Note: Descriptions are shown in the official language in which they were submitted.
--1--
s ~=:~
Ba~r
1. Field of Invention
__ _
This invention relates to synthetic surgical devices hav-
ing improved properties made from copolymers of glycolide
and ~-caprolactone and, more particularly, to oriented
filaments and sutures prepared from such polymers and to
me~hods of manufacturing such polymers.
2. Descri tion of the Prior Art
P _ . ____
Homopolymers and copolymers of lactide and glycolide are
well known in the preparation of synthetic absorbable
sutures as disclosed, for example, in U.S. Patent Nos.
3,636,956; 2,703,316; 3,468,853; 3,865,869, and 4,137,9~1.
Also, in V.S. Patent No. 3,867,190, it is known to include
certain cylic comonomers with glycolide including ~-
caprolactone. In fact, the use of cylic ester monomers in
the ormation of polyesters for the fabrication of synthe-
tic surgical articles is well known in the art. The
conventional polymerization method of forming polymers of
the cylic esters is through ring opening polymerization.
In U.S. Patent 4,300,565, there is disclosed surgical
articles fabricated from synthetic absorbable copolymers
formed by copolymerizing glycolide with a cylic ester
monomer in a specific manner. Hence, it should be
appreciated that broadly copolymers of -caprolactone and
other cyclic esters, such as lactide or glycolide, are
well known and described in the art as well as are various
methods for their production.
rll~ss6
The synthetic absorbable sutures have gained considerable
acceptance in the surgical field; however, the "handle-
abilityU or the compliance; i.e., flexibility and "limp-
ness", has no~ al~ays been considered satisfac~ory in
monofilament configurations. It is believed that monofil-
ament constructions are more suitable for surgical uses
than the multifilament or braided configurations as they
tend to produce less infection and trauma at the wound
closure site. However, the monofilaments tend to be
stiffer and harder to handle than ~he braided configura-
tion of the same diameter. Over the years, various
polymer combinations have been tried in an attempt to
obtain the desired very delicate interplay between the
properties of suture absorbability, in vlvo strength
lS retention, initial knot strength, and high compliance or
low modulus. These desired properties, other than
absorbability~ are obtained in some suture materials; for
example, in thoQe describecl in Ca~dian Patent ~o. 1 J 141,915
issued March 1, 1983 inventors Gertzman et al. The ~uture
materials described have the desired strengths, compliance
and flexibility but are not absorbable andl hence, are
limited in their use. To the best of our knowledge the
only synthetic, absorbable sutures which in some instances
may have the properties as described above are those made
from polydioxanone as described in U.S. Patent 4,052,988.
~ It should be appr~ciated, that to design molecular chains
needed for the production of highly compliant absorbable
materials, an obvious route is to copolymerize suitable
comonomers or mixtures of pre-polymers and monomers fol-
lowing procedures similar to those used in the formation
of compliant non-absorbable sutures. However, such is not
the case for those polymers are of the AA-BB non-
absorbable type. Furthermore, copolymerizing comonomers
of glycolide and ~-caprolactone following the teaching of
U.S. Paten~ No. 3,867,l90 which ~escribes the copolymers
1.
~3~ ~46~0
containing 15~ or less of the ~-caprolactone moieties does
not procduce compliant materials. Copolymers containiny
less than 15% caprolactone are random in nature and the
monofilaments made therefrom display high modulus and low
compliance. It is known that copolymers containing ].ess
than 85~ glycolide moieties with random microstructure do
not generally offer good fiber forming polymers because of
their improper level of crystallinity. Hence it wou]d be
expected that copolymers containing more than 15% capro-
lactone sequences would have poor crystallinity and bevirtually amorphous and unsuitable for the production of
strong monfil~ment suture materials.
Summary of the Invention
The present invention describes new copolymers containing
specific weight percents of epsilon (~)-caprolac~one and
specific weight percents of glycolide or a mixture of
glycolide and lactide. These new copolymers produce syn-
thetic absorbable surgical articles having new and novelproperties and produce filaments or suture materials
having desirable straight and knot tensile strengths,
controllable absorbability, suitable in vivo strengths
while unexpectedly displaying unique high compliance char-
acteristics and low modulus. In accordance with the pre-
sent invention, the new copolymers have a tensile strength
of at least 30,000 psi and a Young's modulus of less than
350,000 psi. When in filament form, sutures made from our
novel copolymers preferably have a tensile strength of at
30 least 50,000 psi and a Young's modulus oE Less than
250,000 psi. The novel copolymers of the present inven-
tion comprise from about 20 to 35 weight percent of F-
caprolactone and from 65 to 80 weight percent of glycolide
or mixtures of glycolide and lactide~ In preferred embod-
iments of the present invention, when mixtures of glyco-
lide and lactide are used, the mixture shoulcl contain les
Errll-55~;
--4--
than 20 percent by weight of L(-)lactid~e. The new copoly-
mers may be used as molded or shaped articles or they may
be fabricated into filaments and appropriate sutures by
techniques well known in the art and may have needles
attached to said suture as desired. The filaments may be
annealed to produce materials having tensile strengths of
at least 50,000 psi while maintaining a Young's modulus of
less than 250,000 psi. Our new copol~mers may be designed
to retain _ vivo strengths of at least 40 percent after
7 days while being completely absorbed in vivo in less
than 150 days. In certain embodi~ents of the present
invention the novel copolymers have inherent viscosities
of at least 0.8 dl/g as determined on a 0.1 g/dl solution
in hexafluoroisopropanol ~HFIP) at 25C. In certain
embodiments of the present invention, our novel copolymers
have a crystallinity of at least 5% and preferably at
least 10%o
Also in accordance with the presen~ invention, our novel
copolymers are produced by polymerizing a mixture of
glycolide and F-caprolactone in the presence of from about
0.004 to 0.02 weight percent of catalyst. The catalyst
may be a metal salt or oxider preferably a tin salt or
oxide as, for example, stannous octoate, dibutyltin oxide
and the like. The polymerization is carried out at a
temperature of below 250C. for a period of time suffi-
cient to produce a conversion of the monomers to polymer
of at least 80%. In other novel processes for producing
the copolymers of the present invention, a first step is
used to produce a low molecular weight copolymer of F-
caprolactone and glycolide. In the first step, the
copolymer should comprise at least 50~ by weight of
~-caprolactone to obtain an ~-caprolactone rich pre-
polymer. The first step is carried out at a temperature
of below 220C. and is followed by a second step wherein
additional glycolide is added to the pre-polymer. This
ET~l-556
--5--
additional mixture is polymerized at a temperature of
above 120C. for a period of time sufficient to produce a
conversion of at least 80%.
Polymers produced by the methods described above may be
readily extruded and drawn as is well known in the art to
produce oriented filamentary material. The oriented fila-
ments may be used with or without annealing to produce
sutures. Needles may be attached to the oriented fila-
ments to produce needled sutures. The sutures with orwithout needles may be sterilized by well known steriliza-
~ion techniques to produce new and novel sterile surgical
sutures. The polymers may also be fabricated by other
techniques such as injection moldiny and the like and then
sterilized by techniques well known in the art to produce
new and novel s~erile synthetic devices.
Detailed Descri~tion_of the Present Invention
In the following description and examples, all parts and
percentages are by weight unless otherwise specified.
The method of the present invention comprises either a
single stage or a two stage polymerization process. In
the single stage pol~nerization process, an essentially
random copolymer of glycolide monomer with ~-caprolactone
is produced. The polymerization is carried out in a con-
ventional manner using a polymeri2ation reactor equipped
with heating and stirring means. The polymerization is
carried out in the presence of rom about .00~ to .02
weight percent of a metal salt or metal oxide, preferably
dibutyltin oxide or stannous octoate. The poly~erization
i5 conducted with pure and dry reactants and under a dry
and inert atmosphere at temperatures sufficient to main-
tain the reaction mixture at a temperature close to themelting point of the polymer bein~ produced. The ~nount
~T~I-SS~
~%~
--6--
of ~-caprolactone should be sufficient so that in the
inal copolymer there will be Erom about 20 percent by
weight to 35 percent by weight of the ~-caprolactone moie-
ties. The amount of glycolide used should be su~ficient
so that in the final polymer there is from about 65 weight
percent to about 80 weight percent of t:he glycolide moie-
ties. The polymerization should be conducted for a time
sufficient to have a conversion of the r,lonomers to copoly-
mer of at least 80 percent and preferably more than 90
percent.
The following example describes a preferred copolymer of
the present invention as well as a preferred method for
producing the copolymer.
A flame dried 100 ml glass ampoule equipped with a Teflon-
coated magnetic spinbar is charged with 14.27 grams
20 (0.125 mole) of f-caprolactone, 43.53 grams (0.375 moles)
glycolide 0.0591 grams 1,6-hexanediol and a catalytic
amount of stannous octoate (0.25 ml of a 0.033 molar solu-
tion in toluene). The pressure in ~he ampoule is reduced
to evaporate the toluene. The ampoule is repeatedly
purged and vented with dry nitrogen and the pressure
adjusted with dry nitrogen to about 3/4 of an atmosphere.
The ampoule is sealed with a flame. The sealed ampoule is
immersed in a silicone oil bath preheated to 100C. This
temperature is maintained for 15 minutes, with stirring as
long as possible, and the temperature increased to 150C.
which is maintained for 15 minutes. The temperature is
raised to 190C. and the polymerization continued for
18 hours at 190C. The resultant copolymer is isolated,
chilled, ground, and dried under vacuum at room tempera-
ture. Some unreacted monomer is removed by heating thec3round copolymer under vacuum at 110C. or 16 hours.
r..~rll-ss6
-7~
Approximately 95 percent conversion of monomers to copoly-
mer is obtained. The resultant copolyrner comprises
23 percent by weight of ~-caprolactone moieties and
77 percent by weight glycolide moieties. The inherent
S viscosity of the resultant copolymer is lr 66 dl/g as
measured using a 0.1 g/dl solution in hexaflourisopropanol
(HFIP) at 25~C.
Example II
For comparison purposes, Example 6 described in U.S.
Patent 3,867,190 which describes a glycolide copolyrner
with 15 weight pecent ~-caprolactone is carried out.
A flame dried 100 ml glass ampoule equipped with a Teflon-
coated magnetic spinbar is charged under dry and oxygen
free conditions with 6.0 gram~ (0~053 mole) F-
caprolactone, 34.0 grams (0.293 mole) glycolide and
0.12 gram litharge. After repeated purging with nitrogen
the pressure is adjusted with nitrogen to about 3/4 of an
atrnosphere and the ampoule is flame sealed. The sealed
ampoule is ~mmersed in a silicone oil bath and heated to
145 to 150aC. The ampoule is maintained in this tempera-
ture range for 31 hours. The copolymer is isolated,
ground and dried under vacuum at room temperature. Some
unreacted monomer is removed by heating the ground copoly-
mer at reduced pressure at 110C. for 16 hours. The con-
version of monomers to copolymer is approximately 97 per-
cent. The resultant copolymer comprises 15 percent by
weight of ~-caprolactone moieties and 85 percent by weight
of glycolide moieties. The resultant copolymer is
practically insoluble in HFIP.
Attempts to extrude and draw the copolyrner to produce an
oriented filament are unsuccessful as the copolymer under-
~oe~s degr;ldation at the temperature required to obtain a
un~orm melt.
ET~556
.~ ~; * Trad~rnark
-8-
ple III
An attempt to make a suitable filament forming copolymer
in accordance with the teachings of U.S. Patent 3,867,190
using the amounts and types of catalyst in accordance with
the methods of the present invention is conducted.
A 1ame dried 100 ml glass ampoule equipped with a Teflon-
coated magnetic spinbar is charged under dry and oxygen-
10 free conditions with 6.0 grams (0.053 mole) ~-
caprolactone, 34.0 grams ~0.293 mole) glycolide, and
0.90 ml of a 0.33 molar stannous octoate in toluene solu-
tion. The pressure in the ampoule is reduced to remove
the toluene. After repeated purging and venting with
nitrogen the pressure is adjusted wi~h nitrogen ~o about
3/4 of an atmosphere and the a~spoule 1ame sealed. The
sealed ampoule is immersed in a ~ilicone oil bath and
heated to 145 to 150C. This temperature range is main-
tained for 31 hours. The copolymer is isolated, ground
2n and dried under vacuum at room temperature. Some unreac-
ted monomers are removed by heating the ground copolymer
at reduced pressure at 110C. or 16 hours. Approximately
97% conversion of mono~ers to copolymer is obtained. The
resultant copolymer comprises 15 percent by weight o F-
caprolactone moieties and 85 percent by weight of glyco-
lide moieties. The resultant copolymer is practically
insoluble in HFIP. The resultant copolymer is not extrud-
able and orientable so as to produce filament satisfactory
for producing sutures. On trying to extrude the resultant
cop~lymer it undergoes degradation at the temperature
range necessary to maintain a uniform melt.
In preferred embodiments o the single step method for
producing the copolymers of the present invention, it is
desired that about 22 percent to 32 percent by weight of
the ~-caprolactone moiety be ohtained in the final
po:Lymer .
~r~1 -556
- 9 -
As previously described, an alternate novel method for
producing the new copolymers of the present invention is
to initially form a low molecular weight pre-polymer of
F-caprolactone and glycolide. This pre-polymer is rich in
E~caprolactone, that is, it comprises at least 50 weight
percent of -caprolactone. The pre-polymer is produced at
tempera~ures below about 220C. Once the pre-polymer is
formed, additional glycolide or glycolide/caprolactone or
lactide mixture rich in glycolide is added to the pre-
polymer and the resultant mixture further polymerized attemperatures of from about 120C. to 250C. and preferably
from about 180C. to 240C. This two step polymeriæation
is carried out to a conversion of at least 85 percent.
The following is a specific example of ihis alternate
method for producing the novel copolymers of the present
invention.
A flame dried multineck glass reactor is charged under dry
and oxygen free conditions with 71.8 grams (0.629 mole) -
caprolactone, 31.3 ~rams (0.27 mole) glycolide, 0.0882
gra~ glycolic acid and 0.43 ml. o a 0.33 molar stannous
octoate in toluene solution. The reactor is outfitted
with an adapter with a hose connection and a dry mechani-
cal stirrer. The pressure in the reac~or is reduced and
the toluene removed. The reactor is purged and vented
with nitrogen which is maintained at a pressure of one
atmosphere for the remainder of the run. The reactor is
immersed in a silicone oil bath and heated to 120C. which
is maintained for 10 minutes. Over the course of 30
minutes ~he temperature is increased to 200C. which is
maintained or 20 minutes. The bath is allowed to cool to
L50C, the stirrer is stopped and the reactor withdrawn
from ttle bath. A smalL sample, about 0.2 grams, of the
ETII~5$6
- 1 0 -
reaction mass is withdrawn under a ~lanket of nitrogen.
The sample has an inherent viscosity of 0.51 dl~g. To the
reactor i5 added 45.6 grams (0.399 mole) ~-caprolactone
and 185.6 grams ~1.599 moles) glycolide. ~he reactor is
reintroduced into the silicone oil bath. The temperature
drops to 120C. which is maintained for 10 minutes while
providing good stirring. In the course of 15 minutes the
temperature is increased to 205C. which is maintained for
4 hours.
lU
The copolymer is isolated, ground~ and dried under vacuum
at room tempera~ure Some unreacted monomers are removed
by heating the ground copolymer at reduced pressure at
100C. to constant weight. A conversion of monomers to
copolymer of approximately 87% is obtained. The resultant
copolymer comprises 26 percent by weight of ~-caprolactone
moieties and 74 percent by weight of glycolide moieties.
The resultant copolymer has an inherent viscosity of
1.53 dl/g as measured using a 0.1 g/dl solution in HFIP at
25C.
Example V
The procedure of Example I is essentially followed as set
out in that example except that the ampoule is charged
with 17.1 grams ~0.150 mole) f-caprolactone, 40.6 grams
(0.350 mole) glycolide, 0.1182 gram (0.001 mole), 1,6-
hexanediol, and 0.25 ml. of a 0.033 molar stannous octoate
in toluene solution. The sealed ampoule is immersed in a
silicone oil bath preheated to 100C. This temperature is
maintained for 30 minutes with stirring as long as pos-
sible. In the course of 50 minutes the temperature is
raised to 190C which is maintained for 7 hours. The
percent conversion of monomers to copolymer is approx-
imately 90% and the resultant copolymer has an inherent
ET~1-556
viscosity of 1.24 dl/g as measured using a 0.1 g/dl solu-
tion in HFIP at 25C. The resultant copolymer comprises
23 percent by weight of E-caprolactone moieties.
Example VI
The procedure of Example I is followed as set out in that
example except that the ampoule is charged with 14.3 grams
(0.125 moles) -caprolactone, 43.5 grams (0.35 mole)
10 glycolide, 0.0591 gram (0.0005 mole) 1,6-hexanediol, and
0.51 ml. of an 0 033 molar stannous octoate in toluene.
The sealed ampoule is immersed in a silicone oil bath
preheated to 100C. That temperature is maintained for 15
minutes and then increased over the course of less than an
hour to 195C. which is maintained for 2 hours. The
copolymer is isolated, ground and dried under vacuum at
room temperature. Some unreacted ~onomer is removed by
heating the ground copolymer at reduced pressure at 110C~
for 16 hours. The conversion of monomers to copolymer is
approximately 90%. The resultant copolymer has an inher-
ent viscosity of 1.62 dl/g measured at 25C. at a 0.1 g/dl
concentration in HFIP. The resultant copolymer comprises
17 percent by weight of E-caprolactone moieties.
~
The procedure as set forth in Example IV is followed as
set forth therein except the reactor is charged with
22.8 yrams (0.200 mole) ~-caprolactone, 10 grams
30 (0.0862 mole) glycolide, 33.8 mg (0.286 mmole) 1,6-
hexanediol, and 0.216 ml. of a 0.33 molar stannous octoate
in toluene solution. The charged reactor is immersed in a
silicone oi1 bath and heated to 190C. over the course of
35 minutes. Heating is discontinued and the reactor in
35 the bath allowed to cool to 120C. over a period of 30
minutes, While maintaininy the temperature at 120C. and
RTII 556
~12-
under a nitrogen blanket 6.5 grams (0.G57 mole) ~-
caprolactone and 59.7 grams (0.514 mole) glycolicle is
added to the reactor. The reaction mass is maintained at
120C. for 40 minutes with good stirring. Over the course
S of 15 minutes the temperature is increased to 195C~ which
is maintained for 2 1/2 hours. The copolymer is isolated,
ground and dried under vacuum at room temperature. Some
unreacted monomers are removed by heating the ground co-
polymer at reduced pressure at 85C. for 16 hours. A
conversion of monomer to polymer of greater than 90~ is
obtained. The resultant copolymer has an inherent visco-
sity of 1.60 dl/g as measured during a 0.1 g/dl concentra-
tion in HFIP at 25C. The resultant copolymer comprises
26 percen~ by weight of f caprolactone moieties.
Example VIII
The procedure as set forth in Example VII is carried out
as set for~h therein with the exception that the reactor
20 is charged with 22.8 grams ~0.200 mole) f-caprolactone,
7.7 grams (0.066 mole) glycolide, 0.1182 gram (0.001 mole)
1,6-hexanediol and 0.25 ml. of .033 molar stannous octoate
in toluene solution. The initial polymerization is
carried out at 150C. and the reactor then further charged
25 with 27.1 grams (0.233 mole) glycolide. The polymeri~a-
tion is continued for approximately 2 1/2 hours at a tem-
perature of from 190C. to 205C. A percent conversion of
greater than 80% is attained. The resultant copolymer has
an inherent viscosity of 1.00 dl/g as measured using a
0.1 g/dl solution in HFIP at 25C. The resultant copoly-
mer contains 23 percent by weight of F-caprolactone
moieties.
ETl1-556
-13-
Exam~le IX
The procedure as set forth in Example VIIX i5 followed as
set forth therein except that 17.12 grams of F-
caprolac~one and 10.15 grams of glycolide are used ini-
tially, 30.47 grams of glycolide are added prior to the
second polymerization and the second pol~meri~ation is
carried ou~ at 205C. for 6 1/4 hours. A percent conver-
sion oE approximately 90% is attained. The resultant
copolymer has a viscosity o~ 1.23 dl/g as measured using a
0.1 g/dl solution in HFIP at 25C. The resultant copoly-
mer contains 22 percent by weight of ~-caprolactone
moietiesO
Example X
A series of experiments is run at various ratios of ~-
caprolac~one and glycolide as shown in the following
Table 1. A flame dried 100 ml glass ampoule equipped with
a Teflon-coated magnetic spinbar is charged with -
caprolactone and glycolide in the amounts shown in the
following table and 0.1182 gram 1,6-hexanediol and a
catalytic amount of stannous octoate (0.25 ml of a
0.033 molar solution in toluene). The pressure in the
ampoule is reduced to evaporate the toluene. After
repeated purging and venting with nitrogen the pressure is
adjusted with nitrogen to about 3/4 of an atmosphere and
the ampoule is flame sealed. The reactor is immersed in a
silicone oil bath preheated to 100C. This temperature is
maintained for 15 minu~es with stirring and then raised to
150C. This temperature is maintained for 15 minutes and
then raised to 190C. which is maintained for 18 hours.
This procedure is followed with examples a through h,
however, with example i, the temperature is raised to
205C. which is maintained for ?. hours. 'rhe bath is
E.TH-sr~6
-14- ~2246~
allowed to cool to 190C which is maintained for the final
heating period; the cooling period and final heating
period total 18 hours. The polymers from each example are
isolated, chilled and ground. The percent conversion and
inherent viscosity as measured using a 0.1 g/dl solution
in HFIP at 25C. for each copolymer are given i.n the
following Table 1.
ETH-556
a~
o~
0 ~r a~ ~ co ~ oo ~ 1~ u~
~ ~ -~ ~ ~ ~ ~ ~ ~
~ u
~ -~ ~
R R U~ co --
~) ~ ~1 ~1 o
S~ O O O --~ --I ~ '~
~ ~I
U~
,
H ::~
o
.,
dP a~
o
_l
a~
~ ~ t~
~ u~ ~r ~ ~r ~ ~ ~
E~ ~ Q)
--I "3 O O O C:~ O O O ~ O
o ~1 ~
O ~D ~ ~ ~ ~ ~ ~'3
u 0
U~ ~
_I er ~ o~ ~ ~ o r o o
a5 U 1~
^ C 1~ O U~ o ~ O Lr~ C~ O
U~ O ~ Il~ r-- o ~`I 1~ 1` It ) 1~
O O O ~ ~ ~1 ~ _I ~S
O
O ~ O O O O O O O O O
--1 ~_ _ _ _ _ _ _ _ _
- o
~1 ~r o
1 ~J
-16-
Example XI
A flame dried 100 ml. glass ampoule equipped with a
Teflon-coated magnetic spinbar is chargled with 22.8 grams
5 (00200 moles) -caprolactone, 34.8 grams ~0.300 moles)
glycolide, 0.1182 yrams (0.001 mole) 1,6-hexanediol, and
0.25 ml of a 0.033 mole stannous octoate in toluene
solution. The reactor is immersed in a silicone oil bath
preheated to 100C. This temperature is maintained for 15
minutes with stirring. The temperature is increased to
150C. and maintained for 30 minutes and then increased to
190C. which is maintained for 17 hours. The polymer is
isolated, ground and dried under vacuum at roo~ tempera-
ture. Some unreacted monomer is remove by heating the
15 ground polymer at reduced pressure at 110C. for 16 hours.
A conversion of monomer ~o polymer of better than 90% is
obtained. The resultant copolymer has an inherent visco-
sity of 1.39 dl/g in HFIP at 25 at a concentration of
0.1 g/dl~
In this example, the resultant copolymer contains about
37~ by weight of -caprolactone moieties and the resulting
copolymer is practically amorphous. It is unsuitable for
manufacturing dimensionally stable oriented filaments and
surgical sutures.
Example XII
A flame dried 100 ml ampoule equipped with a Teflon-coated
magnetic spinbar is charged with 11.41 g. of F-
caprolactone (0.4 mole), 0.0739 g. l,b-hexanediol
(0.625 m.mole), and a catalytic amount of stannous octoate
(0.25 ml. of an 0.033 molar solution in toluene). The
pressure in the ampoule is reduced to evaporate the
toluene. The ampoule is repeatedly purged and vented with
dry nitrogen and the pressure adjusted with dry nitrogen
ET~1~S56
-17-
to about 3/4 atmosphere. The ~mpoule is sealed with a
flame. The sealed ampoule is immersed in a silicone oil
bath preheated to 100C. This temperature is maintained
for 15 minutes r stirring when possible, and the tempera-
ture increased to 150C. and maintained for lS minutes.
The temperature is raised to 190C. and the polymeriæation
continues ror 18 hours at 190C. The resultant terpolymer
is isolated, chilled, ground, and dried under vacuum at
room temperature. Some unreacted monomer is removed by
heating the ground terpolymer under vacuum at 110C. for
16 hours; a weight loss of 2.8 percent is experienced.
The inherent viscosity of the resultant terpolymer is
1.48 dl/g. in. in 0.1 g/dl solution in hexafluoroisopro-
panol (HFIP) at 25C. The new synthetic absorbable
copolymers of the present invention may be converted to
oriented filament materials by techniques of extruding and
drawing well known in the art for producing filamentous
materials. The filaments may be sterilized with or
without attached needles to produce sterile surgical
sutures as is well-known in the art. A preferred
technique for extruding and drawing the copolymers of the
present invention is described in the following Example.
Exam~e XIII
The copolymer is melt spun in an Instron Rheometer at a
temperature at least 10C. above the melting temperature
of the copolymer. A 40 mil die with a L/D ratio of 24 is
used. A sheer rate of 213 sec~l is used for the extru-
sion~ The extrudate is taken up through ice water andwound on a spool. The wound fibers are stored at reduced
pressure for 2 to 24 hours. The monofilaments are
oriented by drawing in one or two stages. The drawn fila-
ments are heat set by heating at the desired temperature
E'rll-556
~22~
-18-
under constant strain with or without allowing for 5%
relaxation.
The filamentary materials are usually annealed as is well-
known in the art under conditions which improve suture
properties. The fllaments may be annealed under tension
at temperatures of rom about 50C. to 120C. for periods
of time of from 1 hour to 4~ hours. In preferred embodi-
ments we anneal our filament materials under tension at
10 temperatures of from 60C. to 110C. and at times from 4
to 16 hours.
The filament materials are tested for various physical
properties such as knot tensile strength, straight tensile
strength, elongation, and Young's modulus. The copolymers
also may be tested for inherent viscosity, melting
temperature and p~rcent crystallinity.
The following describes ~he various test methods used to
determine the properties of the filament materials and/or
the copolymers.
The characteristic properties of the filaments of the
present invention are readily determined by conventional
test procedures. The properties are determined using an
Instron tensile tester under the following conditions:
crosshead speed (XH) : 2 in/min
Chart speed (S) : 10 in/min
Sample length (~L) : 2 in
Scale load (SL) : 21 lbs/in.
Young's modulus is calculated from the slope of the
stress-strain curve of the sample in the initial lin~ar,
elastic region as follows:
ET~1-556
6~
--19--
Young's Modulus (psi) = tan~ x GL CS x SL
XH x XS
~ is the angle between the slope and the horizontal, XS is
the initial cross-sectional area of the fiber (in2), SL is
the scale load and XH, CS, and GL are as identified above.
The straight tensile strength is calculated by dividing
the force required to break (lbs) by the initial cross-
sectional area of the fiber (in2). The elongation tobreak is read directly from the stress-strain curve of the
sample allotting 10~ per inch of horizontal displacemen~.
The knot tensile strength of a filament is determined in
separate experiments. The test article is tied into a
surgeon's knot with one turn of the filament around flex-
ible tubing (1/4 inch inside diameter and 1/16 inch wall
thickness). The surgeon's knot is a square Xnot in which
the free end is first passed twice, instead of once,
through the loop and pulled taut, then passed once through
a second loop, and the ends drawn taut so that a single
knot is superimposed upon a compound knot. The first knot
is started with the left end over the right end and suf-
ficient tension is exerted to tie the knot securely. The
specimen is placed in the Instron tensile tester with the
knot approximately midway between the clamps. The knot
tensile strength is calculated by dividing the force
required to break (lbs) by the initial cross-sectional
area of the fiber (in2).
The temperature profile of a copolymer is determined using
a Differential Scanning Calorimeter (DSC) by first heating
the copolymer to its initiaL melting temperature (Tm
initial) ollowed by rapid cooling the melted samE)le. The
quenched coplymer i~ then reheated at a rate o~ 20C. per
ETM-556
-20-
minute and the glass transition temperature (Tg)l tem-
perature of crystallization (Tc) and me~lting temperature
(Tm) observed. The crystalliniky of the polymer as
reported is measured by X~ray diffraction techniques as
are well-known.
In all instances the inherent viscosity reported is
measured at 25C. at a concentration of 0.1 g/dl in
hexafluorispropyl alcohol (HFIP).
The composition of the final copolymer is determine by NMR
analysis.
The various copolymers produced in Examples I through XII
are measured for one or more of the following properties:
inherent viscosity, melting temperatures and percent
crystallinity. The results of these tests are given in
the following Table 20
ETH-556
, ~
r In ~ ~ O d'
~,
U~ O ~ ~ ~ ~ O a~ I
~o ~ o U~ o o o
u ~ O ~r co O
E~ I` ~ ~ r~ ~ ~ ~ G~
_~ ~
_ .. ~ . _ .
~ r~ ~ o _I ~ o ~o w
E~ _~ ~ ~ ~ ~ ~ ~ ~
~ _ .
Q (~ m~
E~ e~
c
~_I
~ ~o 3 ~ o o ~ ~ ~
v~ oo~ --oo--------
r tn ~ C ~
H ~H H H H
v - _ _ .
O
a
O
1~ ~
O O ~ ~n "~ ~o ~ r` ~ ~ ~ u~ o ~ o u U~ U~ r` u~ I~ I
Q- O
(~ H
dP
aJ H
r-l ~ H H ~_~
0~ H H ~ H 1-1 H ~ 1~ H H
~ ~ 1~ C X ~C X ~: ~< X
rLl
~1
-22~
The copolymers of the present inention produced in accor-
dance with the previously described Examples l through XII
are converted to filament materials where possible as
previously described. In some instances the filaments are
annealed while in other instances they are not annealedO
The resultant filament materials are measured for one or
more of the follow.ing properties: straight tensile
strength, knot tensile strength, elongation, and Young's
modulus.
The results of these tests are provided in the following
Table 3.
556
u~
c ~ u~ ~ I I ~ o ~ D co o o co ~ er
o o~ ~
-
O o ~o~a~mmLr U~t-~O~OO
---- -- --- ~
aJ
v ~ r~
C~ erII ~I1~~InIII~IIII~
E~
- ~
a) 3~
S~ ~ Sl, ~ ~ ~1
Q
, 1 ~
~ a ~
. v e
,~ ~ O o~ o u~ r~ I ~
r~, r~orrcor~s~Drr~rrrl~r r
~:: O u~ D W ~D ~D ~ ~D ~D I a
IQ C ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ S~
~C . oC o~o~ OOOOOOOOOO O
c o u ,~ D co r ~ a) ~ ~ ~ co / a~ Z C
r-~ ~ rl r~
a~ ~ dP C~
C C o
~: ~ u~ a~ I o o In O O U~
r~
r _ ~ C
E~ ~ ~ a~
o .~ ~ r_~ ~
u~ ~r sJ ~ r ~ Ln er o ~ ~r ~ o u~ r o ~r v
c~ r~ ou~rl-r~ rr~rrrrrr r ~n
`~ r,~ ~ ~
r-l Z; ~ I; ~ ~ ~ ~ ~ r~ I _i r; r~ ~ ~I r~ ~1 r~ I r; O
a) ~ u~
Ç ~5 3 ~ ~ ~ _1 ~r) ~ r~ r~~ ~ E-t d~ ~ _I ~) ~ ~D I ri ~ l
-r ~ ~ 11.~ ~ ~ ~
~r~ U~ C
~, r~~
C C C ~ ~ C. C C. 5 G C C C C C C C C C
er .~r~.~r~ r~ rl~ r~ r~r~r~ri r~
3 ~ u u C) t) U ~ U ~ e) ~ U O U U U U U U.CI U
~ m
a c~ c
. ~ _. ~
e; o o
0o
:~ o o o o u~ ~ c m u~ o u~ o m o o o o ~ o
r ~ ~ ~x7 co ,~ ~ o~ c~ ~ ~ ~7 ~ ~ ~ ~ ~ ~ O ~
x e
t~ E~ a~
___ , _ _ . _ ._ - cr~
~ ~ H 'U~
tl H H4 ~ Hl H H ~ U ~ 1 H
E~ O 1--~ H 1~~ C X ~ ~ ~d X ~ ~?C X ~
rd 'Z ~.
til
~3
-24~
Fibers made from copolymers produced in accordance with
some of the Examples previously described are annealed and
sterilized and tested for absorption characteristics.
The percent breaking strength retention after various
lengths of time is determined.
The breaking strength of a sample is determined by implan-
ting two strands of a sample in the dorsal subcutis of
each of eight (8) Long-Evans rats. Thus, 16 strands of
each sample are implanted corresponding to the two implan-
tation periods; eight examples of each sample for each of
the periods. The periods of in vivo residence are 7 and
14 days. The ratio of the mean value (of 8 determina-
tions) of the breaking strength ~determined with an
Instron Tensile tester in accordance with standard testing
procedure) at each period to the mean value ~of 8 determi-
nations) obtained for the sample prior to implantation
cons~i~utes i~s breaking strength for that period.
Table 4 provides the -~esults of the brea~ing strength
retention for the examples as indicated.
Table 4
25 Example Processing Conditions ~ Breaking Strength
No. Annealing Sterilization Retention At
7 daYs 14 daYs
. . ~
IV 5 hr./110C. Ethylene Oxide 44 11
VII 16 hr./76C. Cobalt 60 62 37
I 6 hr./80C. Cobalt 60 54 13
Xh 6 hr./80C. Cobalt 60 52 12
Xi 6 hr./~0C. Cobalt 60 49 11
Xe 6 hr./80C. Cobalt 60 58 24
Xf 6 hr./80C. Cobalt 60 61 22
ET~-,56
~;~2~
-25-
The filaments of the present invention may be used as
mono-~ilamen-t or multifilament sutures and may be woven,
braided, or knitted. The polymers of t:he present
invention are also useful in the manufacture of cast films
S and other solid surgical aids as are well known in the
art.
Many different embodiments of this invention will be
apparent to those skilled in the art and may be made
without departing from the spirit and scope thereof. It
is understood that this invention is not limited to the
specific embodiments thereof except as defined in the
appended claims.
556
