CA1224600A

CA1224600A - SURGICAL ARTICLES OF COPOLYMERS OF GLYCOLIDE AND .epsilon.- CAPROLACTONE AND METHODS OF PRODUCING THE SAME

Info

Publication number: CA1224600A
Application number: CA000437933A
Authority: CA
Inventors: Shalaby W. Shalaby; Dennis D. Jamiolkowski
Original assignee: Ethicon Inc
Current assignee: Ethicon Inc
Priority date: 1982-10-01
Filing date: 1983-09-29
Publication date: 1987-07-21
Also published as: DE3335588A1; JPH0696633B2; GB2127839A; GB8326335D0; JPH0343906B2; DE3335588C2; NZ205680A; JPS5982865A; GB2127839B; AU1979583A; JPH03269013A

Abstract

Abstract Novel copolymers of .epsilon.-caprolactone and glycolide useful in making surgical articles and particularly surgical sutures having Young's modulus of less than 250,000 psi. New and improved polymerization methods for producing the novel .epsilon.-caprolactone and glycolide copolymers.

Description

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~;

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 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~

~%~

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 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 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 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 ~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 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.

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

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 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~

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~

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 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 , ~
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.

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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~

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.

Claims

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A sterile surgical article of a polymeric material having a tensile strength of at least 30,000 psi and Young's modulus of less than 350,000 psi, said polymeric material comprising from about 20 to 35 weight percent epsilon (.epsilon.)-caprolactone and from about 65 to 80 weight percent glycolide based sequences.

2. A sterile surgical article according to Claim 1 comprising from about 25 to 35 weight percent .epsilon.-caprolactone and 65 to 75 weight percent glycolide based sequences.

3. A sterile surgical article according to Claim 1 wherein the polymeric material has an inherent viscosity of at least 0.8 dl/g measured at 25°C. in a 0.1 g/dl solution in hexafluorisopropyl alcohol.

4. A sterile surgical article according to Claim 1 wherein the article comprises an oriented filament.

5. A sterile surgical article according to Claim 4 wherein the filament is annealed.

6. A sterile surgical article according to Claim 1 wherein the article is a sterile suture having a Young's modulus of less than 250,000 psi.

7. A sterile suture according to Claim 5 having a needle attached to at least one end of said suture.

8. A sterile suture according to Claim 6 having a tensile strength of at least 50,000 psi.

9. A sterile suture according to Claim 6 comprising from about 20 to 30 weight percent .epsilon.-caprolactone and from about 70 to 80 weight percent glycolide.

10. A sterile suture according to Claim 9 wherein the suture is a monofilament.

11. A sterile suture according to Claim 10 wherein the monofilament has been annealed.

12. A sterile suture according to Claim 6 wherein the polymeric material has an inherent viscosity of at least 0.8 dl/g measured at 25°C. in a 0.1 g/dl solution in hexafluoroisoproyl alcohol.

13. A sterile suture according to Claim 12 wherein the polymeric material has a crystallinity of at least 20 percent.

14. A sterile surgical article according to Claim 6 or 7 wherein the polymeric material has a Young's modulus of from about 75,000 psi to about 150,000 psi.

15. A process for producing copolymers of glycolide and .epsilon.-caprolactone, said polymers being capable of being heat formed into strong filaments having a Young's modulus of 300,000 psi or less which comprises polymerizing a mixture of glycolide and .epsilon.-caprolactone in the presence of from about 0.004 to 0.02 weight percent metal salt or metal oxide catalyst, said polymerization being carried out at a temperature below 250°C. for a period of time sufficient to produce a conversion of the monomers to copolymers of at least 80 percent wherein a copolymer having a crystallinity of at least 5 percent is produced.

16. A process according to Claim 15 wherein from about 20 to 30 weight percent of .epsilon.-caprolactone is used.

17. A process according to Claim 16 wherein the catalyst is stannous octoate.

18. A process according to Claim 15 wherein the polymerization is carried out at temperature of 190°C.

19. A process according to Claim 18 wherein the polymerization is carried out for 10 hours or longer.

20. A process according to Claim 19 wherein the conversion of monomers to copolymer is at least 90 percent.

21. A process according to Claim 20 wherein the copolymer has a crystallinity of at least 10 percent.

22. A process for producing a copolymer of glycolide and .epsilon.-caprolactone comprising:

forming a low molecular weight pre-polymer of .epsilon.-caprolactone and glycolide, said pre-polymer comprising more than 50 weight percent of .epsilon.-caprolactone, and being produced at a temperature of below 220°C., and adding additional glycolide to said pre-polymer and polymerizing said mixture containing the additional glycolide at a temperature above 140°C. for a period of time sufficient to produce a conversion to copoly-mer of at least 80 percent and copolymer having a crystallinity of at least 5 percent.

23. A process according to Claim 22 in which the pre-polymer has at least 60 weight percent .epsilon.-caprolactone.

24. A process according to Claim 22 wherein the low molecular weight pre-polymer is produced using metal salt or metal oxide.

25. A process according to Claim 23 wherein from about 0.004 to 0.02 weight percent of catalyst is used.

26. A process according to Claim 25 wherein the catalyst is stanneous octoate.

27. A process according to Claim 26 wherein a conversion to copolymer of at least 90 percent is obtained.