based on the weight of the mixture.

15. A composition according to claim 10 wherein said
poly(oxyalkylene) is selected from the group consisting of polyethylene oxide,
polypropylene oxide, poly(oxyethylene-oxypropylene) copolymers, polypentylene
oxide, poly-1,4-butane diol and block copolymers of polyoxyethylene and
polyoxypropylene.

16. A composition as in claim 10 wherein said poly(oxyalkylene) is
polyethylene oxide.

17. A composition as in claim 16 wherein said polyethylene oxide is
present in an amount less than 30 percent based on the weight of the mixture.

18. A method of coating a medical device comprising applying to
the device a blend of a poly(oxyalkylene) and a bioabsorbable copolymer having soft
segments.

19. A method as in claim 18 wherein said soft segments are
provided in said copolymer by polymerizing one or more comonomers selected from



- 12 -


the group consisting of trimethylene carbonate, dioxanone, caprolactone, alkylene
oxalates, hydroxybutyrates, esteramides, hydroxyvalerates, urethanes, hexamethylene
carbonate and mixtures thereof with one or more monomers selected from the groupconsisting of glycolide and lactide.

20. A method according to claim 18 wherein said poly(oxyalkylene)
is present in the blend in an amount less than about 30 percent based on the total
weight of the blend.

21. A method according to claim 18 wherein poly(oxyalkylene) is
present in the blend in an amount from about 10 to about 20 percent based on thetotal weight of the blend.

22. A method according to claim 18 wherein the copolymer
comprises glycolide in an amount up to about 50 mole percent and trimethylene
carbonate in an amount up to about 75 mole percent.

23. A method according to claim 18 wherein the copolymer
comprises about 35 mole percent glycolide and about 55 mole percent trimethylenecarbonate.

24. A method according to claim 18 wherein the step of applying
said blend comprises:
preparing a solution by dissolving a poly(oxyalkylene) and a
said copolymer in a solvent;
applying said solution to the medical device; and




- 13 -


removing said solvent.

25. A method according to claim 18 wherein said poly(oxyalkylene)
is selected from the group consisting of polyethylene oxide, polypropylene oxide;
poly(oxyethylene-oxypropylene), copolymers, polypentylene oxide, poly-1,4-butanediol and block copolymers of polyoxyethylene and polyoxypropylene.

26. A method as in claim 18 wherein said blend further comprises
an effective amount of a medico-surgically useful substance.

27. A method as in claim 26 wherein said medico-surgically useful
substance is an antithrombogenic agent.

28. A method of coating a medical device comprising applying a
blend of a poly(oxyalkylene) and a copolymer of glycolide and trimethylene carbonate
to at least a portion of the medical device.

29. A method according to claim 28 wherein said poly(oxyalkylene)
is present in the blend in an amount less than about 30 percent based on the total
weight of the blend.

30. A method according to claim 28 wherein poly(oxyalkylene) is
present in the blend in an amount from about 10 to about 20 percent based on thetotal weight of the blend.

Description

Note: Descriptions are shown in the official language in which they were submitted.


2~92~46




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.

2092~6




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




; . -, , .
.
-
- . - -

2~9~




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.




., ;~ ~ '-: ',

2~926~




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
.


.

2~2~




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,


.: ~

2~92~ ~




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




.

- . , ...
. . . .. .

2 ~ 9 2 6 ~ ~




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




. ~ . . .
- .- - , -. :

2~.~2~



- 8 -


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.




. , : ~ , : ,

; ~ . :

Representative Drawing

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Administrative Status

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Administrative Status

Title Date
Forecasted Issue Date Unavailable
(22) Filed 1993-03-12
(41) Open to Public Inspection 1993-09-26
Dead Application 1995-09-12

Abandonment History

There is no abandonment history.

Payment History

Fee Type Anniversary Year Due Date Amount Paid Paid Date
Application Fee $0.00 1993-03-12
Registration of a document - section 124 $0.00 1993-09-21
Owners on Record

Note: Records showing the ownership history in alphabetical order.

Current Owners on Record
UNITED STATES SURGICAL CORPORATION
Past Owners on Record
MUTH, ROSS R.
TOTAKURA, NAGABHUSHANAM
Past Owners that do not appear in the "Owners on Record" listing will appear in other documentation within the application.
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Document
Description 
Date
(yyyy-mm-dd) 
Number of pages   Size of Image (KB) 
Cover Page 1993-09-26 1 23
Abstract 1993-09-26 1 10
Claims 1993-09-26 5 142
Drawings 1993-09-26 1 13
Description 1993-09-26 8 329