CA1281483C - Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefrom - Google Patents
Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefromInfo
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- CA1281483C CA1281483C CA000523853A CA523853A CA1281483C CA 1281483 C CA1281483 C CA 1281483C CA 000523853 A CA000523853 A CA 000523853A CA 523853 A CA523853 A CA 523853A CA 1281483 C CA1281483 C CA 1281483C
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- Prior art keywords
- dioxanone
- lactide
- copolymer
- mixture
- hours
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
- C08G63/66—Polyesters containing oxygen in the form of ether groups
- C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L17/00—Materials for surgical sutures or for ligaturing blood vessels ; Materials for prostheses or catheters
- A61L17/06—At least partially resorbable materials
- A61L17/10—At least partially resorbable materials containing macromolecular materials
- A61L17/12—Homopolymers or copolymers of glycolic acid or lactic acid
Abstract
ABSTRACT
A crystalline copolymer is produced by first polymerizing p-dioxanone to form a mixture of monomer and homopolymer, and then adding lactide to this mixture and polymerizing to form a copolymer. The copolymer is useful for making surgical devices such as pliability monofilament sutures and ligatures made therefrom. The process of making the copolymer is also disclosed.
A crystalline copolymer is produced by first polymerizing p-dioxanone to form a mixture of monomer and homopolymer, and then adding lactide to this mixture and polymerizing to form a copolymer. The copolymer is useful for making surgical devices such as pliability monofilament sutures and ligatures made therefrom. The process of making the copolymer is also disclosed.
Description
,f~14~.3 C~YSTALLIN~ COPOLYM~S OF P-DIOX~NONE AND LACTIDE AND
SURGICAL DEVICES MADE THE~FRO~ __ _ __ The inven~ion relates to cry~talline copolyme~ of p-dioxanone and lactide, a proce~s fo~ making 6aid copolymers, and to surgical device~ such as high - pliability monofilament ~uture6 and ligature6 made therefrom.
Backqround of the Invention Surgical de~ice~, in particular abfiorbable monofilament ~utures and ligatures and hemostatic ligating clips, made from p-dioxanone homopolymer are valuable commercial articles. This invention is directed ~o a means for pro~iding p-dio~anone polymer~ that have properties that are differen~ from tho6e that can be ob~ained in the homopolyme~. Thi6 invention thereby provides a mean~ for extending the utility of p-dioxanone polymers.
P-dioxanone polymer~ ars di~clo6ed by Doddi et al. in U.S.
Patent No. 4,052,988, who al o disclo6e and claim sutures and other 6urgical device6 made from such polymers. In the paragraph bridging Columns 8 and 9 of the Doddi et al.
patent, it i6 disclosed that lactide may be copolymerized with p-dioxanone to produce absorbable ~utures.
Surgical filament~ 6uch as 6uture~ and ligature6 of p-dioxanone homopolymer are commercially available in the form of monofilaments. One of the desirable characSeristic~ of a monofilament suture i6 to exhibit a combina~ion of high 6trength (in the form of ~traight tensile and knot tensile 6treng~h) and good pliability.
~onofilaments of p-dioxanone homopolymer6 are peIceived by the surgeon as being rather ~tiff. One of tha ~aluable .~ :
ET~-S72 8~
advantages of this invenSion is that it provides p-dioxanone polymers that are more pliable and. in many cases, stronger than p-dioxanone homopolymer, thereby substantially enhancing the utility of p-dioxanone polymers.
Brief SummarY of the Invention The polymers of the invention are certain copolymers of p-dioxanone and lactide, the predominant portion of the copolymers being polymerized p-dioxanone with the remainder being polymerized lactide. The invention also provides sterilizable surgical devices made from these copolymers, pre~erably monofilament sutures and ligatures that have a desirable combination o~ high strength and excellent pliability (in part as exhibited by low Youngis modulus). Other surgical devices are also provided by the invention. Illustrations include parts of surgical s~aples, small diameter tubes such as those that are used as sheaths to protect nerve and small vessel anastomoses, fabrics including woven or knitted tubular ~abrics, and the like.
The invention also provides a process for producing the segmented copolymers of the invention which comprises:
adding lactide to a mixture of p-dioxanone homopolymer and p-dioxanone monomer and subjecting the resulting reaction mixture to an elevated tempeeature for a period o~ time sufficient to produce a copolymer of p-dioxanone and lactide.
`:
.
- ~7,?~L4~33 ~he Prior Art In addition to the Doddi et al. pa~ent cited above (which is considered by Applicants to be the most rele~ant prior art~, a number of o~her patents are relevant in that they disclose the production of absorbable copolymers by the sequential addition o~ monomers. These patents include Okuzumi et al., U.S. Patent Nos. 4,137,921 and 4,157,437 and Rosensaft et al., U.S. Patent Nos. 4,243,775 and ~,300,565.
Detailed Description of the Invention The most convenient way to carry out the process of the invention is ~o first carry out the melt polymerization of p-dioxanone monomer to produce a mixture of poly(p-dioxa-none) homopolymer and p-dioxanone monomer, and without separating the monomer and polymer, use the resulting mixture in the process of the invention. This homopolymerization is carried out in the presence o~ a catalytically effective amount of a suitable metal-containing catalyst such as stannous octoate or stannous oxalate. Typical proportions of catalyst are found in monomer:catalyst molar ratios of from about L0,000:1 to about 60,000:1, and preferably from about 15,000:1 to about 40,000:1. The polymerization is carried out in the presence of an initiator such as an alkanol, a glycol, a hydroxyacid, or an amine. Specific illustrations of such initiators include l-dodecanol, diethylene glycol, glycolic acid, lactic acid, ethanolamine, and the like.
Typical proportions of the initiator are found in - monomer:initiator molar ratios of from about 500:1 to about 1800:1. The polymerization of p-dioxanone is carried ou~ at elevated temperatures under an inert atmosp~ere for a period of time suf~icient to produce a ~8~L4~73 mixture of p-dioxanone homopolymer and p-dioxanone monomer. Typical polymeri2ation reaction tempe~atures are within the range of from about 100C. to about 1~0C., and is preferably about 110C. The polymerization reaction is normally carried out until an equilibrium is reached between polymer and monomer. This is usually attained at about lS to 30 weight per cent monomer, based on weight of monomer plus polymer. Depending on the temperature and catalyst concentration, this reaction usually takes from about 4 to 8 hours. At the prefeered temperature of about 110C., the usual reaction time is S to 6 hours.
Lactide is then added to the mixture oe p-dioxanone homopolymer and monomer, and the resulting reaction mixture is subjected to elevated temperature for a period of time sufficient to produce the copolymers of the invention. As a general rule, ~he reaction temperature for this polymerization will be within the range of from about 110C. to about 160C., and preferably from about 120C. to about 1~0C. ~t reaction temperatures within this range, the polymerization will be complete within a period of from about 1 to about 4 hours. The examples below illustra~e specific reaction conditions.
The proportion of lactide that is added to the mixture o~
p-dioxanone homopolymer and monomer is usually from about 2 to about 30 weight per cent and pre~erably from about 5 to about 20 weight per cent, based on total weight of the reaction mixture (i.e., total weight of lactide, ~0 p-dioxanone homopolymer, and p-dioxanone monome~). The Examples below illustrate the production of the copolymers of the invention.
,ETH-672 Example 1 Preparation of Po_ydioxanone-melt/L(-lLactide at 90/l0 initial mole composition.
A flame dried, Z50 milliliter, round bottom, three-neck flask was charged with 69.15 grams (0.6777 mole) of p-dioxanone, 0.1684 gram of l-dodecanol, and 0.076 milliliter of stannous oc~oate (0.33 molar solution in toluene). The contents o~ the reaction flask were held under high vacuum at room temperature for about 16 hours.
The flask was fitted with a flame dried mechanical stirrer and an adaptor with a hose connection. The reactor was purged with nitrogen threa times before being vented with nitrogen. The reaction mixture was heated to 110C. and maintained there for 5 hours. To the reaction flask, 10.85 grams (0.0753 mole) of L(-)lactide was added and the temperature was raised to 160C. over the next 20 minutes. The bath temperature was maintained there for 2 hours. The temperature of the oil bath was lowered to 85C. and maintained there for about 16 hours. The polymer was isolated, ground, and dIied 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. A weight loss of 14.8% was observed. The resulting polymer had a melting range of 96-100C. by hot stage microscopy, an inherent viscosity of 2.27 dl/g, and a crystallinity content of about 31~ by X-ray diffraction. ~ll inheren~ viscosity ("I.V.") values repocted herein were measured at a concentration of 0.1 gram of polymer per deciliter of hexafluoroisopropyl alcohol, at 25C. The molar ratio of PDOJPL (i.e., polymerized p-dioxanone/polymerized lactide) in the copolymer product was found to be 90.5/9.5 by NMR.
(Since lactide is a cyclic dimer of two lactic acid units, as used herein, polymerized lactide also comprises two lactic acid units.) ~2c~ 3 Exam~le 2 PrePaeation of Polydioxanone-melt/L(-)Lactide at 80/20 initial mole composition.
A flame dried, 250 milliliter, round bottom, three-neck flask was charged with 59.12 grams (0.5794 mole) of p-dioxanone, 0.1620 gram of l-dodecanol, and 0.0732 milliliter of stannous octoate (0.33 molar solution in toluene). The contents of the reaction flask were held under high vacuum at room temperature for about 16 hours.
The flask was fitted with a flame dried mechanical stirrer and an adaptor with a hose connection. The reactor was purged with nitrogen thrée times before being vented with lS nitrogen. The reaction mixture was heated to 110C. and maintained there for 5 hours. To the reaction flask, 20.88 grams ~0.1149 mole) of L~-)lactide was added and the temperature was raised to 160C. over the next 20 - minutes. The bath temperature was maintained there for 2 hours. The temperature of the oil bath was lowered to 85C. and maintained there for about 16 hours. The polymer was isolated, ground, and dried 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. A weight loss of 11.9% was obseeved. The resulting polymer had a melting Z5 range of 96-99C. by hot stage microscopy, an inherent viscosity of 2.53 dl/g, and a crystallinity content of about 24%. The molar ratio of PD0/PL in the polymer was found to be 82.4/17.6 by NMR.
Ex~rusion In the preparation o~ fibers, especially surgical filaments, the copolymers are melt extruded through a spinnerette in a conventional manner to form one or more ETH-fi72 ,, . ~
SURGICAL DEVICES MADE THE~FRO~ __ _ __ The inven~ion relates to cry~talline copolyme~ of p-dioxanone and lactide, a proce~s fo~ making 6aid copolymers, and to surgical device~ such as high - pliability monofilament ~uture6 and ligature6 made therefrom.
Backqround of the Invention Surgical de~ice~, in particular abfiorbable monofilament ~utures and ligatures and hemostatic ligating clips, made from p-dioxanone homopolymer are valuable commercial articles. This invention is directed ~o a means for pro~iding p-dio~anone polymer~ that have properties that are differen~ from tho6e that can be ob~ained in the homopolyme~. Thi6 invention thereby provides a mean~ for extending the utility of p-dioxanone polymers.
P-dioxanone polymer~ ars di~clo6ed by Doddi et al. in U.S.
Patent No. 4,052,988, who al o disclo6e and claim sutures and other 6urgical device6 made from such polymers. In the paragraph bridging Columns 8 and 9 of the Doddi et al.
patent, it i6 disclosed that lactide may be copolymerized with p-dioxanone to produce absorbable ~utures.
Surgical filament~ 6uch as 6uture~ and ligature6 of p-dioxanone homopolymer are commercially available in the form of monofilaments. One of the desirable characSeristic~ of a monofilament suture i6 to exhibit a combina~ion of high 6trength (in the form of ~traight tensile and knot tensile 6treng~h) and good pliability.
~onofilaments of p-dioxanone homopolymer6 are peIceived by the surgeon as being rather ~tiff. One of tha ~aluable .~ :
ET~-S72 8~
advantages of this invenSion is that it provides p-dioxanone polymers that are more pliable and. in many cases, stronger than p-dioxanone homopolymer, thereby substantially enhancing the utility of p-dioxanone polymers.
Brief SummarY of the Invention The polymers of the invention are certain copolymers of p-dioxanone and lactide, the predominant portion of the copolymers being polymerized p-dioxanone with the remainder being polymerized lactide. The invention also provides sterilizable surgical devices made from these copolymers, pre~erably monofilament sutures and ligatures that have a desirable combination o~ high strength and excellent pliability (in part as exhibited by low Youngis modulus). Other surgical devices are also provided by the invention. Illustrations include parts of surgical s~aples, small diameter tubes such as those that are used as sheaths to protect nerve and small vessel anastomoses, fabrics including woven or knitted tubular ~abrics, and the like.
The invention also provides a process for producing the segmented copolymers of the invention which comprises:
adding lactide to a mixture of p-dioxanone homopolymer and p-dioxanone monomer and subjecting the resulting reaction mixture to an elevated tempeeature for a period o~ time sufficient to produce a copolymer of p-dioxanone and lactide.
`:
.
- ~7,?~L4~33 ~he Prior Art In addition to the Doddi et al. pa~ent cited above (which is considered by Applicants to be the most rele~ant prior art~, a number of o~her patents are relevant in that they disclose the production of absorbable copolymers by the sequential addition o~ monomers. These patents include Okuzumi et al., U.S. Patent Nos. 4,137,921 and 4,157,437 and Rosensaft et al., U.S. Patent Nos. 4,243,775 and ~,300,565.
Detailed Description of the Invention The most convenient way to carry out the process of the invention is ~o first carry out the melt polymerization of p-dioxanone monomer to produce a mixture of poly(p-dioxa-none) homopolymer and p-dioxanone monomer, and without separating the monomer and polymer, use the resulting mixture in the process of the invention. This homopolymerization is carried out in the presence o~ a catalytically effective amount of a suitable metal-containing catalyst such as stannous octoate or stannous oxalate. Typical proportions of catalyst are found in monomer:catalyst molar ratios of from about L0,000:1 to about 60,000:1, and preferably from about 15,000:1 to about 40,000:1. The polymerization is carried out in the presence of an initiator such as an alkanol, a glycol, a hydroxyacid, or an amine. Specific illustrations of such initiators include l-dodecanol, diethylene glycol, glycolic acid, lactic acid, ethanolamine, and the like.
Typical proportions of the initiator are found in - monomer:initiator molar ratios of from about 500:1 to about 1800:1. The polymerization of p-dioxanone is carried ou~ at elevated temperatures under an inert atmosp~ere for a period of time suf~icient to produce a ~8~L4~73 mixture of p-dioxanone homopolymer and p-dioxanone monomer. Typical polymeri2ation reaction tempe~atures are within the range of from about 100C. to about 1~0C., and is preferably about 110C. The polymerization reaction is normally carried out until an equilibrium is reached between polymer and monomer. This is usually attained at about lS to 30 weight per cent monomer, based on weight of monomer plus polymer. Depending on the temperature and catalyst concentration, this reaction usually takes from about 4 to 8 hours. At the prefeered temperature of about 110C., the usual reaction time is S to 6 hours.
Lactide is then added to the mixture oe p-dioxanone homopolymer and monomer, and the resulting reaction mixture is subjected to elevated temperature for a period of time sufficient to produce the copolymers of the invention. As a general rule, ~he reaction temperature for this polymerization will be within the range of from about 110C. to about 160C., and preferably from about 120C. to about 1~0C. ~t reaction temperatures within this range, the polymerization will be complete within a period of from about 1 to about 4 hours. The examples below illustra~e specific reaction conditions.
The proportion of lactide that is added to the mixture o~
p-dioxanone homopolymer and monomer is usually from about 2 to about 30 weight per cent and pre~erably from about 5 to about 20 weight per cent, based on total weight of the reaction mixture (i.e., total weight of lactide, ~0 p-dioxanone homopolymer, and p-dioxanone monome~). The Examples below illustrate the production of the copolymers of the invention.
,ETH-672 Example 1 Preparation of Po_ydioxanone-melt/L(-lLactide at 90/l0 initial mole composition.
A flame dried, Z50 milliliter, round bottom, three-neck flask was charged with 69.15 grams (0.6777 mole) of p-dioxanone, 0.1684 gram of l-dodecanol, and 0.076 milliliter of stannous oc~oate (0.33 molar solution in toluene). The contents o~ the reaction flask were held under high vacuum at room temperature for about 16 hours.
The flask was fitted with a flame dried mechanical stirrer and an adaptor with a hose connection. The reactor was purged with nitrogen threa times before being vented with nitrogen. The reaction mixture was heated to 110C. and maintained there for 5 hours. To the reaction flask, 10.85 grams (0.0753 mole) of L(-)lactide was added and the temperature was raised to 160C. over the next 20 minutes. The bath temperature was maintained there for 2 hours. The temperature of the oil bath was lowered to 85C. and maintained there for about 16 hours. The polymer was isolated, ground, and dIied 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. A weight loss of 14.8% was observed. The resulting polymer had a melting range of 96-100C. by hot stage microscopy, an inherent viscosity of 2.27 dl/g, and a crystallinity content of about 31~ by X-ray diffraction. ~ll inheren~ viscosity ("I.V.") values repocted herein were measured at a concentration of 0.1 gram of polymer per deciliter of hexafluoroisopropyl alcohol, at 25C. The molar ratio of PDOJPL (i.e., polymerized p-dioxanone/polymerized lactide) in the copolymer product was found to be 90.5/9.5 by NMR.
(Since lactide is a cyclic dimer of two lactic acid units, as used herein, polymerized lactide also comprises two lactic acid units.) ~2c~ 3 Exam~le 2 PrePaeation of Polydioxanone-melt/L(-)Lactide at 80/20 initial mole composition.
A flame dried, 250 milliliter, round bottom, three-neck flask was charged with 59.12 grams (0.5794 mole) of p-dioxanone, 0.1620 gram of l-dodecanol, and 0.0732 milliliter of stannous octoate (0.33 molar solution in toluene). The contents of the reaction flask were held under high vacuum at room temperature for about 16 hours.
The flask was fitted with a flame dried mechanical stirrer and an adaptor with a hose connection. The reactor was purged with nitrogen thrée times before being vented with lS nitrogen. The reaction mixture was heated to 110C. and maintained there for 5 hours. To the reaction flask, 20.88 grams ~0.1149 mole) of L~-)lactide was added and the temperature was raised to 160C. over the next 20 - minutes. The bath temperature was maintained there for 2 hours. The temperature of the oil bath was lowered to 85C. and maintained there for about 16 hours. The polymer was isolated, ground, and dried 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. A weight loss of 11.9% was obseeved. The resulting polymer had a melting Z5 range of 96-99C. by hot stage microscopy, an inherent viscosity of 2.53 dl/g, and a crystallinity content of about 24%. The molar ratio of PD0/PL in the polymer was found to be 82.4/17.6 by NMR.
Ex~rusion In the preparation o~ fibers, especially surgical filaments, the copolymers are melt extruded through a spinnerette in a conventional manner to form one or more ETH-fi72 ,, . ~
3~L4~33 filaments, in accordance with the following general procedure used for laboratory scale experiments.
Extrusion of the copolymers described herein was accomplished using an INSTRON Capillary Rheometer or a single screw extruder. The copolymers evaluated in the INSTRON Capillary Rheometer were packed in the preheated (80 to 90oC.) extrusion chamber and extruded through a 40 mil die (L/D=24.1) after a dwell time of 9 to 13 minutes at the extrusion temperature and a ram speed of 2 cm/min.
While extrusion tempecatures depend both on the polymer Tm and on the melt viscosity of the material a~ a given temperature, extrusion of the subject copolymers at temperatures of about 10 to 75C. above the Tm is usually satisfactory. The extrusion temperatures of the example copolymers described herein ranged from 130 to 200C.
The extrudate typically was taken up through an ice water quench bath at 24 feet/minute, although other bath temperatures and take-up speeds occasionally were used.
The extrudate filaments (which have been allowed to cyrstallize sufficiently - usually, storage of the extruded filament at room temperature foe 1 to 24 hours will suffice to permi~ the requisite crystallization to take place~ are subsequently drawn about 6X to 7.5X in a one or multistaqe drawing process in order to achieve molecular orientation and improve tensile properties. The manner of drawing is as follows:
.
The extrudate ~diameter ranqe, usually 18-20 mils) passed ~0 through rollers at an input speed of four feet per minute and into a heated draw bath of glycerine. The temperatures of the draw bath can vary from about 25 to 90C.; the exameles described herein employ temperatures between 49 and 60C. The draw ratio in this first stage ~5 ~t~ .3 of drawing can vary from 3X to about 7X; the examples described herein employ draw ratios from 4X to 6X. The paetially drawn fibers are then placed over a second set of rollers into a glycerine bath (second stage) kept at S temperatures ranging from 50 to 95C.; the examples described herein employ second stage draw temperatures of 67 to 73OC. Draw ratios of up to 2X are applied in this second s~age, but a ratio range of from 1.17X to L.625X
was e~ployed in the examples. The fiber is passed through a water-wash, taken up on a spool, and dried. A set of hot rollers can be substituted for a portion or all of the glycerin0 draw bath. The resulting oriented ~ilaments have good straight and knot tensila strengths.
Dimensional s~ability and in vivo tensile strength retention of the oriented filaments may be enhanced by subjecting ~he filaments to an annealing treatment. This optional treatment consists of heating the drawn filaments to a temperature of from about 40 to 95C., most preferably from about 60 to 90C. while rest`raining the ~ilaments to prevent any substaneial shrinkage. This pcocess may begin with the filaments initially under tension or with up to 20% shrinkage allowed prior to restraint. The filaments are held at the annealing temperature for a few minutes to several days or longer depending on the temperature and processing conditions.
In general, annealing at 60 to 90C. for u~ to about 24 hours is satisfactory for the copolyme~s of the invention. Optimum annealing time and temperature for maximum fibec in vivo stcength retention and dimensional stability is readily determined by simple experimenta~ion for each fiber composition.
48;3 g The filaments thus produced may be fabricated into sutures or ligatures, attached ~o surgical needles, packaged, and sterili~ed by known techniques.
The charac~eristic properties of the filaments of the invention are readily determined by conventional test procedures. The tensile properties (i.e., straight and knot tensile strengths, Young's Modulus, and elongation) displayed herein were determined with an INSTRON ~ensile tester. The settings used to determine the straight tensile, kno~ tensile, break elongation, and Young's Modulus were the following, unless indicated:
Gauge ChartCrosshead Length Speed Speed (cm) (cm/min)(cm/min) Straight Tensile 12 20 L0 Knot Tensile 5 10 - 10 Break Elongation 12 20 10 Young's ModulusL2 20 10 ~he straight tensile strength is calculated by dividing the focce to break by the initial cross-sectional area of the fiber. The elongation at break is read directly ~rom the stress-strain curve of the sample allotting 4-1/6~ per centimeter o~ horizontal displacement.
Young's Modulus is calculated from the slope of ~he stress-strain curve of the sample in the linear elastic : region as follows:
tan~ x GL x CS x SL
Young's Modulus , XH x XS
~5 ~8~48~
0 i t~e angle betwee~ the slope and the horizontal, ~S
ifi the initial cro~s-6e~tional area of the fiber, SL i6 the ~cale load~ XH i6 the cro6shead speed, CS i8 ~he cha~t 6peed, and ~L i6 the gauge~length. T~e SL ~ay be selected to provide a e clo~e ~o 45.
The knot tensile strength of a f iber ~8 determined in 6eparate experiments. The ~est ar~icle i~ tied int~ a s~rgeon~ knot ~ith one turn of the filament around flexible ~ubing of 1/4 inch inside diameter and 1/16 inch wall thicknes6. The 6u~geon'~ k~ot i~ a ~quare knot in which ~e free end is fir~t pa~sed twi~e, in6tead o~ once, through the loop, and the end6 draw~ taut ~o that a ~ingle knot i~ fiuperimposed upon a ~ompound k~ot. T~e ~irst knot i~ ~tarted with ~he left end over the right end and 6uf ficient ten6ion i6 exerted to ~ie t~e knot securely.
The 6p2cime~ i6 placed in the INSTRON ten6ile te~ter with the knot approximately midway between the cla~ps. The knot ten6ile ~trengt~ i~ calculated by dividing the force required to b~eak by the initial cross-6ectional area of the f iber.
The ten~ile streng~h ~alue~ and Young' 6 modulu~ (Y.M.) are reported a6 KPSI. or ~SI ~ 103.
Examples 3 and 4 .
The copolymers de~cribed in Example6 1 and 2, respectively, ~ere extruded i~o monofilament fiber~ by the proc~dure de6cribed above.
Bo~h ~iber~ were drawn a total of ~.5~ in twn ~tage~, undeL the following conditions:
ET~-672 L4~3 5taqe 1 Staqe 2 Example 3 5xt53oc.) 1.3X(69C.) Example 4 4X(53C.) 1.62SX(67C,) .Certain physical and in vitro strength properties of these drawn fibers, after annealing (70C./8 hours/restrained ~rom shrinking~ are displayed in Table I.
Table I
Examples _3 4 Diameter (mils) 7.8 7.0 15 Str. Tensile (KPSI) 49 72 Knot Tensile (KPSI) 39 5~
Elong. (~) 59 48 Y.M. (KPSI) 103 152 % BSR (pH 7.26, Phosphate Buffer, 50C.) In ~itro( ) 4 Days 66 67 7 Days 54 45 _______________________~______ . ____ ______________________ (1) In vitro ~SQ = Breaking strength retention (~
retention o~ initial tensile strength) after the indicated number of days in phosphate buffer at pH-7.26 and 50C.
___________________________________________________________ ~TH-672 ~ ~~\
ExamPle 5 Preparation of Polydioxanone-melt~L(-2Lactide at 90/10 initial weiq~t composition (92.7/7.3_mole %)_ A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was charged with 1800 grams (17.632 moles) of p-dioxanone, 3.9 milliliters of l-dodecanol, and l.9Z milliliters of stannous octoate (0.33 molar solution in toluene). The contents of the reactor were held under high vacuum at room ~emperature for about 16 hours. The reactor was purged with nitrogen.
The reaction mixture was heated ~o 110C. and maintained there for 5-l/2 hours. A sam~le o~ the polymer was removed (I.V. = 0.54 dl/g, unreacted monomer content =
25.5%) and 200 gram6 ~1.3877 mole) of L~-)lactide was added. The temperat~re was raised to and maintained at around 125C~ ~or about 2 hours. The polymer was isolated, ground, and dried 48 hours/80C./0.1 mm ~g. ~o remove any unreacted monomer. A weight loss of 22.3~ was observed. The resulting polymer had a melting temperature of about 102C. by hot stage microscoey, an inherent viscosity of 2.15 dl~g, a crystallinity content of about 33% by X-ray diffrac~ion, and a PD0/PL molar ratio o~
93.3/6.7 by NMR.
ExamPle 6 Preparation o~ Polvdioxanone-melt/L(-2Lactide at 90~10 nitial weiqht composition (92.7~7.3 mole ~2 A thoroughly dried mechanically stirred 1.5 ga~lon stainless steel reactor was charged with 1800 gram (17.632 moles) of p-dioxanone, 3.9 milliliters o~
4~3~
l-dodecanol, and 1.92 milliliters o~ stannous octoate (0.33 molar solution in toluene). The contents of the reactor wece held under high vacuum at room temperature for about 16 hours. The reactor was pucged with nitrogen. The reaction mixture was heated to 110C. and maintained there for 5-1/2 hours. A sample of the polymer was ~emoved (I.V. = 1.37 dl~g, free monomer analysis, 18.4%) and 200 grams (1.3877 mole~ of L(-)lactide was added. The tempsrature was raised to and maintained a~
around 125C. for about 2 hours. The polymer was isola~ed, ground, and dried 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. ~ weight 10s5 of 28.1% was observed. The Eesulting polymer had a melting range of 98-102C. by ho~ stage microscopy, and an inherent viscosity--of 1.85 dl/g.
Examples 7 and 8 T~e copolymers described in Examples 5 and 6, respectively, ~ere extruded into monofilament fibers.
Certain physical properties of oriented and annealed ~ibets are shown in Table II, below. The orientation conditions were as follows:
~g~_~ Staqe 2 Total Draw Ratio Example 7 5.5X(~9C.) 1.27X(72C.) 7X
Example 8 5X(55C.) 1.4X(73C.) 7X
The annealing conditions for both fibers were 12 hours at 60C., restrained from shrinking.
12' ? 3~L4 8. 3 Table II_ Example_7 ExamPle 8 5 Fiber ProPerties Oriented Annealed Oriented Annealed (Natural~ (2) 12h~60C. 12h/60C.
Diameter (mils) 7.~ 7.9 7.4 7.6 5tr. Tensile XPSI 92 9~ 108 99 Knot Tensile, KPSI 45 ~8 46 47 Elongation ~ Break % 65 3~ 62 42 Young's Modulus KPSI 85 143 88 lal In ~itro BSR
-4 days/50C. - 70% - 67%
7 days~50C. - - - 56%
In Vivo BSR( ) 21 Days 64% 59%
28 Days 48% 49%
56 Days 9% 11%
In Vivo ~bsorptio~(4) 9L Days 69 73 ll9 Days 30 6a 154 Days O o -_______________________________ (2) "Natucal" means undyed.
(3)/(4) In vivo BSR and absorption are explained below.
______ ___________________________________________________ Breakinq Strenqth Reteotion In_Vivo The breaking strength reten~ion (BSR) ~n vivo of a ~iber is determined by implanting two strands of the fiber in the dorsal subcutis of each of a number of Long-Evans rats. The number of rats used is a function of the number .
... .
L4~33 of implantation periods, employing 4 rats per period giving a total of eight (8) examples for each of the periods. Thus 16, 2g, or 32 segments of each fiber are implanted corresponding to two, three, or four implantation periods. The periods of in ViVQ residence are 7, 14, 21, or 28 days. The ratio of the mean value of a determinations of the breaking strength (determined with an INSTRON tensile tester employing the following settings: a gauge length of 1 inch, a chart speed of 1 inch/minute, and a crosshead speed of 1 inch/minuts) at each period to the mean value (of 8 detecminations~
obtained for the fiber prior to implantation constitutes its breaking strength retention for that period.
In Vivo AbsorPtion The in vivo absorption test is carried out as follows:
Two 2-centimeter sections oE the sample filaments are Z0 implanted into both the lef~ and right gluteal muscles of two female rats for each period of the study. This procedure yields a potential total of 8 cross-sections per period, for periods of 5, 91, 119, 154 and 210 days.
The implants are recovered at the designated intervals and fixed in buffered ~ormalin. Muscle cross-sections ace made and stained with HSE and examined microscopically.
Tissue reaction~ are evaluated, and the diameter of the remaining filament is determined. The filament diameter after 5 days is used as the 100% reference point for determining the percent cross sectional area remaining after the later periods.
~ --\
~ 8~L4a~
ExamPle 9 Preparation o~ PolYdioxanone-melt/L(-)Lactide at 90/10 initial weiqht comPosition (_2.7/7.3 mole %) A thoroughly dried mechanically sti~red 1.5 gallon stainlass steel reactor was charged with 1800 grams (1~.632 moles) of p-dioxanone, ~.9 milliliters of l-dodecanol, and 1.92 milliliters of stannous octoate (0.33 molar solution in toluene). The contents of the reactor were held under high vacuum a~ room temperature for about 16 hours. The reactor was purged with nitrogen. The reaction mixture was heated to 110C. and maintained there for 5-1/2 hours. A sample of the polymer lS was removed (I.V. = 0.79 dl/g., free monomer = 10.5~ --- this free monomer content analysis may have been in error, since it seem6 low) and 200 grams (1.3877 mole) of L(-)lactide was added. The temperature was raised to and maintained at around 125C. for about 2 hours. The 20 polymer was isolated f ground, and dried 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. A weight loss o~
22% was observed. The resulting polymer had a melting range of 102-106C. by hot stage miccoscopy, an inherent viscosity of 1.95 dl/g, and a PD0/PL molar ratio o~
25 93.8/6.2 by NMR.
Example lO
~ aration o~ Polydioxanone-melt/L(-)lactide at 90/10 30 initial weiqht composition ~92.7/7.3 mol %) in a Pilot ~la____ize reactor A thoroughly dried mechanically stirred lO-gallon stainless steel "Helicone" Feactor was charged, under ~TH-672 ~2~3~L483 nitrogen purge, with 8,950 grams (87.745 moles) o~
p-dioxanone, 9.5~ milliliters of stannous octoate catalyst solution (0.33 molar solution in toluene)~ and 15.~6 qrams of l-dodecanol. The contents o~ the reactor were held under a vacuum (1 mm of mercury or less) for 20 minutes.
The vacuum was released with dry nitrogen and the contents were again subiected to a vacuum of at lea~t 1 mm of mercury for an additional 20 minutes. The reactor was then purged with nitrogen. The reaction mixture was heated to 110C. The poly~eri~a~ion time was 6 hours from the time the temperature reached 100C. At the end of the six-hour ~irst stage polymerization, (I.V. = 1.20 dl/g, unreacted monomer = 25.3~), 994 grams (6.903 moles) of L(-)lactide was added to the reactor under nitrogen purge. The temperature was raised to about 140C. and was maintained there for 2 hours. ~fter the two-houL period, - the polymer was isolated, cooled, ground, sieved, and then dried in a 1 cubic foot vacuum tumble drier, under vacuum, ~or ten hours at ambient temperature (about 25~C.), the~
12 hours at 60C., and then 20 hours at 70C., to remove any unreacted monomer(s). A summa~y o~ ~he polymer p~operties is presented in Table V, below.
The copolymers o~ Example 9 and 10 were extruded into mono~ilaments by melting at 133-160C. and pumping the melt through a 60-mil capillary die having a 5/1 length to diameter ratio. The extrudate was quenched by passage through a cold (i. e., up to room temperature) water bath and was then drawn in two stages. The ~irst stage drawing was done on rolls at room temperature, and the second s~age drawing included passing the ~ilament through a heated oven. Some o~ the extrusion and drawing conditions are displayed below in Table III:
~TH-672 ,, ~'~8 !L4~g3 Table III
_xame~e 9 ExamPle 10 Block~Die Temp. C.116~121 133/135 1st and 2nd Godet speed, feet/min. 12 13 3rd Godet speed, fee~/min. 60 60 Oven Temperature, C. 49 77 4th Godet speed, feet~min. 75 85 Total draw ratio 6.3X 6.5X
The fibers were allowed to crystallize further overnight at room temperature, and then were redrawn in one stage through a heated oven. The total draw ratio varied from 1.20X to 1.33X, and the oven temperature was 82C. ~fter redrawing, the fibers were annealed under dry nitrogen for 6 hours with no relaxation at 90C. The tensile p~operties of size 2/0 samples of the Example 9 and 10 fibers are displayed below in Table IV:
Table IV
Example 9ExamPle 10 Diameter, mils 12.9 13.1 Straight tensile, KPSI 93 86 ~not tensile, KPSI 54 51 Elongation, % 49 54 Young's Modulus, KPSI 184 152 ET~-672 ....
ExamPle 11 _reparation of D~C violet ~2 dYed Polydioxanone-melt/L(-~lactide at_91/9 initial weiqht comPoSition (93.4/6.6 mol %) in a pilot Plant size reactor The polymer preparation procedure followed was similar to that described in Example 10, with the following dif~erences:
Initial charge was 10,250 grams (100.49 moles) o~
p-dioxanone, 11.82 milliliters of stannous octoate catalyst solution, 16.35 grams of l-dodecanol, and 10.25 grams of ~&C violet #2 dye. ~t the end of the six-hou~ ficst stage ~olymerization (I.V~ = 1.14 dl/g, unreacted monomer =
23.5~), 1025 grams (7.118 moles) of L(-)lactide was added.
The polymer, after isolation, cooling, grinding, and sieving~ was dried in a vacuum tumble drier for 10 hours at ambient temperature and then 32 hours at 70C. A summary of the polymer properties is presented in Table V:
Table V
Examele 10 Example 11 Inherent viscosity,dl/g 2.02 1.82 Tg,C. (DSC) -6 _9 Tm,C.(DSC) 104 110 Crystallinity, % 34 38 (X-ray diffraction) PD0/PL Uol ratio, by NMR 9~.7/7.3 93.0/7.0 .
The copolymer of Example 11 was extruded into a monofilament in a manner similar to ~hat des~ribed above for Examples 9 and 10. Some of the extrusion and drawing , . .
conditions for the production of size 2/0 fibers are shown below in Table VI:
Table V~
~lock/Die Temp., C~ 132/133 1st and 2nd Godet speed, fpm 13 3rd Godst sæeed, fpm 60 Oven Temperature, C. 77 10 4th Godet speed, ~pm 92 Total draw ratio 7.lX
The fiber was allowed to crystallize further overnight at roo~ temperature, and then was redIawn in one stage through a heated oven under conditions similar to those described above for Examples 9 and 10. After redrawing, the fibers were annealed under dry nitrogen at 90C. with no relaxation for 6 hours. The annealed fiber tensile properties of this size 2/0 fiber are displayed below in Table VII:
Table VII
J
Diameter, mils 15.0 25 Straight tensile, KPSI 86 Knot Tensile, KPSI 51 Elongation, ~ 63 Young's Modulus, KPSI 192 In vitro BSR
(5 ~ays/550C./pH=9.1) 57.6 48,~
Example 12 Preparation of Polydioxanone-melt~k~=~Lac~ide at 70/30 5 initial weiqht comPosition (76.7t23.3 mole %) A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was charged with 1400 grams (13.7137 moles) of p-dioxanone, 0.77 milliliter of diethylene glycol, 1.81 milliliters of stannous octoate (0.33 molar solution in toluene), and 1.0 gram of D~C
violet #2. The contents of the reaction flask were held under high Yacuum at room temperature for about 16 hours.
The reac~or was purged and vented with nitrogen. The reaction mixture was heated to 110C. and maintained there for 6 hours. A sample of the polymer was removed (fo~
I.V. and free monomer content analysis) and 600 grams (4.1631 moles) of L(-)lactide was added. The temperature was raised to, and maintained at, around 135C. for about 2 hours. The polymer was isolated, ground, and dried to remove any unreacted monomers. A weight loss of 27.3~ was observed. The resulting polymer had a melting range o~
980- 04C. (by hot melt microscoPy) at 25~ crystallinity, an inherent viscosity of 2.4~ dl/q, and a PD0/PL mol ratio 25 o~ 83.6/16.4 by NMR.
Example 13 Preparation of Pol~dioxanone-melt/L(-)Lactide at 93/7 bY
weiqht_(95/5 bY mole ; A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was charged with 1860 grams ~18.2196 moles) of p-dioxanone, 3.93 milliliters of r' l-dodecanol, 1.94 milliliters of stannous octoate (0.33 molar solution in toluene), and 1.0 gram of D~C violot ETH ~72 ., .
3~L4~
~2. The contents of the reactor were held under high vacuum at room temperature for about 16 hours. The eeactor was purged and vented with nitrogen. The reaction mixture wa~ heated to 110C. and maintained there for 6 hours. A sample of the polyme~ was removed (I.V. = 1.88 dl/g, free monomer content = 19.2%) and 140 grams (0.9714 mole) of Lt-)lactide was added. The temperature was raised to, and maintained at, 125-135C. for about 2 hours. The polymer was isolated, ground, and dcied to remove any unreacted monomers. A weight loss of 24.2~ was - observed. The resulting polymer had a melting range of 100-106C. by hot melt microscopy, a crystallinity of 26%, and an inherent viscosity of 2.09 dl/g.
Pro~erties of Fibers from ExamPles 12 and 13 The copolymers described in Examples 12 and 13 were extruded, drawn, and redrawn into monofilament fibers in a manner similar to that described above for ExamPles 9 ~Q
11. The redrawn fibers were annealed 6 hours at 90C.
with no relaxation tunder nitrogen). The tensile properties of these f ibers were the following:
Table VIII
Example 12 ExamPle 13 Diameter, mils13.7 13.6 Straig~ tensile, KPSI 78 96 Knot tensile, KPSI 43.4 50 Elongation, ~ ~ 33 Young's Modulus, KPSI 331 253 Example 14 E'rH-672 ''' ' , . :, .. ,.: : , 4~33 PreParation of PolYdioxanone-melt/L(-lLactide at 93/7 bY
weiqht ~5/5 by mole %) 5 A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was char~ed with 1~60 grams (~8.2196 moles) of p-dioxanone, 1.09 milliliters of diethylene glycol, 1.94 milliliters of stannous octoate (0.33 molar solution in toluene~, and 1.0 gram of D~C
viole~ #2. The conten~s of the reactor were held under high vacuum at room temperature for about 16 hours. The reactor was purged and vented with nitrogen. The reaction mixtuLe was heated to 110C. and maintained there for 6 hours. A sample of the polymer was removed (I.V. = 2.34 dl/g, free monomer = 21.5%~ and 140 grams (0.9714 mole) of L(-~lactide was added. The temperature wa~ raised to, and maintained at, 125-135~C. for about 2 hours. The polymer was isolated, ground, and dried to remove any unreacted monomers. A weight loss of 24% was observed. The cesulting polymer had a melting range of 97-103C.by hot stage microscopy, and an inherent viscosity of 2.65 dl/g.
Example 15 PreParation of Polydioxanone-melt/D~L-Lactide at 70t30 initial com~osition (76.7/23.3 moLe %1 A flame dried, 250 milliliter, round bottom, two-neck flask was charged with 70 grams (0.6862 mole) o~
p-dioxanone, O.L82 millilite~ of l-dodecanol, and 0.090 milliliter of stannous octoate (0.33 molar solution in toluene). The contents of the reaction ~lask were held under high vacuum at room temperature for about 16 hours.
4~3 The flask was fitted with a flame dried mechanical sti~rer and an adaptor with a hose connection. The reactor was purged with nitrogen three times befo~e being vented with nitrogen. The reaction mix~ure was heated to 110C. and maintained there for 6 hours. To the reaction ~lask, 30 grams (0.2081 mole) of D,L-lactide was added and the temperature was raised to 140C. and maintained there for 2 hours. The polymer was isolated, ground, and dried at 60-80C.~6~ Hrs/0.1 mm Hg. to remove unreactad monomers.
A weight loss of 29.6% was observed. The resulting ~olymer had a melting range of 98-102C., and an inherent viscosity oE 1.69 dl/g.
The copolymer described in Example 15 was extruded into monofilament fibers. The physical properties of drawn and annealed t6 hrs/90C.) fibers are shown in Table IX.
Table IX
_ Example L5 Initial composition of PD0-melt/D,L-lactide 70/30 by weight %
76.7/23.3 by mole I.V., dl/g 1.69 Tm 108C. (DSC) Tg -7.5C. (DSC) Crystallinity 29%
30 Fiber Properties Size_ ?/ Size 4/0 (annealed 6 hrs/90C./
no shrinkage) 35 Diameter (mils) 13.36 7,73 ET~-672 Straight Tensile, KPSI 59 78 Knot Tensile, KPSI 39 50 Elonga~ion, % 60 42 You~g's Modulus, KPSI 203 24 It is ~robable that the subject copolymers comprise long blocXs of polymerized p-dioxanone, which are crystallizable, with shorter segments containing random sequences of polymerized p~dioxanone and lac~ide. These shor~er segments are essentially non-crystallizable. which accounts for the fact that the copolymers of this invention have a slightly lower degree of crystallization than the p-dioxanone nomopolymer.
NMR analyses of the copolymers of the invention indicate that the comonomers are chemically linked therein. X-ray analyses of the copolymers indicate the presence of poly(p-dioxanone) crystallinity. It also indicates the presence of long enough segments or blocks to give rise to crystallinity. The results of these two analytical ~echniques support the view that the ~olymers o~ the invention are not random copolymers. ~andom copolymers are known to be essentially non-crystalline. Gel permeation chromatography data also support the view that the subjec~ copolymers do not comprise blands of two or more di~tinct ~olymers.
Based on the foregoing discussion the segmented copolymers of the invention may be characterized as ~ollows:
Contain from about 70 to about 98 weight per cent polymerized p-dioxanone, the remainder being co-polymerized lactide. For the ~referred suture utility, the copolymer~ contain from about 90 to ~7 mol ~er cent co-polymerized p-dioxanone, the remainder being E'rH-672 1'~81~83 polymerized lactide.
In the natural (undyed) state, the copolyme~ has a melting temperature, by differential scanning calorimetry or hot stage microscopy, of from about 90 to about 110C. (the addition of dye may raise the melting temperature by as much as about 5C.);
In the molten state, by optical microscopy, the copolymer ~0 has a single phase;
By X-ray diffraction analysis, the copolymer has a crystallini~y of from about 20 to about 45 per cent; and By gel permeation chromatography, the copolymer shows only a single molecular weigh~ distribution curve.
The subject copolymers can be made having inherent viscosities from about 1.6 to about 2.7, and are preferably made having IV's of from about 1.9 to about 2.2. As a general rule, it is dif~icult to pcocess p-dioxanone homopolymers into fibers if such homopolymers have I.V.'s greatec than abou~ 1.95. Therefore, this invention provides a means for providing p-dioxanone polymer fibers of hi~her molecular weight than has been heretofore available. The copolymers of ~his invention appear to be more thermally stable than p-dioxanone homopolymer.
Drawn and annealed monofilaments, from which surgical sutures and li~atures are made, made from the copolymers of the invention are usually more pliable ~han comparably sized monofilament fibers made from p-dioxanone homopolymer. At the same time, the monofilamene fibers of the subject invention usually have equal or higher 48~3 strength than the monofilament fibers made from the homopolymer. Thi6 advantageoUS combination of pro~erties is illustrated by the following Example 16:
Example 16 By a procedure analogous to th~t described in Example 5, above, a copolymer was made f~om p-dioxanone and L(-)lactide in molar proportions of 95/5. The resulting polymer had a melting range of 99-100C. by hot stage microscopy, an I.V. of 2.17 dl/g, a per cent crystallinity of about 28 by X-ray dif~raction, and a PD0/PL molar ratio of 95J5 by NMR.
The copolymer was extruded and drawn into monofilaments by a procedure analogous to those described above. The drawing conditions were as follows:
1st stage draw 4x at 47C.
2nd stage draw 1.6S75x at 69~C.
Total draw ratio 6.75x The drawn monofilamen~s were annealed 6 houcs at 80C., with a 5% relaxation. Representative pcoperties of the drawn and annealed monofilaments ace displayed in Ta~le X, below, along with properties of typical commercial p-dioxanone homopolymer drawn and annealed under similar conditions:
, , .
Table X
ExamRle L6 Homopolymer D~awn and Control-Drawn Drawn Annealed and Annealed Diameter, mils 7.0 7.6 7-8 Str. Tensile, KPSI 100 ~7 ~1 Knot Tensile, KPSI 55 54 52 Elongation, %. 56 50 49 Youngs Modulus, KPSI 137 169 271 The properties of monofilaments produced from the copolymers of the invention are dependent upon a number of factors, such as PD0/PL ratio, molecular weight, drawing and annealing conditions, and the like. As a general rule, howevec, drawn and annealed mono~ilament fibers made from the preferred copolymers (which have PD0/PL mol ratios o~ from about 90/10 to about 97/3), will exhibit the following proeerties:
Straight tensile, KPSI70 - 110 25 Knot Tensile, KPSI 40 - 70 Elongation, per cent 30 - 65 Young'~ Modulus, KPSI100 - 250 In vivo BSR, 3 weeks50 - 70%
4 weeks40 - 50~
8 weeks 5 - 15%
In vivo Absorption. to zero less than 5 to 6 months ~TH-672
Extrusion of the copolymers described herein was accomplished using an INSTRON Capillary Rheometer or a single screw extruder. The copolymers evaluated in the INSTRON Capillary Rheometer were packed in the preheated (80 to 90oC.) extrusion chamber and extruded through a 40 mil die (L/D=24.1) after a dwell time of 9 to 13 minutes at the extrusion temperature and a ram speed of 2 cm/min.
While extrusion tempecatures depend both on the polymer Tm and on the melt viscosity of the material a~ a given temperature, extrusion of the subject copolymers at temperatures of about 10 to 75C. above the Tm is usually satisfactory. The extrusion temperatures of the example copolymers described herein ranged from 130 to 200C.
The extrudate typically was taken up through an ice water quench bath at 24 feet/minute, although other bath temperatures and take-up speeds occasionally were used.
The extrudate filaments (which have been allowed to cyrstallize sufficiently - usually, storage of the extruded filament at room temperature foe 1 to 24 hours will suffice to permi~ the requisite crystallization to take place~ are subsequently drawn about 6X to 7.5X in a one or multistaqe drawing process in order to achieve molecular orientation and improve tensile properties. The manner of drawing is as follows:
.
The extrudate ~diameter ranqe, usually 18-20 mils) passed ~0 through rollers at an input speed of four feet per minute and into a heated draw bath of glycerine. The temperatures of the draw bath can vary from about 25 to 90C.; the exameles described herein employ temperatures between 49 and 60C. The draw ratio in this first stage ~5 ~t~ .3 of drawing can vary from 3X to about 7X; the examples described herein employ draw ratios from 4X to 6X. The paetially drawn fibers are then placed over a second set of rollers into a glycerine bath (second stage) kept at S temperatures ranging from 50 to 95C.; the examples described herein employ second stage draw temperatures of 67 to 73OC. Draw ratios of up to 2X are applied in this second s~age, but a ratio range of from 1.17X to L.625X
was e~ployed in the examples. The fiber is passed through a water-wash, taken up on a spool, and dried. A set of hot rollers can be substituted for a portion or all of the glycerin0 draw bath. The resulting oriented ~ilaments have good straight and knot tensila strengths.
Dimensional s~ability and in vivo tensile strength retention of the oriented filaments may be enhanced by subjecting ~he filaments to an annealing treatment. This optional treatment consists of heating the drawn filaments to a temperature of from about 40 to 95C., most preferably from about 60 to 90C. while rest`raining the ~ilaments to prevent any substaneial shrinkage. This pcocess may begin with the filaments initially under tension or with up to 20% shrinkage allowed prior to restraint. The filaments are held at the annealing temperature for a few minutes to several days or longer depending on the temperature and processing conditions.
In general, annealing at 60 to 90C. for u~ to about 24 hours is satisfactory for the copolyme~s of the invention. Optimum annealing time and temperature for maximum fibec in vivo stcength retention and dimensional stability is readily determined by simple experimenta~ion for each fiber composition.
48;3 g The filaments thus produced may be fabricated into sutures or ligatures, attached ~o surgical needles, packaged, and sterili~ed by known techniques.
The charac~eristic properties of the filaments of the invention are readily determined by conventional test procedures. The tensile properties (i.e., straight and knot tensile strengths, Young's Modulus, and elongation) displayed herein were determined with an INSTRON ~ensile tester. The settings used to determine the straight tensile, kno~ tensile, break elongation, and Young's Modulus were the following, unless indicated:
Gauge ChartCrosshead Length Speed Speed (cm) (cm/min)(cm/min) Straight Tensile 12 20 L0 Knot Tensile 5 10 - 10 Break Elongation 12 20 10 Young's ModulusL2 20 10 ~he straight tensile strength is calculated by dividing the focce to break by the initial cross-sectional area of the fiber. The elongation at break is read directly ~rom the stress-strain curve of the sample allotting 4-1/6~ per centimeter o~ horizontal displacement.
Young's Modulus is calculated from the slope of ~he stress-strain curve of the sample in the linear elastic : region as follows:
tan~ x GL x CS x SL
Young's Modulus , XH x XS
~5 ~8~48~
0 i t~e angle betwee~ the slope and the horizontal, ~S
ifi the initial cro~s-6e~tional area of the fiber, SL i6 the ~cale load~ XH i6 the cro6shead speed, CS i8 ~he cha~t 6peed, and ~L i6 the gauge~length. T~e SL ~ay be selected to provide a e clo~e ~o 45.
The knot tensile strength of a f iber ~8 determined in 6eparate experiments. The ~est ar~icle i~ tied int~ a s~rgeon~ knot ~ith one turn of the filament around flexible ~ubing of 1/4 inch inside diameter and 1/16 inch wall thicknes6. The 6u~geon'~ k~ot i~ a ~quare knot in which ~e free end is fir~t pa~sed twi~e, in6tead o~ once, through the loop, and the end6 draw~ taut ~o that a ~ingle knot i~ fiuperimposed upon a ~ompound k~ot. T~e ~irst knot i~ ~tarted with ~he left end over the right end and 6uf ficient ten6ion i6 exerted to ~ie t~e knot securely.
The 6p2cime~ i6 placed in the INSTRON ten6ile te~ter with the knot approximately midway between the cla~ps. The knot ten6ile ~trengt~ i~ calculated by dividing the force required to b~eak by the initial cross-6ectional area of the f iber.
The ten~ile streng~h ~alue~ and Young' 6 modulu~ (Y.M.) are reported a6 KPSI. or ~SI ~ 103.
Examples 3 and 4 .
The copolymers de~cribed in Example6 1 and 2, respectively, ~ere extruded i~o monofilament fiber~ by the proc~dure de6cribed above.
Bo~h ~iber~ were drawn a total of ~.5~ in twn ~tage~, undeL the following conditions:
ET~-672 L4~3 5taqe 1 Staqe 2 Example 3 5xt53oc.) 1.3X(69C.) Example 4 4X(53C.) 1.62SX(67C,) .Certain physical and in vitro strength properties of these drawn fibers, after annealing (70C./8 hours/restrained ~rom shrinking~ are displayed in Table I.
Table I
Examples _3 4 Diameter (mils) 7.8 7.0 15 Str. Tensile (KPSI) 49 72 Knot Tensile (KPSI) 39 5~
Elong. (~) 59 48 Y.M. (KPSI) 103 152 % BSR (pH 7.26, Phosphate Buffer, 50C.) In ~itro( ) 4 Days 66 67 7 Days 54 45 _______________________~______ . ____ ______________________ (1) In vitro ~SQ = Breaking strength retention (~
retention o~ initial tensile strength) after the indicated number of days in phosphate buffer at pH-7.26 and 50C.
___________________________________________________________ ~TH-672 ~ ~~\
ExamPle 5 Preparation of Polydioxanone-melt~L(-2Lactide at 90/10 initial weiq~t composition (92.7/7.3_mole %)_ A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was charged with 1800 grams (17.632 moles) of p-dioxanone, 3.9 milliliters of l-dodecanol, and l.9Z milliliters of stannous octoate (0.33 molar solution in toluene). The contents of the reactor were held under high vacuum at room ~emperature for about 16 hours. The reactor was purged with nitrogen.
The reaction mixture was heated ~o 110C. and maintained there for 5-l/2 hours. A sam~le o~ the polymer was removed (I.V. = 0.54 dl/g, unreacted monomer content =
25.5%) and 200 gram6 ~1.3877 mole) of L~-)lactide was added. The temperat~re was raised to and maintained at around 125C~ ~or about 2 hours. The polymer was isolated, ground, and dried 48 hours/80C./0.1 mm ~g. ~o remove any unreacted monomer. A weight loss of 22.3~ was observed. The resulting polymer had a melting temperature of about 102C. by hot stage microscoey, an inherent viscosity of 2.15 dl~g, a crystallinity content of about 33% by X-ray diffrac~ion, and a PD0/PL molar ratio o~
93.3/6.7 by NMR.
ExamPle 6 Preparation o~ Polvdioxanone-melt/L(-2Lactide at 90~10 nitial weiqht composition (92.7~7.3 mole ~2 A thoroughly dried mechanically stirred 1.5 ga~lon stainless steel reactor was charged with 1800 gram (17.632 moles) of p-dioxanone, 3.9 milliliters o~
4~3~
l-dodecanol, and 1.92 milliliters o~ stannous octoate (0.33 molar solution in toluene). The contents of the reactor wece held under high vacuum at room temperature for about 16 hours. The reactor was pucged with nitrogen. The reaction mixture was heated to 110C. and maintained there for 5-1/2 hours. A sample of the polymer was ~emoved (I.V. = 1.37 dl~g, free monomer analysis, 18.4%) and 200 grams (1.3877 mole~ of L(-)lactide was added. The tempsrature was raised to and maintained a~
around 125C. for about 2 hours. The polymer was isola~ed, ground, and dried 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. ~ weight 10s5 of 28.1% was observed. The Eesulting polymer had a melting range of 98-102C. by ho~ stage microscopy, and an inherent viscosity--of 1.85 dl/g.
Examples 7 and 8 T~e copolymers described in Examples 5 and 6, respectively, ~ere extruded into monofilament fibers.
Certain physical properties of oriented and annealed ~ibets are shown in Table II, below. The orientation conditions were as follows:
~g~_~ Staqe 2 Total Draw Ratio Example 7 5.5X(~9C.) 1.27X(72C.) 7X
Example 8 5X(55C.) 1.4X(73C.) 7X
The annealing conditions for both fibers were 12 hours at 60C., restrained from shrinking.
12' ? 3~L4 8. 3 Table II_ Example_7 ExamPle 8 5 Fiber ProPerties Oriented Annealed Oriented Annealed (Natural~ (2) 12h~60C. 12h/60C.
Diameter (mils) 7.~ 7.9 7.4 7.6 5tr. Tensile XPSI 92 9~ 108 99 Knot Tensile, KPSI 45 ~8 46 47 Elongation ~ Break % 65 3~ 62 42 Young's Modulus KPSI 85 143 88 lal In ~itro BSR
-4 days/50C. - 70% - 67%
7 days~50C. - - - 56%
In Vivo BSR( ) 21 Days 64% 59%
28 Days 48% 49%
56 Days 9% 11%
In Vivo ~bsorptio~(4) 9L Days 69 73 ll9 Days 30 6a 154 Days O o -_______________________________ (2) "Natucal" means undyed.
(3)/(4) In vivo BSR and absorption are explained below.
______ ___________________________________________________ Breakinq Strenqth Reteotion In_Vivo The breaking strength reten~ion (BSR) ~n vivo of a ~iber is determined by implanting two strands of the fiber in the dorsal subcutis of each of a number of Long-Evans rats. The number of rats used is a function of the number .
... .
L4~33 of implantation periods, employing 4 rats per period giving a total of eight (8) examples for each of the periods. Thus 16, 2g, or 32 segments of each fiber are implanted corresponding to two, three, or four implantation periods. The periods of in ViVQ residence are 7, 14, 21, or 28 days. The ratio of the mean value of a determinations of the breaking strength (determined with an INSTRON tensile tester employing the following settings: a gauge length of 1 inch, a chart speed of 1 inch/minute, and a crosshead speed of 1 inch/minuts) at each period to the mean value (of 8 detecminations~
obtained for the fiber prior to implantation constitutes its breaking strength retention for that period.
In Vivo AbsorPtion The in vivo absorption test is carried out as follows:
Two 2-centimeter sections oE the sample filaments are Z0 implanted into both the lef~ and right gluteal muscles of two female rats for each period of the study. This procedure yields a potential total of 8 cross-sections per period, for periods of 5, 91, 119, 154 and 210 days.
The implants are recovered at the designated intervals and fixed in buffered ~ormalin. Muscle cross-sections ace made and stained with HSE and examined microscopically.
Tissue reaction~ are evaluated, and the diameter of the remaining filament is determined. The filament diameter after 5 days is used as the 100% reference point for determining the percent cross sectional area remaining after the later periods.
~ --\
~ 8~L4a~
ExamPle 9 Preparation o~ PolYdioxanone-melt/L(-)Lactide at 90/10 initial weiqht comPosition (_2.7/7.3 mole %) A thoroughly dried mechanically sti~red 1.5 gallon stainlass steel reactor was charged with 1800 grams (1~.632 moles) of p-dioxanone, ~.9 milliliters of l-dodecanol, and 1.92 milliliters of stannous octoate (0.33 molar solution in toluene). The contents of the reactor were held under high vacuum a~ room temperature for about 16 hours. The reactor was purged with nitrogen. The reaction mixture was heated to 110C. and maintained there for 5-1/2 hours. A sample of the polymer lS was removed (I.V. = 0.79 dl/g., free monomer = 10.5~ --- this free monomer content analysis may have been in error, since it seem6 low) and 200 grams (1.3877 mole) of L(-)lactide was added. The temperature was raised to and maintained at around 125C. for about 2 hours. The 20 polymer was isolated f ground, and dried 48 hours/80C./0.1 mm Hg. to remove any unreacted monomer. A weight loss o~
22% was observed. The resulting polymer had a melting range of 102-106C. by hot stage miccoscopy, an inherent viscosity of 1.95 dl/g, and a PD0/PL molar ratio o~
25 93.8/6.2 by NMR.
Example lO
~ aration o~ Polydioxanone-melt/L(-)lactide at 90/10 30 initial weiqht composition ~92.7/7.3 mol %) in a Pilot ~la____ize reactor A thoroughly dried mechanically stirred lO-gallon stainless steel "Helicone" Feactor was charged, under ~TH-672 ~2~3~L483 nitrogen purge, with 8,950 grams (87.745 moles) o~
p-dioxanone, 9.5~ milliliters of stannous octoate catalyst solution (0.33 molar solution in toluene)~ and 15.~6 qrams of l-dodecanol. The contents o~ the reactor were held under a vacuum (1 mm of mercury or less) for 20 minutes.
The vacuum was released with dry nitrogen and the contents were again subiected to a vacuum of at lea~t 1 mm of mercury for an additional 20 minutes. The reactor was then purged with nitrogen. The reaction mixture was heated to 110C. The poly~eri~a~ion time was 6 hours from the time the temperature reached 100C. At the end of the six-hour ~irst stage polymerization, (I.V. = 1.20 dl/g, unreacted monomer = 25.3~), 994 grams (6.903 moles) of L(-)lactide was added to the reactor under nitrogen purge. The temperature was raised to about 140C. and was maintained there for 2 hours. ~fter the two-houL period, - the polymer was isolated, cooled, ground, sieved, and then dried in a 1 cubic foot vacuum tumble drier, under vacuum, ~or ten hours at ambient temperature (about 25~C.), the~
12 hours at 60C., and then 20 hours at 70C., to remove any unreacted monomer(s). A summa~y o~ ~he polymer p~operties is presented in Table V, below.
The copolymers o~ Example 9 and 10 were extruded into mono~ilaments by melting at 133-160C. and pumping the melt through a 60-mil capillary die having a 5/1 length to diameter ratio. The extrudate was quenched by passage through a cold (i. e., up to room temperature) water bath and was then drawn in two stages. The ~irst stage drawing was done on rolls at room temperature, and the second s~age drawing included passing the ~ilament through a heated oven. Some o~ the extrusion and drawing conditions are displayed below in Table III:
~TH-672 ,, ~'~8 !L4~g3 Table III
_xame~e 9 ExamPle 10 Block~Die Temp. C.116~121 133/135 1st and 2nd Godet speed, feet/min. 12 13 3rd Godet speed, fee~/min. 60 60 Oven Temperature, C. 49 77 4th Godet speed, feet~min. 75 85 Total draw ratio 6.3X 6.5X
The fibers were allowed to crystallize further overnight at room temperature, and then were redrawn in one stage through a heated oven. The total draw ratio varied from 1.20X to 1.33X, and the oven temperature was 82C. ~fter redrawing, the fibers were annealed under dry nitrogen for 6 hours with no relaxation at 90C. The tensile p~operties of size 2/0 samples of the Example 9 and 10 fibers are displayed below in Table IV:
Table IV
Example 9ExamPle 10 Diameter, mils 12.9 13.1 Straight tensile, KPSI 93 86 ~not tensile, KPSI 54 51 Elongation, % 49 54 Young's Modulus, KPSI 184 152 ET~-672 ....
ExamPle 11 _reparation of D~C violet ~2 dYed Polydioxanone-melt/L(-~lactide at_91/9 initial weiqht comPoSition (93.4/6.6 mol %) in a pilot Plant size reactor The polymer preparation procedure followed was similar to that described in Example 10, with the following dif~erences:
Initial charge was 10,250 grams (100.49 moles) o~
p-dioxanone, 11.82 milliliters of stannous octoate catalyst solution, 16.35 grams of l-dodecanol, and 10.25 grams of ~&C violet #2 dye. ~t the end of the six-hou~ ficst stage ~olymerization (I.V~ = 1.14 dl/g, unreacted monomer =
23.5~), 1025 grams (7.118 moles) of L(-)lactide was added.
The polymer, after isolation, cooling, grinding, and sieving~ was dried in a vacuum tumble drier for 10 hours at ambient temperature and then 32 hours at 70C. A summary of the polymer properties is presented in Table V:
Table V
Examele 10 Example 11 Inherent viscosity,dl/g 2.02 1.82 Tg,C. (DSC) -6 _9 Tm,C.(DSC) 104 110 Crystallinity, % 34 38 (X-ray diffraction) PD0/PL Uol ratio, by NMR 9~.7/7.3 93.0/7.0 .
The copolymer of Example 11 was extruded into a monofilament in a manner similar to ~hat des~ribed above for Examples 9 and 10. Some of the extrusion and drawing , . .
conditions for the production of size 2/0 fibers are shown below in Table VI:
Table V~
~lock/Die Temp., C~ 132/133 1st and 2nd Godet speed, fpm 13 3rd Godst sæeed, fpm 60 Oven Temperature, C. 77 10 4th Godet speed, ~pm 92 Total draw ratio 7.lX
The fiber was allowed to crystallize further overnight at roo~ temperature, and then was redIawn in one stage through a heated oven under conditions similar to those described above for Examples 9 and 10. After redrawing, the fibers were annealed under dry nitrogen at 90C. with no relaxation for 6 hours. The annealed fiber tensile properties of this size 2/0 fiber are displayed below in Table VII:
Table VII
J
Diameter, mils 15.0 25 Straight tensile, KPSI 86 Knot Tensile, KPSI 51 Elongation, ~ 63 Young's Modulus, KPSI 192 In vitro BSR
(5 ~ays/550C./pH=9.1) 57.6 48,~
Example 12 Preparation of Polydioxanone-melt~k~=~Lac~ide at 70/30 5 initial weiqht comPosition (76.7t23.3 mole %) A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was charged with 1400 grams (13.7137 moles) of p-dioxanone, 0.77 milliliter of diethylene glycol, 1.81 milliliters of stannous octoate (0.33 molar solution in toluene), and 1.0 gram of D~C
violet #2. The contents of the reaction flask were held under high Yacuum at room temperature for about 16 hours.
The reac~or was purged and vented with nitrogen. The reaction mixture was heated to 110C. and maintained there for 6 hours. A sample of the polymer was removed (fo~
I.V. and free monomer content analysis) and 600 grams (4.1631 moles) of L(-)lactide was added. The temperature was raised to, and maintained at, around 135C. for about 2 hours. The polymer was isolated, ground, and dried to remove any unreacted monomers. A weight loss of 27.3~ was observed. The resulting polymer had a melting range o~
980- 04C. (by hot melt microscoPy) at 25~ crystallinity, an inherent viscosity of 2.4~ dl/q, and a PD0/PL mol ratio 25 o~ 83.6/16.4 by NMR.
Example 13 Preparation of Pol~dioxanone-melt/L(-)Lactide at 93/7 bY
weiqht_(95/5 bY mole ; A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was charged with 1860 grams ~18.2196 moles) of p-dioxanone, 3.93 milliliters of r' l-dodecanol, 1.94 milliliters of stannous octoate (0.33 molar solution in toluene), and 1.0 gram of D~C violot ETH ~72 ., .
3~L4~
~2. The contents of the reactor were held under high vacuum at room temperature for about 16 hours. The eeactor was purged and vented with nitrogen. The reaction mixture wa~ heated to 110C. and maintained there for 6 hours. A sample of the polyme~ was removed (I.V. = 1.88 dl/g, free monomer content = 19.2%) and 140 grams (0.9714 mole) of Lt-)lactide was added. The temperature was raised to, and maintained at, 125-135C. for about 2 hours. The polymer was isolated, ground, and dcied to remove any unreacted monomers. A weight loss of 24.2~ was - observed. The resulting polymer had a melting range of 100-106C. by hot melt microscopy, a crystallinity of 26%, and an inherent viscosity of 2.09 dl/g.
Pro~erties of Fibers from ExamPles 12 and 13 The copolymers described in Examples 12 and 13 were extruded, drawn, and redrawn into monofilament fibers in a manner similar to that described above for ExamPles 9 ~Q
11. The redrawn fibers were annealed 6 hours at 90C.
with no relaxation tunder nitrogen). The tensile properties of these f ibers were the following:
Table VIII
Example 12 ExamPle 13 Diameter, mils13.7 13.6 Straig~ tensile, KPSI 78 96 Knot tensile, KPSI 43.4 50 Elongation, ~ ~ 33 Young's Modulus, KPSI 331 253 Example 14 E'rH-672 ''' ' , . :, .. ,.: : , 4~33 PreParation of PolYdioxanone-melt/L(-lLactide at 93/7 bY
weiqht ~5/5 by mole %) 5 A thoroughly dried mechanically stirred 1.5 gallon stainless steel reactor was char~ed with 1~60 grams (~8.2196 moles) of p-dioxanone, 1.09 milliliters of diethylene glycol, 1.94 milliliters of stannous octoate (0.33 molar solution in toluene~, and 1.0 gram of D~C
viole~ #2. The conten~s of the reactor were held under high vacuum at room temperature for about 16 hours. The reactor was purged and vented with nitrogen. The reaction mixtuLe was heated to 110C. and maintained there for 6 hours. A sample of the polymer was removed (I.V. = 2.34 dl/g, free monomer = 21.5%~ and 140 grams (0.9714 mole) of L(-~lactide was added. The temperature wa~ raised to, and maintained at, 125-135~C. for about 2 hours. The polymer was isolated, ground, and dried to remove any unreacted monomers. A weight loss of 24% was observed. The cesulting polymer had a melting range of 97-103C.by hot stage microscopy, and an inherent viscosity of 2.65 dl/g.
Example 15 PreParation of Polydioxanone-melt/D~L-Lactide at 70t30 initial com~osition (76.7/23.3 moLe %1 A flame dried, 250 milliliter, round bottom, two-neck flask was charged with 70 grams (0.6862 mole) o~
p-dioxanone, O.L82 millilite~ of l-dodecanol, and 0.090 milliliter of stannous octoate (0.33 molar solution in toluene). The contents of the reaction ~lask were held under high vacuum at room temperature for about 16 hours.
4~3 The flask was fitted with a flame dried mechanical sti~rer and an adaptor with a hose connection. The reactor was purged with nitrogen three times befo~e being vented with nitrogen. The reaction mix~ure was heated to 110C. and maintained there for 6 hours. To the reaction ~lask, 30 grams (0.2081 mole) of D,L-lactide was added and the temperature was raised to 140C. and maintained there for 2 hours. The polymer was isolated, ground, and dried at 60-80C.~6~ Hrs/0.1 mm Hg. to remove unreactad monomers.
A weight loss of 29.6% was observed. The resulting ~olymer had a melting range of 98-102C., and an inherent viscosity oE 1.69 dl/g.
The copolymer described in Example 15 was extruded into monofilament fibers. The physical properties of drawn and annealed t6 hrs/90C.) fibers are shown in Table IX.
Table IX
_ Example L5 Initial composition of PD0-melt/D,L-lactide 70/30 by weight %
76.7/23.3 by mole I.V., dl/g 1.69 Tm 108C. (DSC) Tg -7.5C. (DSC) Crystallinity 29%
30 Fiber Properties Size_ ?/ Size 4/0 (annealed 6 hrs/90C./
no shrinkage) 35 Diameter (mils) 13.36 7,73 ET~-672 Straight Tensile, KPSI 59 78 Knot Tensile, KPSI 39 50 Elonga~ion, % 60 42 You~g's Modulus, KPSI 203 24 It is ~robable that the subject copolymers comprise long blocXs of polymerized p-dioxanone, which are crystallizable, with shorter segments containing random sequences of polymerized p~dioxanone and lac~ide. These shor~er segments are essentially non-crystallizable. which accounts for the fact that the copolymers of this invention have a slightly lower degree of crystallization than the p-dioxanone nomopolymer.
NMR analyses of the copolymers of the invention indicate that the comonomers are chemically linked therein. X-ray analyses of the copolymers indicate the presence of poly(p-dioxanone) crystallinity. It also indicates the presence of long enough segments or blocks to give rise to crystallinity. The results of these two analytical ~echniques support the view that the ~olymers o~ the invention are not random copolymers. ~andom copolymers are known to be essentially non-crystalline. Gel permeation chromatography data also support the view that the subjec~ copolymers do not comprise blands of two or more di~tinct ~olymers.
Based on the foregoing discussion the segmented copolymers of the invention may be characterized as ~ollows:
Contain from about 70 to about 98 weight per cent polymerized p-dioxanone, the remainder being co-polymerized lactide. For the ~referred suture utility, the copolymer~ contain from about 90 to ~7 mol ~er cent co-polymerized p-dioxanone, the remainder being E'rH-672 1'~81~83 polymerized lactide.
In the natural (undyed) state, the copolyme~ has a melting temperature, by differential scanning calorimetry or hot stage microscopy, of from about 90 to about 110C. (the addition of dye may raise the melting temperature by as much as about 5C.);
In the molten state, by optical microscopy, the copolymer ~0 has a single phase;
By X-ray diffraction analysis, the copolymer has a crystallini~y of from about 20 to about 45 per cent; and By gel permeation chromatography, the copolymer shows only a single molecular weigh~ distribution curve.
The subject copolymers can be made having inherent viscosities from about 1.6 to about 2.7, and are preferably made having IV's of from about 1.9 to about 2.2. As a general rule, it is dif~icult to pcocess p-dioxanone homopolymers into fibers if such homopolymers have I.V.'s greatec than abou~ 1.95. Therefore, this invention provides a means for providing p-dioxanone polymer fibers of hi~her molecular weight than has been heretofore available. The copolymers of ~his invention appear to be more thermally stable than p-dioxanone homopolymer.
Drawn and annealed monofilaments, from which surgical sutures and li~atures are made, made from the copolymers of the invention are usually more pliable ~han comparably sized monofilament fibers made from p-dioxanone homopolymer. At the same time, the monofilamene fibers of the subject invention usually have equal or higher 48~3 strength than the monofilament fibers made from the homopolymer. Thi6 advantageoUS combination of pro~erties is illustrated by the following Example 16:
Example 16 By a procedure analogous to th~t described in Example 5, above, a copolymer was made f~om p-dioxanone and L(-)lactide in molar proportions of 95/5. The resulting polymer had a melting range of 99-100C. by hot stage microscopy, an I.V. of 2.17 dl/g, a per cent crystallinity of about 28 by X-ray dif~raction, and a PD0/PL molar ratio of 95J5 by NMR.
The copolymer was extruded and drawn into monofilaments by a procedure analogous to those described above. The drawing conditions were as follows:
1st stage draw 4x at 47C.
2nd stage draw 1.6S75x at 69~C.
Total draw ratio 6.75x The drawn monofilamen~s were annealed 6 houcs at 80C., with a 5% relaxation. Representative pcoperties of the drawn and annealed monofilaments ace displayed in Ta~le X, below, along with properties of typical commercial p-dioxanone homopolymer drawn and annealed under similar conditions:
, , .
Table X
ExamRle L6 Homopolymer D~awn and Control-Drawn Drawn Annealed and Annealed Diameter, mils 7.0 7.6 7-8 Str. Tensile, KPSI 100 ~7 ~1 Knot Tensile, KPSI 55 54 52 Elongation, %. 56 50 49 Youngs Modulus, KPSI 137 169 271 The properties of monofilaments produced from the copolymers of the invention are dependent upon a number of factors, such as PD0/PL ratio, molecular weight, drawing and annealing conditions, and the like. As a general rule, howevec, drawn and annealed mono~ilament fibers made from the preferred copolymers (which have PD0/PL mol ratios o~ from about 90/10 to about 97/3), will exhibit the following proeerties:
Straight tensile, KPSI70 - 110 25 Knot Tensile, KPSI 40 - 70 Elongation, per cent 30 - 65 Young'~ Modulus, KPSI100 - 250 In vivo BSR, 3 weeks50 - 70%
4 weeks40 - 50~
8 weeks 5 - 15%
In vivo Absorption. to zero less than 5 to 6 months ~TH-672
Claims (16)
1. Process for producing a crystalline copolymer of p-dioxanone and lactide which comprises subjecting a mixture of p-dioxanone homopolymer, p-dioxanone monomer, and lactide to an elevated temperature for a period of time sufficient to produce a crystalline copolymer of p-dioxanone and lactide.
2. Process of claim 1 which comprises the steps of:
(a) polymerizing p-dioxanone monomer in the presence of a catalytically effective amount of a polymerization catalyst and an initiator to produce a first mixture of p-dioxanone homopolymer and p-dioxanone monomer; and (b) adding lactide to said first mixture to produce a second mixture, and subjecting said second mixture to an elevated temperature for a period of time sufficient to produce a crystalline copolymer of p-dioxanone and lactide.
(a) polymerizing p-dioxanone monomer in the presence of a catalytically effective amount of a polymerization catalyst and an initiator to produce a first mixture of p-dioxanone homopolymer and p-dioxanone monomer; and (b) adding lactide to said first mixture to produce a second mixture, and subjecting said second mixture to an elevated temperature for a period of time sufficient to produce a crystalline copolymer of p-dioxanone and lactide.
3. The process of claim 2 wherein said first mixture contains from about 15 to 30 weight per cent p-dioxanone monomer, based on total weight of said first mixture.
4. The process of claim 2 wherein the lactide is employed in an amount of from about 2 to about 30 weight per cent, based on total weight of p-dioxanone and lactide charged in steps (a) and (b).
5. The process of claim 2 wherein step (b) is carried out at a temperature of from about 110°C. to about 160°C.
6. A crystalline copolymer of p-dioxanone and lactide produced by the process of claim 1.
7. A crystalline copolymer of p-dioxanone and lactide produced by the process of claim 2.
8. A crystalline copolymer of p-dioxanone and lactide produced by the process of claim 3.
9. A copolymer of p-dioxanone and lactide containing from about 70 to about 98 weight per cent polymerized p-dioxanone, the remainder being co-polymerized lactide, said copolymer being characterized as follows:
an inherent viscosity of from about 1.6 to 2.7;
a melting point of about 90° to about 110°C., a ccystallinity of about 20 to about 45 per cent:
a single molecular weight distribution curve:
and, single phase in the molten state, by optical microscopy
an inherent viscosity of from about 1.6 to 2.7;
a melting point of about 90° to about 110°C., a ccystallinity of about 20 to about 45 per cent:
a single molecular weight distribution curve:
and, single phase in the molten state, by optical microscopy
10. The copolymer of claim 9 containing from about 90 to 97 mol per cent polymerized p-dioxanone. the remainder being co-polymerized lactide.
11. A drawn and oriented filament comprising the copolymer of claim 10.
12. The filament of claim 11 in the form of a monofilament.
13. The filament of claim 12 in the form of a sterile surgical suture.
14. The monofilament of claim 12 having the following properties:
straight tensile strength 70 - 110 kpsi knot tensile strength 40 - 70 kpsi elongation 30 - 65%
Young's modulus 100 - 250 kpsi In vivo BSR, 3 weeks 50 - 70%
4 weeks 40 - 50%
3 weeks 5 - 15%
In vivo absorption, to zero less than 5 to 6 months
straight tensile strength 70 - 110 kpsi knot tensile strength 40 - 70 kpsi elongation 30 - 65%
Young's modulus 100 - 250 kpsi In vivo BSR, 3 weeks 50 - 70%
4 weeks 40 - 50%
3 weeks 5 - 15%
In vivo absorption, to zero less than 5 to 6 months
15. The sterile surgical suture of claim 13 attached to a needle.
16. A surgical device comprising the crystalline copolymer of claim 9.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/802,546 US4643191A (en) | 1985-11-29 | 1985-11-29 | Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefrom |
| US802,546 | 1985-11-29 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1281483C true CA1281483C (en) | 1991-03-12 |
Family
ID=25184000
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000523853A Expired - Lifetime CA1281483C (en) | 1985-11-29 | 1986-11-26 | Crystalline copolymers of p-dioxanone and lactide and surgical devices made therefrom |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US4643191A (en) |
| EP (1) | EP0225163A3 (en) |
| JP (3) | JP2603229B2 (en) |
| AU (1) | AU585098B2 (en) |
| BR (1) | BR8605851A (en) |
| CA (1) | CA1281483C (en) |
| ZA (1) | ZA869012B (en) |
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| US5502158A (en) * | 1988-08-08 | 1996-03-26 | Ecopol, Llc | Degradable polymer composition |
| US4932962A (en) * | 1989-05-16 | 1990-06-12 | Inbae Yoon | Suture devices particularly useful in endoscopic surgery and methods of suturing |
| US5076807A (en) * | 1989-07-31 | 1991-12-31 | Ethicon, Inc. | Random copolymers of p-dioxanone, lactide and/or glycolide as coating polymers for surgical filaments |
| JP2907996B2 (en) * | 1989-11-08 | 1999-06-21 | 三井化学株式会社 | fishing line |
| US5026589A (en) * | 1989-12-28 | 1991-06-25 | The Procter & Gamble Company | Disposable sanitary articles |
| US5047048A (en) * | 1990-01-30 | 1991-09-10 | Ethicon, Inc. | Crystalline copolymers of p-dioxanone and ε-caprolactone |
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| US5037950A (en) * | 1990-02-09 | 1991-08-06 | Ethicon, Inc. | Bioabsorbable copolymers of polyalkylene carbonate/RHO-dioxanone for sutures and coatings |
| US5019094A (en) * | 1990-05-09 | 1991-05-28 | Ethicon, Inc. | Crystalline copolymers of p-dioxanone and poly(alkylene oxides) |
| US5080665A (en) * | 1990-07-06 | 1992-01-14 | American Cyanamid Company | Deformable, absorbable surgical device |
| US5100433A (en) * | 1990-11-08 | 1992-03-31 | Ethicon, Inc. | Suture coated with a copolymer coating composition |
| US5272221A (en) * | 1991-04-09 | 1993-12-21 | Mitsui Toatsu Chemicals, Incorporated | Nylon composition having increased hydrolyzability and method for increasing hydrolyzability of nylon |
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| US5391768A (en) * | 1993-03-25 | 1995-02-21 | United States Surgical Corporation | Purification of 1,4-dioxan-2-one by crystallization |
| US5522841A (en) * | 1993-05-27 | 1996-06-04 | United States Surgical Corporation | Absorbable block copolymers and surgical articles fabricated therefrom |
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| US4052988A (en) * | 1976-01-12 | 1977-10-11 | Ethicon, Inc. | Synthetic absorbable surgical devices of poly-dioxanone |
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-
1985
- 1985-11-29 US US06/802,546 patent/US4643191A/en not_active Expired - Lifetime
-
1986
- 1986-11-26 CA CA000523853A patent/CA1281483C/en not_active Expired - Lifetime
- 1986-11-26 EP EP86309203A patent/EP0225163A3/en not_active Ceased
- 1986-11-28 ZA ZA869012A patent/ZA869012B/en unknown
- 1986-11-28 AU AU65799/86A patent/AU585098B2/en not_active Expired
- 1986-11-28 BR BR8605851A patent/BR8605851A/en not_active IP Right Cessation
- 1986-11-29 JP JP61283178A patent/JP2603229B2/en not_active Expired - Lifetime
-
1996
- 1996-03-12 JP JP8081948A patent/JP2788223B2/en not_active Expired - Lifetime
- 1996-08-12 JP JP8227376A patent/JP2916419B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JP2916419B2 (en) | 1999-07-05 |
| JPH08276002A (en) | 1996-10-22 |
| US4643191A (en) | 1987-02-17 |
| EP0225163A3 (en) | 1987-10-28 |
| BR8605851A (en) | 1987-08-25 |
| EP0225163A2 (en) | 1987-06-10 |
| AU6579986A (en) | 1987-06-04 |
| ZA869012B (en) | 1988-07-27 |
| JP2788223B2 (en) | 1998-08-20 |
| JPS62164718A (en) | 1987-07-21 |
| AU585098B2 (en) | 1989-06-08 |
| JP2603229B2 (en) | 1997-04-23 |
| JPH09118742A (en) | 1997-05-06 |
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