CA1279737C - Bioabsorbable surgical suture coating - Google Patents

Abstract

BIOABSORBABLE SURGICAL SUTURE COATING
ABSTRACT
A bioabsorbable coating for a surgical suture or ligature is disclosed. The coating is manufactured from a diblock or a triblock copolymer.

Description

373~

BIOABSORBABLE SURGICAL SUTURE COATING
Backaround And summary of The In~ention This invention relates to the use o~ a block hydrogel as a coating a~d lubricating ~inish ror a surgical suture or ligature~ -As early as 1972, R. Perret and A.
Skoulious, Makromol. Chem. 156, 143-156 (1972);
Makromol. Chem. 162, 147-162 (1972); and Makromol.
Chem. 162, 163-177 (1372) disclosed the synthesis and characterization o~ thermoplastic poiytcapro-lactone)-poly(ethylene oxide)-poly(caprolactone) (PCL-PEO-PCL) ABA triblock copolymers. The puri~ication and crystallization behavior o~ th2se materials was extensively discussed. However, no mention was made as to the biodegradability o these polymers, their swelling behavior, or to any medical use such as suture materials or as suture coatings.
Pitt and Schindler, U.S. Patent 4,379,138 have published extensively on the biodegradability of PCL; therefore~ the PCL-PEO-PCL triblock polymers should make attractive biodegradable hydrogel materials but this use was never mentioned.
Reed, Ph.D. Dissertation, Univ. of Liverpool (1978) has disclosed the synthesis of poly(lactide)-PEO~poly~lactide) (PLA-PEO-PLA) ABA
: triblock copolymers. The biodegradability o~ these materials was recognized; however, there was no mention of their potential hydrogel nature, or the use of these materials as suture coatings.

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Casey, et al.l U.S. 4,452,973 (6/5/84) disclosed the synthesis of poly(glycolic acid)-PE0-poly(glycolic acid) (PGA-PEO-PGA) thermo-plastic biodegradable ABA triblock polymers. Th intended u~e for these materials was as absorbable sutures having the required flexibility for use as a monofilament~ The patent discloses the use of trimethylene carbonate in combination with glycolide to prepare the A portion of the ABA triblock pol~mer.
~hurchill, et al~, U.S. 4,526,938 (9/2/85) also disclosed the use of degradable ABA triblock polymexs a~ hydrog~ls. In this case, the m~ddle block was also PEO and th~ endblocks were gen~rally PLA or PLA/~GA copolymers although the use o~ PGA, PCL or poly(3 hydroxy-butyric acid) was mentionQd with no specific experimental details given. No mention was made to using Gly/TMC endblocks for these hydrogels, or to using these materials as suture coatings.
Mattei (U.S. Patent 4,027,676 to Ethicon, June 7, 1977) has disclosed suture coatings consisting o bl~nds of ab~orbable copol~mers of glycolide and lactide as a ~ilm forming resin, polyalkylene glycols as a lubricant, and a hydrophobic material such as a fatty acid or an ester of a fatty acid to improve tie-down per~ormance. However, no mention was made of using blocX polymers formed from polytalkylene glycols) and absorba~lR polymers. A particular disadvantage o~ the Mattei method of using blends of poly(alkylene glycols) with absorbable copolymers is the tendency ~or the poly(alkylene glycols) to dissolve prematurely if exposed to an aqueous ~ ~ ~ 9'7;~

environment (see, e.g., Example 4 of UOS.
4,027,676)) rendering the coating less effective.
Mattei (U.S. Patent 4,201,216 to Ethicon May 6, 1980) has also disclosed the use of an absorbable copolymer of glycolide and lactide as a film ~ormer blended with salts of C6 or higher fatty acids as suture coatings. No mention was made o~
using block polymers with poly(alkylene glycols) ~or this appliration.
Mattei has also disclosed the use of polyvalent metal fatty acid salt gels as suture coating ma~erials tU.S. Patent 4,185,637 to Ethicon Jan. 29, 1980). No mention is made of using block copolymers o~ poly(alkylPne glycols) for this applicationo Conventional hydrogels which are made by crosslinking water soluble poly~ers have several drawbacks which are associated with their crosslinked nature. These include a lack of both solubility and processability. In contrast the block copolymers of this invention are thermoplasticO They ara soluble in common organic solvents and are ~usible.
The biodeyradable thermoplastic hydrogels of this invention are useful as a suture coating material for surgical sutures or ligatures. Their solubility in common organic solvents allows for a coating composition to be applied by conventional solution techniques~ When applied in this manner the coating pol~mer will improve tie-down performance and lubricity of the surgical suture as compared to an identical uncoated surgical suture.
The polymers of this invention will also degrade to non-toxic low molecular weight materials capable of 9'7~3~AJ3~
., being elimin~ted from the body withGut adverse reaction or response.
A bioabsorbable coating for a surgical suture or ligature comprising a iblock copolymer has been invented. The copolymer has a first block comprising a polyalkylene oxide and a second block consisting essentially of glycolic acid ester and trimethylene carbonate linkages. In one embodiment, th~ polyalXylene oxide bloc~ is from 5 to 25 percent by weight of the copolymer. In another embodiment, the number average molecular weight of the polyalkylene oxide block is from about 4,000 to 30,000. In yet another e~bodiment, the polyalXylen oxide block is derived from a polyalkylene oxide terminated on one end by a Cl to C6 alkyl group and on the okher end by a hydroxyl group.
In a specific embodiment of any of the above embodim~nts, the polyalkylene oxide block is derived from a homopolymer of ethylene oxide. In another specific embodiment of any of the above, the polyalkylene oxide block is derived from a block or random copolymer o~ ethylene oxide and a cy~.lic ether. In a more specific embodiment, the cyclic : ether is selected from the group consi~ting o~

t~3 ( C~I2 ) X ~2 o or R :
(C~2)y - CH

wherein x is 2 to abou~ 9, y is 1 to about 9 and R
is a Cl to C6 alkyl group.
In yet another speci~ic embodi~nt, the polyalkylena oxide block is derived fro~ a block or random copslymer o~ a first cyclic ether s~lected from the group consisting of ( CH2 ~ X CH2 \ /
~.

wherein x is 2 to abouk 9, and a second cyclic ether selected from the group consisting o~

R
(CHz~y - CH

wherein y is 1 to about 9 and R is a Cl to C6 alkyl group.

In a more specific embodiment (to the above specific embodiments), the inherent viscosity ~ 3 73~

of th2 copolymer, as measured at 30C for a O.5 (w/v) solution in chloroform or methylene chloride, is 0.25 to about 1. 50 dl/gO
In a still further embodiment, ~he surgical suture or ligature containing the bioabsorbable diblock copolymer coating is also bioabsorbabla. The suture or ligature is manufactured from a polymer. The polymer is prepared ~rom one or more monomers selected ~rom the group consisting of lactides, In one e~bodiment, the suture or ligature is manufactured from a ho~opolymer prepared from the monomer glycolide. In another embodiment, the sutur~ or ligature is manufactured from a copolymer prepared from the monomers glycolide and lactide. In a specific embodiment, the suture or ligature is in multifilamentary fo~m. In a more specific embodiment, the coating comprises about 1/10 to 5%
by weight of tha coated suture or ligature. IN a most specific embodiment, the coaking comprises about 1 to 3% by weight of the coated suture ~r ligature.
A bioabsorbable coating for a surgical uture or ligature comprising a triblock copolymer has also been invented. The middl~ block (of the txiblock copolymer) is obtained by removing both terminal hydroxyl hydrog~ns either form a homopolymer of ethylene oxide, or from a block or random copolymer of ethylene oxide and a cyclic ether. In one embodiment, the cyclic ether is selected from the group consisting of 7~7;~

( C~ c ~ CH2 \ /
o or R
(CH2)y - CH

wherein x is 2 to abou~ 9, y is 1 to about 9 and R
is a Cl to C6 alkyl group. In a spçcific e~bodiment, the middle block is obtained from a blo~k copolymer of ethylene oxid~ and a cyclic ether of the formula:
C~3 20\ /
O

Further, a bioabsorbable coating for a : sur~ical sutur~ or ligature comprising an 2S alternative triblock copolymer has been invented.
The middle block is obtained by removing both terminal hydroxyl hydrogens from a block or random copolymer of a first cyclic ether selected from the group consisting of ( C~I2 ~ X - CH2 wherein x is 2 to about 9~ and a second cyclic ether selected ~rom the group con~istlng o.

(CH2)v - CH

wherein y is 1 to about 9 and R is a Cl to C6 alkyl group.
In a further e~bodiment of any of the above embodiments, each end block of the triblock copolymer consists essentially of glycolic .acid ester and trimethylene carbonate linkages. In a specific embodiment, the middle block is ~rom 5 to 25 percent by weight o~ the copolymer. In a more specific embodiment, the number average molecular weight of the middle block is from about 4,.000 to 30,000.
In a most spaci~ic embodiment (to the ahove specific embodi~ents~, the inherent viscosity of ths copolymer, as measured at 30C for a 0.5%
~w~v) solution in chloroform or methylene chloride, is 0.25 to about 1.50 dl~g. In a still further embodiment, the surgical suture or ligature containing the bioabsorbable bioabsorbablQ triblo~k copolymer coating is also bioabsorbable. The suture or ligature is manufaatured from a polymer. The polymer is prepared from one or more mo~omers selected from the group consisting of lactides. In one embodiment, the suturQ or ligature is manu~actured from a homopolymer prepared from the monomer glycolide. In another embodiment, the suture or ligature is manufactured from a copolymer prepared from the monomers glycolide and lactide.

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In a speoific embodiment, the sutuxe or ligature is in multifilam~ntary formO In a more specific embodiment, the coating comprises about 1~10 to 5%
by weight of the coated suture or ligature. In a most speciflc embodiment, the coating comprises about 1 to 3% by weight of the coated suture or ligature.
Descri~tion of the Invention This invention relates to the use of degradable thermoplastic hydrogels consisting of block polymers as a coating and lubricating finish ~or surgical articles including sutures and ligatures. These materials will impart lubricity to, and improYe the tie-down propertie~ of a multi~ilament absorbabl~ suture or ligature in both wet and dry state~ The sutur~ or ligature can be manufactured from a homopolymer (e.g., DexonTM, ~merican Cyanamid Co., NJ, USA) or copolymer (e.g., ~icrylTM, Ethicon, Inc., NJ, USA) of glycolic acid.
.20 In addition, these materials are capable of being complekely degraded and eliminated from the body over a period o~ time. A particular advantaga o~.
these materials is their thermoplastic nature, that ~ is, ~hey can be applied t~ sutures by conventional solution or thermal techniques.
Recently, there has been interest in using hydrogels in a wide variety of biomedical applications such as contact lenses, burn dressings, blood and ~issue compatible implan~s, lubricant coatings for surgical implants, and drug delivery devices. In some of these areas, crosslinked hydrogel materials have met with great success.
However, these materials suffer drawbacks, such as a lack o~ processibility, which are a consequence o~
their crosslinked nature.

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our approach ~o this problem was to investigate the use of block copolymers as thermoplastic biodegradable hydrogels for suture coating applications. In an ABA triblock example of these block polymers, the middle ~B) block is a water svluble polymex such as a poly(alkylene oxide) and the end blocks (A) arQ comprised of degradable random copolymers o~ glycolide (Gl~) and trimethylene carbonate (TMC). The middle and end blocks o~ this block copolymer are chemically incompatible and the result is a phase separated system with poly(alkylene oxide) regions dispersed ~hroughout tha Gly/TMC ~atrix. When exposed to an aqueous en~ironment, the block polymer pic~s up an amount of water which i~ a ~unction o~ the composition and molecular weight o~ the various ~lock structures. The thermoplastic nature of the block pslymars allows for lubricant coatings to be applied by Xnown solution or m~lt processes. The cry~talline poly(alkylene oxide) segment~ serve, in the dry st~te, as temperature dêpendent crosslinks which hold the coating securely in place and minimize coating flow on storage of the surgical suture.
The method of choice for preparing the above block copol~ers i~ the melt phase ring-opening copolymerization of glycolide and trimethylene carbonate using specially purified, commercially available difunctional or monofunctional poly(alkylene glycols) as initiators.
These polymerizations are conducted in a s~irred reactor at about 165C under nitrogen. When maximum melt viscosity has been reached, the polymer is discharged and allowed to cool to room temperature.
35 Oligomeric material can be removed by .b~7~3737 -- 11 ~

reprecipitation from methylene chlorida solutions into methanol or ethanol.
Samples of the abov2 polymers are extrudPd at 60-100C with an extxuder to yield fibers of 1.5 S mm averase diameter. The fibers are then cut into 1" lengths and several are placed in deionized water at room temperature. At various tim~ intervals, the fibers are withdrawn, wiped thoroughly to remove any sur~ace liquid, and the water uptake i~ measured gravimetrically. Alternatively, ~he uptake can be : measur~d from thin films ~0.6 mm) prepared by compression molding the pol~mer at ~0~, or by casting thin films o~ the polymer fxom solution.
: The ~ho~e embodim nt~ are more fully described in the ~ollowing examples.
Example 1 Puri~ication o~ Materials DL-lac~ide: DL~lac~ide was purchased from Purac, Inc. One kilogram o~ DL-lactide is refluxed ~or 1 1/2 hours with toluene (1500 g) which has been dried by dis~illation ~rom benzophenone ketyl. The rssidual water is removed from the DL lactide by collection of the toluene/water azeotrope in a Dean-Stark trap. The dry DL-lactide solution i5 allowed to cool to room temperature and placed in the refrigerator overnight. The crystallized DL-lactide is then quickly filtexed and dried in a vacuum oven at room temperature. Recrystalli2ation yield is 84%.
Polyethylene Glycol-8,000: Polyethyl2ne glycol-8,000 (PEG 8,000) (160 g) is dissolved in ~ethanol (1600 ml). The PEG solution is then freed of catalyst impurities and deionized by slowly passing the solution through a methanol conditioned in~icating mixed bed anionic and cationic 3r 12 ~

ion-exchange resin (Amberlite MB 3, Rohm and Haas Company, PA, U.S.A.). After elution ~rom the column, the PEG i5 crystallized by placing the solution in a freezer overnight. The crystalline PEG is then filtered and air dried for 2 hours. The PEG is further puri~ied by recrystallization from acetone (1600 ml). The recrystallized PEG is filtered and dried in a vacuum oven at room temperature overnight. Prior to polymerization, the desired amount of purified PEG is dried further hy heating in a vacuum oven at 70C with P~05 as a desiccant. PEG-14,000 and PEG-20,000 are purified in the same way.
Pluronic*F68: Pluronic F68 was puxified ~y the same technique as described for PEG above ~ut without the acetone recrystallization step. The methanol recrystallized Pluronic F68 was filtered and dried in a vacuum ovPn at room temperature.
Pxior to polymerization, the Pluronic F68 was ~urther dried by heating in a vacuum oven at 70C
with P205 as a desiccant.
Pluronic P105: Pluronic P105 was puri~ied by the same method described for PEG abova~ The polymex was recovered from the `m thanol solution using a rotary evaporator. Residual methanol was removed by drying in vacuum to constant weight. The material was not recrystallized from acetone. Prior to polymerization the Pluronic P105 was dried further by heating in a vacuum oven at 50C with P205 as a desiccant.
Polyethylene Glycol Methyl Ethero Polyethylene glycol methyl ether, nominal molecular wei~ht 5000, was puri~ied in the same way as described for PEG above.
* Trade Mark 73~
~.3 Exam~le SYntheSiS Of (&1Y~TMC~ ~PEO 14 . 000) - ~G1Y~TMC~
ABA Triblock Copolymer ~qlv/PEO/TMCo 34~41/2~) A 250 ml flas~c is charged with PEG-14000 (50 g, 0. 0036 mole) . Th~ ~lask is placed in a vacuum oven and the PEG is ~ried overnight under ~acuum at 70C with P205 as a drying a~ent. The flask is then placed in a glove bag under N2.
Glycolide (25.0 g, 0.21 mole) and trimethylene carbonate (25.0 g, 0.24 mole) are charged to the flask and the contents are melted and mixed under N2. The monomer mixture is then guickly transferred into a stirred reactor which has been heated under a nitrogen flow to 165C. Stannous octoate (o.i6 ml, 4.9 x 10 4 mole) is then qu~ckly charged to the reactor with the use of a syringe. The polymer melt i5 stirred at 40 rpm for approximately 3 hours at 165C. This time period corresponds to a maximum in the melt visco~ity. The polymer is discharged from the reactor and allowed to cool ko room temperature.
A portion of the ~rude pol~mer (42.8 g) is dissolved in C}I2C12 (250 ml) and rep:recipitated dropwise int.o rapidly stixred absolute ethanol (3000 ml). After filtration and drying to constant weight, the repreaipitation yield was determined to be 96~. The inherent viscosity of the polymer (O.5g/d~, in CHC13 at 30c) wa~ 0.38 dL/g. The composition was analyzed by lH-NMR and was found to be 34/41/25 weight percent Gly/PE0/TMC. The Tg of the polymer was 11C, the melting point (Tm) was 5~C.

. ~ 7 3 7 37 - 14.-Exam~les 3-14 Several polymers were prepared as in Example 2 with varying PEG contents and PEG
molecular weights tTable I). In many of the Gly/PE0/TMC triblock copolymers, the charged ratio of Gly/TMC is 60/40 weight percent. This allows ~or maximum Tg of the rubbery end blocks (9C) while still maintaining solubility in co~mon organic solvents. Differ~ntial scanning calorimetry (DSC) clearly shows phase separation in these materials.
The Tg of the rubbery end blocks (7-16C) is very close to the Tg of a 60/40 random Gly/TMC polymer.
In addition, the Tm of the crYs~alline PEO se~ments ara only lowered 5-10C.
Example 15 Sy~th2sis_0f (GlY~TMC)-~PEO-8000~1Gl~/TMC?
ABA. ~ly~PEO~MCo 59/6~35~
Glycolide (117 . 0 g, 1. 01 mole), trimethylene carbonate (71.0 g, 0,~0 mole), PEG 8000 .20 (12 . o g) and stannous octoate (o. 33 ml, 1. o x lo 3 mole) were co~ined in a stirred reactor as in Example 2. The reaction mixture was then stirred at 16sc and 36-40 rpm for 1.5 hours. The polymer was recovered as in Example 2. The properties o~ this polymer are summarized in Table I.
_ mple 16 Synthesis of (Gly~TMcL-lpEo-8ooo~-(Gly~TMc~ ABA, (Gly/PEO~TMC: 54~8/38) Gly~olide (110.4 g, 0.95 moles), trimethylene carbonate (73.6 g, 0.72 moles), PEG-8000 (15.0 g) and stannous octoate (0.32 ml, 9.96 x 10 4 mole~) were combined and allowed to polYmerize as in Example 15. The properties of this polymer as summariæed in Table I.

- , ' ' ~ :

- :' ' -~f~ 37 Exan~le 17 Synthesis o~ tGly/TMC~-(PEO-8000)~ y~TMC~ ABA~
~Gly~PE0/TMC: 54~10/3~) Glycolide (108.0 g, 0.93 moles), trimethylene carbonatQ (72.0 g, 0.71 moles), PEG~8000 (20.0 g~ and stannous octoate (0.32 ml, 9.~6 x 10 4 mole~) were combined and allowed to polymerize as in Example 15. The properties o~ this material are summarized in Table I.

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Exam~le 18 Synthesis of (Çly/dl-Lact)-~PEO-8000~-(Gly/dl Lactl ABA, (Gly/dl-Lact~/PEO: 36/54~10) Glycolide (54.0 g, 0.46 moles), dl-lactid~
(81.0 g, 0.56 moles), PEG-8000 ~15.0 g) and stannous octoata (0.32ml, 9.96 x 10 4 moles) werP combined - and allo~ed to polymerize as in Example 2. The properties of this polymer are sum~arized in Table II.
Exampl~ 19 SYnthesis of (Glv/l-Lact~PEO-8000)-tGlv/l-Lact~
ABA~ L&lY/l-Lact/pEo~ 27~65~8) Glycolide (53.~ g, 0.46 moles), l-lactide (130.~ g, 0.91 moles), PE&-8000 (16.0 gj and stannous octoate (0.05 ml, 1~56 x 10 4 moles) are combined and allowed to polymerize by the procedure described in Example 15. The properties o~ this polymer are summari~ed in ~able II.
Example 20 Svnthesis of (l-Lact~TMC)-fPEO-8000)~ Lact~TMC) ABA, (1 Lact/~MC~PEO: _43/49/8~
- l-Lactide (8800 g, 0.61 moles), tri~ethylene carbonate (9~OO g, 0~94 moles), PEG-8000 (16.0 g) and stannous octoate (0.31 ml, 9.74 x 10 4 moles) are combined and allowed to polymerize by the procedure described in Example 15.
The properties o~ this polymer are summarized in Table II.
Example 21 Synthesis of ~GlY~dl-Lact~-~PEO-20,000~-(Glv~dl-Lact) ABA,(Glv~dl-Lact/PE0: 21~25/54) dl-lactide (25.0 g, 0.17 moles), glycolide (25.0 g, 0.21 moles), PEG 20,000 (50.0 g) and stannous octoate (0.16 ml, 4.94 x 10 4 moles) are combined and allowed to polymerize by the procedure 3'~

de~cribed in Example 2. Th~ properties of this polymer are described in Table II.

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Example 22 Swellin~ Behavior o~ Ex~e~ 4~
A ~ilm was prepared by solution casting a 20% w/v solution of the polymer o~ Example 3 in CH~C12. After the sol~ent had evaporated overnight, the film was dried further under vacuum at room temperature overnight. Films made from the polymers of Example 3, 4 and 21 were placed in water at 37C
with stirring. After 24 hours, ~ilms fxom Example 3 and Example 4 had formed emulsio~s. By day 3, the ~ilm from Example 21 had also ~ormed an emulsion.
Example 23 Swellinq Behavior o~ Exam~le 7 (Gly/PEO~TMC: 44~29/27~
A sample o~ the polymer ~rom Example 7 ~1.5 g) was extruded at 110C to yield a 105 mm diameter fiber. From th~ fiber 5 samples, lengths each approximately 1" were cut. The samples were placed in deionized water at room temperature.
Periodically, th2 samples were withdrawn, wiped dry, and the water uptake measured gravim~tricallyO The water uptake is shown in Ta~le III. From the values at 1280 ~in~, the equilibrium water uptake for fibers was calculated to be 232 ~ 3%.
Water uptake analysis was perfoxmed on 4 samples of ~ilms o~ the polymer of Example 7 ~12 x 4 x 0.6 mm). The resulks are shown in Table III. The shorter time to reach an equilibrium value of water uptake in the ~ilms is attributable to the greater surface-~to-volume ratio in the ~ilms.

3~7 Table III
_ Water Uptake by_Fibers and Films of 44~29~27 Gly~PEO~TMC (Ex. 7) _ Fibers Films Time % H2OA Time % H20A
(min) Uptake ~min) Uptake ~ 31.1 5 136.7 18 60.9 22 238.7 32~ 89.3 35 271.0 107~9 63 279.5 133.6 81 282.2 158.2 216 279.1 118 183.7 363 ~5~.5 14~ 204.3 1~60 266.3 179 223.3 --1155 237.~
1280 235.5 A = (Wt Swollen - Wt Dry) x 100 Wt Dry ~ 1 .

1~ 79 7~3~

Example 24 Swellinq o~ Various ~ydroqels Water uptake e~periments were ~arried out on fibers o~ several Gly/PEO/TMC hydrogels and one Gly/dl~La~tide/PEO hydrogel (Table IV), Measure-ments were carriad o~t at roo~ tamperature in deionized water. All reported equilibri~tm uptake values are averages of 4 or 5 samples.

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3t737 Several generali~ations about the data in Table IV can be madeO The time to reach an equilibrium value o~ water uptake depends on the shape of the sample (Example 7 fiber vs. ~ilm3. It would also appear that the time to reach an equilibrium value of water uptake decreases as the PEO content increases.
Within the sca~ter in the data, equilibrium water uptake i5 linearly related to the PE0 content in the range 5-30~. There is no noticeable effect of the ~M of the PEO block on the swelling of these triblock polymers (within the rànge of PEO MW 8,000 20,000).
one important di~ference noted in Table IV
is the contrast o~ ~xample 10 (Gly/PE0/T~C) wi~h Example 18 (Gly/PEO~dl~Lactide). 8Oth have approximately the same percent of PE0 8,000;
however, a reprec7pitated sample o~ Example 10 had an eguilibriu~ water content o~ 124% (Teq 1 day) vs.
.20 9.9% by day 13 for a reprecipitated sample of Example 18. The difference can be rationalized by looking at the differences of the two matrices. In the case o~ the sample o~ Example 10 the Gly~TMC
matrix i5 free to de~orm to accommodate the dimensional changes caused by the swelling. With the sample of Example 18, however, the Gly/dl-Lactide matrix has a dry Ty of approximat~ly 30C. At room temperature, it is in a glassy state and cannot deform as easily to accommodate the dimensional changes necessary to swell. This should result in a slower water uptake curve (note that at 13 days equilibrium has not been reached) until the Gly/dl-~actide matrix is sufficiently plasticized by water.

~ ~t~73~

Suture Coatinq Experiments Two methods arP used to apply the coating polymer to an uncoated lJ0 polyglycolic acid braided suture. In the hand dip method, which is largely used to screen potential coati~.g candidates, the braided strand is run under an inverted "U" guide mounted on a holder immer~ed in a solution of the coating polymer. Any sol~ent can be used that will dissolve the coating polymer and not damage th~ PGA
braid. Typically, methylene chloride, chloroform, l,l,l-trichloroethane, or acetone can be used as solvents. A~ker each pas~ through the solution, the coated sutures are air dried in a hood. Several passes can be made through the solution to increase the amount of material picXed-up on the bxaid.
A~ter the final pas~, the braid i~ dri~d at room temperatur~ and reduced pressure for 2-4 hours.
The pre~erred method of coating uses a ?0 pump to supply coating solution to a ceramic guide throuyh which the ~GA braid is pa~sed at a controlled rate. The coated braid is then pa~sed through a hot air oven to remove the coating solvent. This braid is cut, needled, sterilized, vacuum dried and packaged.
A general description for the coating of a surgical suture is as follow~ A commercially available coater (e.g. ~rom the Bouligny Co., U.S.A.I is set to operate on a ~ilzment traveling at a speed of 50 feet per minute. The circulating air in the drying oven is ad~usted to be 80C.
There is only one pass of the filament through the capillary coating apparatus, and then through the drying oven. The coating pump is ~ ~ 79 737 adjusted to give about 5 to 8 dxops per minute at th~ capillary apparatus~
Using the above coating methodt the percent pickup is about 3.5 to 3.6 percent based on S the weight of the filament. It is to be understood that this amount of pickup can be increas~d or dacreased by an person skilled in the art without undue experimentation by adjusting the above parameters. Preferably, the amount of pickup is increased by decreasing the amsunt of solvent in the coating formulation, and vice versa.
The dip~coated braid and the machine coated braid are easily test2d for improvements provided by the coating to both knot repositioning and knot security. Size 1/O PGA braid samples were coated with several Gly/PEO/TMC terpolymers (Table V) and with three lactide based terpolymers (Table VI).

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TABLE V FOOTNOTES

(1) . The coakings were applied to 1/0 polyglycolic acid braid from a 2~ (wt/vol.) solution of the coating material dissolved in methylene chloride.
(2) This test measures the ability of a suture to be snugged in. A loop is passed around a steel rod and tied with a square knotO The knot is set to a prescribad tension with an Xnstro~ tester, and the tension is then removed. After resetting the gage length, the loop is tested to break. The breaking strength o~ the loop and elongation-to- break are recorded. The material elongation ak the point of knot break is determined separately in a straight pull test, and subtracted from the knot breaking elongation to obtain the slippage in mm within thP
knot up to the breaking point. Samples were ~tested lmmediately after 30 saconds immersion in saline ~olution (0.9~ NaC1 in distilled water).
The tensions used to set the knots, and all the other conditions of knot tying and testing, are practic~l laboratory con~itions, but may not correspond to actual surgical practice. The knot snug in may not corr~late with clinical experience.
(3) A strand is tied to itself to form a loop, the knot iæ set to a prescribed tension, the loop is cut, and the cut ends are clamped in the jaws of : an Instron tester. The breaking strength and elongation~to break are measured. The maximum slippage is racorded for the knots that break.
This is defined as the di~ference between the . average elongation-to-break of the knotted suture and the average elongation of an unknotted strand, measured at a load equal to the knot breaking strength. Samples are tested immediately after 30 s~conds immersion in saline solution.

(4) Square knots were formed in hand-dipped 1/0 polyglycolic acid braid using a conventional suture tying board. The knot was then run down to the board to assess the stick-slippiny of the knot : (chatter) as it runs down and to assess the force required to initiate and sustain the run-down.
The abbreviations are: L, Lock; RC, Runs with Chatter; RD, Runs with Difficulty; RW, Runs Well.
The comparisons are made on dry suture and on suture wet with saline.
. * Trade Mark ~ - 29 -3~

TABLE VI
In Vitro Coatinq Performance: Terpolrmers Made With Lactide Knot Run Do~) Coatin~ Polymer fWt ~L Wet Dry Ex. 19 Gly/l-Lactide/ 1-3 L L
PEO: 27/65/8 Ex. 20 l-Lactide/TMCJ 1-3 L L
PEO: 43/49~8 Ex. 21 Gly~dl-Lactide/ 1 3 R~ RW
PEO: 21J25J54 (1) L Loc~s: RW: Runs Well -~ ~79 ~37 From the in vitro data on knot repositioning with these coated hraids, it is evident the Gly/P~O/TMC coatings with PEO contents as low as 6% permit easy movement of a square knot, whereas lactide based terpolymer coatings locked rather than reposition i~ the PEO conte-~t was low (~~%). However, if the PEO content was high in the lactide based terpolymer, the coati~g allowed for good repositioning, indicating that the minimum acceptable PEO content is dependent upo~ the end block composition.
ExamPle 26 A Gly/PEO/TMC 59/6/35 weight ~ polymer from Example 15 was dissolved i~ methylene chloride to give a 2% solids solution~ A s~ze 1/0 uncoated Dexon braid was immersed in this solution a~d dried.
~ultiple immersions wera mada so that different percent pick-up levels were obtained. A sample having 0.9% picX-up (based on the weight of the fiber) was later needled with a tapered needle, wound, packaged and sterilized using standard ethylene oxide sterilizing techniques. A surgeon usad eight o~ these coated sutures to close a midline incision o~ a male dog, while evaluating the knot r~positioning a~d the immediate knot security of these sutures.
Exam~le 27 Same as Example 26 except the polymer used was Gly/PEO/TMC 54/8/38 ~rom Example 16.
: 30 Example 28 Same as Example 26 except the polymer used was Gly/P~O/TMC 5~/10/36 from Example 17.

i''3'~

Example 29 Synthesis of_~Gly/TMC) [Pluronic F68]
~Gly/TMCL ABA 1Gl~Pl~ronic F68~TMC: 56/8~36 PentaBlock Copolymer Pluronic F68 (BASF Wyandotte, U.S.A.) is a triblock copolymer of poly(ethylene oxide) (PE0) (80 mole %) and poly(propylene oxide) (PP0) (20 mole %~
where PP0 ~orms the middle block and the total molecular weight is about 84000 Like PE0, this copolymer is terminatsd with hydroxyl groups whic~
can be.used as an initiator for th~ ring opening polymerization o~ cyclic esters.
Glycolide ~82.8 g~, trimethyl~ne carbonate . (55.2g), Pluronic F68 (12.0 g) and stannou~ octoat~
: 15 (00242 ml), were combined in a stirr~d reactor as in~xample 2. The reaction mixture was then ~tirred at 165~ and 40 rpm for 1.5 hours. The polymer was recovered as in Example 2, a~d then characteriæed as ~ollows: ~ Inh (C~C13): 0.40; Composition: s6/~j3b ( ~ NMR); tg:l4C; Tm 42~C.
Table YII summarizes the in v_vo ratings :: for 1/0 polyglycolic acid braid coated with the Gly/PE0/TMC block polymers, or with the block polymer containing a Pluronic F68 midblock of Examples 26 to 29.

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TABLE VII FOOTNOTES

(1) Coated, needl d, and sterilized suturas were tested in dogs.
~2) The coatlngs were applied to ljO polyglycolic acid braid from a 2% (wt/vol) solution of the coating material dissolved in methylene chloride.
(3) A suture coated with the test material is passed through two sides of a wound in tha animal. A
square knot i8 formed in the suture approximately 12-15 mm from the final knot position required to close the wound. The two ends o~ the suture are then pulled to slide the knot into position.
Xnots that slide properly are rated 1 while knots that fail to move into position are ratad O. The rating for a coating is the sum of the ~ll" ratings divided by the total number of test specimens.
(4) Immediate knot security is determined by using a pair of curved tweezers to tug at the 8 to 10 mm length o~ the ears of a square knot or a square knot with two additional throws. Knots tha~ are secure are rated 1 while knots that can be loosened are rated O. The rating for a coating is the sum of the "1" ratings divided by the total number of test specimens.

~'7~3~737 Example 3Q
S~nthesis of (Gly~TMC)rPluronlc P105~
tGlY/TMC! ABA (Gly~Pluronic P105~TMC: 56/9/35 PentaBlock Copolymer Pluronic P105 (BASF Wyandotte) is a triblock co~olymer o~ poly(ethylene oxide) (~EO) (50 mole %) and poly(propylena oxide) (PPO) (50 mole %) where PPO forms the middle block and the total molecular weight is about 6500. Like PEO, this copolymer is terminated with hydroxyl groups which can be used as an initiator ~or the ring opening polymsrization o~ a cyclic ester.
` Glycolide t54 g), trimethylene carbonate (36 g) Pluronic P105 (10.0 g) and ~tannous octoat~
(0.19 ml), wers co~bined in a stirred reactor as in Example 2. The reaction mixture was then stirred at lÇ5C and 40 rpm ~or 1.5 hours. The polymer was recovered as in Example 2, and then characterized as folllows: ~Inh (C~C13): 0.35; Composition 56/9/35 ( H NMR).
A 1/0 polyglycolic acid braid was coated with 1 to 3% o~ this pol~mer. In ln vitro knot-run-down tests with these coated sutures, s~uare knots were found to run down well both wet and dry.
ExamPle 31 Synth~sis o~ (PEO~-(Gly/TMC) ~B
(Gly/PEO~TMC: 57/6/37! Diblock Copolymer Poly(ethylene glycol) methyl ether (PEO-5000) was purchased from Aldrich Chemical Company. The molecular weight was reported to be 5000. This polymer is terminated by one hydroxyl group and one methyl ether group. Only one end of this molecule, therefore t can be used to initiate - 3~ -the ring opening polymerizatio~ of cycli~ esters, forming an AB di~lock copolymer~
Glycolide (84.6 g), trimethylene carbonate (54.4 g~ PE0 5000 (10.0 g) and ~tannous octoate ~0.242 ml), were combined in a stirred reactor as in Example 2. The reaction mixture was then skirred at 165C and 40 rpm for 1.5 hours. The polymer was recovered as in Example 2, and then characterized as follows: ~Inh (CHC13): 0.42; Composition: 57/~/37 ~1~ NMR); tg: 12C: Tm: 59 C.
A 1/0 polyglycolic acid braid was coatad wlth 1 to 3% of the polymer. In in vitro Xnot-run-down test~ with these coated sutures, square Xnots were found to run down well both wet and dry.

Claims (32)

1. A bioabsorbable coating for a surgical suture or ligature comprising a diblock copolymer having a first block comprising a polyalkylene oxide and a second block consisting essentially of glycolic acid ester and trimethylene carbonate linkages.

2. A coating of Claim 1 wherein the polyalkylene oxide block is from 5 to 25 percent by weight of the copolymer.

3. A coating of Claim 1 wherein the number average molecular weight of the polyalkylene oxide block is from about 49000 to 30,000.

4. A coating of claim 1 or 3 wherein the polyalkylene oxide block is derived from a polyalkylene oxide terminated on one end by a 1 to C6 alkyl group and on the other end by a hydroxyl group.

5. A coating of Claim 4 wherein the polyalkylene oxide block is derived from a homopolymer of ethylene oxide.

6. A coating of Claim 4 wherein the polyalkylene oxide block is derived from a block or random copolymer of ethylene oxide and a cyclic ether.

7. A coating of Claim 6 wherein the cyclic ether is selected from the group consisting of or wherein x is 2 to about 9, y is 1 to about 9 and R
is a C1 to C6 alkyl group.

8. A coating of Claim 4 wherein the polyalkylene oxide block is derived from a block or random copolymer of a first cyclic ether selected from the group consisting of wherein x is 2 to about 9, and a second cyclic ether selected from the group consisting of wherein y is 1 to about 9 and R is a C1 to C6 alkyl group.

9. A coating of Claim 5 or 7 or 8 wherein the inherent viscosity of the copolymer, as measured at 30°C for a 0.5% (w/v) solution in chloroform or methylene chloride, is 0.25 to about 1.50 dl/g.

10. A coating of Claim 9 comprising a bioabsorbable surgical suture or ligature manufactured from a polymer prepared from one or more monomers selected from the group consisting of lactides.

11. A coating of Claim 10 wherein the suture or ligature is manufactured from a homopolymer prepared from the monomer glycolide.

12. A coating of Claim 10 wherein the suture or ligature is manufactured from a copolymer prepared from the monomers glycolide and lactide.

13. A coating of Claim 11 or 12 wherein the suture or ligature is in multifilamentary form.

14. A coating of Claim 13 comprising about 1/10 to 5% by weight of the coated suture or ligature.

15. A coating of Claim 14 comprising about 1 to 3% by weight of the coated suture or ligature.

16. A bioabsorbable coating for a surgical suture or ligature comprising a triblock copolymer having a middle block obtained by removing both terminal hydroxyl hydrogens from either a homopolymer of ethylene oxide, or from a block or random copolymer of ethylene oxide and a cyclic ether.

17. A coating of Claim 16 wherein the cyclic ether is selected from the group consisting of or wherein x is 2 to about 9, y is 1 to about 9 and R
is a C1 to C6 alkyl group.

18. A coating of Claim 17 having a middle block obtained from a block copolymer of ethylene oxide and a cyclic ether of the formula:

19. A bioabsorbable coating for a surgical suture or ligature comprising a triblock copolymer having a middle block obtained by removing both terminal hydroxyl hydrogens from a block or random copolymer of a first cyclic ether selected from the group consisting of wherein x is 2 to about 9, and a second cyclic ether selected from the group consisting of wherein y is 1 to about 9 and r is a C1 to C6 alkyl group.

20. A coating of claim 16 or 18 wherein each end block of the triblock copolymer consists essentially of glycolic acid ester and trimethylene carbonate linkages.

21. A coating of claim 16 or 18 wherein the middle block is from 5 to 25% by weight of the copolymer.

22. A coating of claim 20 wherein the middle block is from 5 to 25% by weight of the copolymer.

23. A coating of claim 21 wherein the number average molecular weight of the middle block is from about 4,000 to 30,000.

24. A coating of claim 23 wherein the inherent viscosity of the copolymer, as measured at 30°C for a 0.5% (w/v) solution in chloroform or methylene chloride, is 0.25 to about 1.50 dl/g.

25. A coating of claim 16 or 18 or 22 or 23 or 24 compris-ing a bioabsorbable surgical suture or ligature manufactured from a polymer prepared from one or more monomers selected from the group consisting of lactides.

26. A coating of claim 20 comprising a bioabsorbable surgical suture or ligature manufactured from a polymer prepared from one or more monomers selected from the group consisting of lactides.

27. A coating of claim 21 comprising a bioabsorbable surgical suture or ligature manufactured from a polymer prepared from one or more monomers selected from the group consisting of lactides.

28. A coating of claim 25 wherein the suture or ligature is manufactured from a homopolymer prepared from the monomer glycolide.

29. A coating of claim 28 wherein the suture or ligature is manufactured from a copolymer prepared from the monomers glycolide and lactide.

30. A coating of claim 28 or 29 wherein the suture or ligature is in multifilamentary form.

31. A coating of claim 30 comprising about 1/10 to 5% by weight of the coated suture or ligature.

32. A coating of claim 31 comprising about 1 to 3% by weight of the coated suture or ligature.