Bioabsorbable copolymer and coating composition containing same
BACKGROUND OF THE INVENTION 
     This invention relates to a bioabsorbable copolymer and, more particularly, to a bioabsorbable copolymer obtained by polymerizing a major amount of ε-caprolactone and a minor amount of at least one other copolymerizable monomer in the presence of an initiator possessing at least two carboxylic acid groups. 
     U.S. Pat. No. 2,362,511 discloses a polyglycolide resin derived from glycolide and from about 20 to about 55 weight percent of a carboxylic acid such as lactic acid, tartaric acid, malic acid, citric acid, etc. 
     U.S. Pat. No. 3,169,945 discloses a homopolymer of ε-caprolactone obtained by polymerizing ε-caprolactone in the presence of a carboxylic acid initiator such as citric acid, aconitic acid, mellitic acid, pyromellitic acid, etc. 
     U.S. Pat. No. 3,942,532 discloses a surgical suture coating composition comprising a polyester derived from the esterification of a low molecular weight glycol and a dimeric acid such as succinic acid, glutaric acid, adipic acid, etc. 
     U.S. Pat. No. 4,624,256 discloses a bioabsorbable copolymer derived from at least 90 weight percent of ε-caprolactone and up to 10 weight percent of a carboxylic acid such as glycolic acid, lactic acid, malic acid, succinic acid, etc. 
     U.S. Pat. No. 4,643,191 discloses a copolymer obtained by: (1) the polymerization of p-dioxanone in the presence of a carboxylic acid initiator such as glycolic acid, lactic acid, etc., to form a mixture of p-dioxanone monomer and homopolymer and (2) subsequent polymerization of (1) with lactide to form the copolymer. 
     U.S. Pat. No. 5,076,807 discloses a bioabsorbable copolymer derived from polymerizing p-dioxanone and glycolide in the presence of a carboxylic acid initiator, e.g., glycolic acid or lactic acid. 
     Copolymers derived from ε-caprolactone and at least one other monomer such as lactide, glycolide, glycolic acid, p-dioxanone and trimethylene carbonate are disclosed in U.S. Patent Nos. 4,605,730, 4,624,256, 4,700,704, 4,788,979, 4,791,929, 4,994,074, 5,076,807, 5,080,665, 5,085,629 and 5,100,433. 
     SUMMARY OF THE INVENTION 
     In accordance with the present invention, a bioabsorbable copolymer is obtained by polymerizing a major amount of ε-caprolactone and a minor amount of at least one other copolymerizable monomer in the presence of an initiator possessing at least two carboxylic acid groups. 
     The particular structure of the bioabsorbable copolymer herein exerts a characteristic influence on its bioabsorption behavior making it useful, among other applications, as a surgical suture coating material. 
     DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     Conventional polymerization techniques that are well known and disclosed in the prior art can be utilized in preparing the bioabsorbable copolymer of the present invention. The bioabsorbable copolymer is obtained by polymerizing a major amount of ε-caprolactone and a minor amount of at least one other copolymerizable monomer in the presence of a carboxylic acid initiator having at least two carboxylic acid groups. The polymerization of these monomers contemplates all of the various types of monomer addition, i.e., simultaneous, sequential, simultaneous followed by sequential, sequential followed by simultaneous, etc. 
     Suitable monomers which can be copolymerized with ε-caprolactone include glycolide, lactide, p-dioxanone and trimethylene carbonate. 
     Suitable carboxylic acid initiators include succinic acid, maleic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, malic acid, tartaric acid, citric acid, aconitic acid, pyromellitic acid, mellitic acid, etc., and combinations thereof. 
     The copolymer herein can contain from about 70 to about 98, and preferably from about 80 to about 95, weight percent ε-caprolactone-derived units, the balance of the copolymer being derived from the other copolymerizable bioabsorbable monomer(s). The inherent viscosity of the copolymer generally ranges from about 0.05 to about 0.35, and preferably from about 0.15 to about 0.25, dl/g when measured in chloroform at a concentration of 0.2500 g/dl at 30° C. The carboxylic acid initiator is generally employed in small amounts, e.g., from about 0.5 to about 5, and preferably from about 0.1 to about 2, weight percent of the total monomer mixture. 
     The bioabsorbable copolymer of the present invention is non-toxic and physiologically inert. Depending on its particular physical and bioabsorption properties (to a large extent influenced by the nature of the initiator and monomers from which it is prepared), the bioabsorbable copolymer herein can be used in the fabrication in whole or in part of a variety of implantable medical devices and prostheses, e.g., clips, staples, sutures, suture coatings, etc. Applied to a suture, a coating composition containing the bioabsorbable copolymer of the invention results in a significant improvement in one or more properties of the suture, e.g., its lubricity, knot tiedown and/or knot security characteristics. 
     The bioabsorbable copolymer of the invention can be applied to a suture by any suitable process, e.g., passing the suture through a solution of the copolymer, e.g., in acetone, methylene chloride, etc., past a brush or other coating solution applicator, or past one or more spray nozzles dispensing the suture coating solution. The suture wetted with the coating solution is subsequently passed through or held in a drying oven for a time and at a temperature sufficient to vaporize and drive off the solvent. If desired, the suture coating composition can optionally contain additional components, e.g., dyes, antibiotics, antiseptics, growth factors, anti-inflammatory agents, etc. 
     While the coating composition herein can be applied to any type of suture, it is essentially intended for application to a braided suture, a preferred type of which is disclosed in U.S. Pat. No. 5,019,093, the contents of which are incorporated by reference herein. The amount of coating composition applied to a braided suture will vary depending upon the structure of the suture, e.g., the number of filaments, tightness of braid or twist, the size of the suture and its composition. 
     The coating composition herein can be used for both &#34;unfilled&#34; as well as &#34;filled&#34; sutures, the latter designating braided bioabsorbable sutures containing a storage stabilizing material as disclosed in U.S. Pat. Nos. 5,037,429 or 5,051,272, the contents of which are incorporated by reference herein. For an &#34;unfilled&#34; suture, the coating composition can be applied at a level of from about 0.5 to about 4 weight percent or more and preferably from about 1 to about 3 weight percent. Advantageously, the coating composition is applied to the suture prior to application of the storage stabilizing material. For a filled suture, the amount of applied coating composition can range from about 0.2 to as much as about 3 weight percent or more and preferably from about 0.5 to about 2 weight percent. As a practical matter, it is generally preferred to apply the minimum amount of coating composition consistent with good tie-down performance. This level of coating add-on can be readily determined for any particular suture coating system employing routine experimental procedures. 
     In the case of an unfilled or filled braided suture, prior to application of the coating composition, it can be advantageous to calender the suture in order to improve the uniformity with which the coating composition is laid down upon the suture surface. A calendering operation can also be beneficial when carried out on a coated suture where the suture is to be filled with a storage stabilizing material. In this case, calendering will tend to break up the coating facilitating penetration of the interior spaces of the suture by the storage stabilizing material. 
     A preferred method for calendering a braided suture and an apparatus for carrying out the method are disclosed in copending U.S. patent application Ser. No. 07/652,939, filed Feb. 8, 1991, the contents of which are incorporated by reference herein. In accordance with Ser. No. 07/652,939, calendering of a braided suture is achieved by applying a compressive force to the suture in a first line or direction generally transverse to the longitudinal direction of the suture, the compressive force being of sufficient magnitude as to flatten the suture in a direction orthogonal to the direction in which the compressive force is applied. Preferably, a second application of compressive force is applied to the suture in a direction generally transverse to that of the first compressive force and transverse to the longitudinal direction of the suture. The second compressive force is substantially equal in magnitude to the first compressive force so that the suture returns to its original cross-sectional configuration. 
     The apparatus for implementing the foregoing calendering method includes at least one pair of rollers which are biased towards each other to apply a compressive force to the suture as the suture passes between them. Optionally, a second pair of rollers is provided which is oriented at an angle (preferably 90°) to the first pair of rollers and transverse to the longitudinal direction of the suture. Following passage between both the first and second pair of rollers, the suture will have been alternately compressed, or flattened, in a first direction and thereafter in a second direction at an angle to the first direction. 
    
    
     The following examples are illustrative of the bioabsorbable copolymer of this invention, its preparation and its application as a coating to sutures. 
     EXAMPLES 1-3 
     In three separate polymerizations, ε-caprolactone (67.5 g), glycolide (7.5 g), stannous octate as catalyst (0,015 g) and citric acid (3.0 g) (Example 1), mallic acid (3.0 g) (Example 2) and tartaric acid (3.0 g) (Example 3) as initiators were mixed under nitrogen for one hour and thereafter copolymerized in a reactor at 160° C. for 24 hours. In each polymerization, greater than 95 weight percent conversion of monomers to copolymer was achieved. 
     The inherent viscosities of the copolymers, which were measured in CHCl 3  at a concentration of 0.2500 g/dl at 30° C., were as follows: 
     
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                       Inherent Viscosity                                 
Example     Initiator  (dl/g)                                             
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1           Citric acid                                                   
                       0.17                                               
2           Mallic acid                                                   
                       0.16                                               
3           Tartaric acid                                                 
                       0.22                                               
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     EXAMPLES 4-16; COMPARATIVE EXAMPLES 1 -6 
     Performance characteristics of size 0 sutures coated with the acid-initiated ε-caprolactone-glycolide copolymers of Examples 1-3 were measured. Sutures coated with another coating composition, i.e., a block copolymer wherein polypropylene glycol comprises one block and a glycolide-lactide copolymer comprises the other block, were similarly tested for comparative purposes. The coating level of copolymer on each suture, expressed in terms of percent by weight of the suture, was determined by NMR. After coating a suture with a solution of copolymer and subsequently drying the suture in an oven for 96 hours, the suture was tested on a tie board to evaluate certain of its performance characteristics, i.e., surgeon&#39;s throw, knot reposition and knot security. 
     A tie board consists of a base on which two plates are perpendicularly affixed. These plates are parallel to one another on the base and are separated by a distance of at least 3 inches. Each plate contains two oppositely disposed openings, the distance between the openings on one plate being longer than that of the other plate. An elastic tube is passed through the openings on both plates to complete a loop which is then tied to secure the loop to the plates. The loop is in the general configuration of an isosceles triangle. To perform the Surgeon&#39;s Throw and Knot Reposition tests as described below, a suture is looped around the elastic tube of the tie board and tied. The elastic tube exerts an outward force on the suture knot. This force approximates the force exerted by living tissue on suture knots. Thus, the tie board is an effective means of evaluating the performance characteristics of surgical sutures. 
     The procedures for evaluating these performance characteristics are described in Table I as follows: 
     
                       TABLE I                                                     
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PROCEDURES FOR MEASURING PERFORMANCE                                      
CHARACTERISTICS OF SUTURES COATED WITH                                    
ε-CAPROLACTONE-GLYCOLIDE COPOLYMERS                               
Performance                                                               
Characteristics                                                           
            Test Procedure                                                
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Surgeon&#39;s Throw                                                           
            A suture is looped around the elastic                         
            tubes of a tie board and tied with a                          
            surgeon&#39;s throw (a half hitch with                            
            an extra loop of the free end). The                           
            ends are pulled apart by hand and the                         
            suture loop pulls the elastic tubes                           
            of the tie board together. The ends of                        
            the suture are then released. If the tubes                    
            stay together for approximately ten                           
            seconds, the trial is counted as a                            
            &#34;pass&#34;. If the surgeon&#39;s throw slips                          
            and the tubes move apart, the trial is                        
            counted as a &#34;failure&#34;.                                       
Knot Reposition                                                           
            A suture is looped around the elastic                         
            tubes of a tie board and tied with                            
            two half hitches in the same direction                        
            (a granny knot). The free ends of                             
            the suture are pulled apart by hand. If the                   
            knot slips and the loop of the suture pulls                   
            the elastic tubes of the tie board together,                  
            the knot is said to reposition and the trial                  
            is counted as a &#34;pass&#34;. If the suture breaks                  
            or if the knot locks in place and cannot                      
            be moved, the trial is counted as                             
            a &#34;failure&#34;.                                                  
Knot Security                                                             
            A 2 cm loop is tied with a surgeon&#39;s                          
            square knot (1 = 1 = 1 = 1) securing                          
            the throws at 20% of the USP XXII                             
            knot strength for 2/0 nonabsorbable                           
            sutures (n = 10 loops per group). The                         
            loop is placed next to a cloth-wrapped                        
            mandrel rotating at .5 rpm. The fixtures                      
            are secured to allow contact of the                           
            cloth material against the fourth throw                       
            or, top throw, of each knot. The cloth                        
            wrapping is moistened with 37° C.                      
            water prior to the test and is periodically                   
            remoistened during the test. For each                         
            pass of the cloth across the knot (for a                      
            total of 100 passes), the knot is inspected                   
            for top throw security. For a knot to                         
            be considered secure, there must be no                        
            relaxation of the knot or loss of the                         
            fourth throw.                                                 
In vitro degradation                                                      
            A suture was immersed in boiling                              
(100° C./48 hours)                                                 
            water for 48 hours and thereafter                             
            weighed to determine the amount of                            
            weight loss                                                   
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     The results of these tests are set forth in Table II as follows: 
     
                                           TABLE II                                
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PERFORMANCE CHARACTERISTICS OF SUTURES                                    
COATED WITH ε-CAPROLACTONE-GLYCOLIDE COPOLYMERS AND               
POLYPROPYLENE GLYCOL/GLYCOLIDE-LACTIDE BLOCK COPOLYMER                    
                  Surgeon&#39;s Throw                                         
                           Knot Reposition                                
                                   Knot Security                          
                                          In Vitro                        
            Coating                                                       
                  (No. passes out                                         
                           (No. passes out                                
                                   (No. throws                            
                                          Degradation                     
       Initiator*                                                         
            Level (%)                                                     
                  of 10 attempts)                                         
                           of 10 attempts)                                
                                   to secure)                             
                                          (100° C./48              
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                                          hours)                          
Example                                                                   
 4     CA   0.7   8        10      3      33                              
 5     CA   1.1   7        10      4      --                              
 6     CA   1.5   7        10      3      --                              
 7     CA   --    5        10      --     --                              
 8     CA   2.9   7        10      --     --                              
 9     MA   0.8   10       10      3      29                              
10     MA   1.3   9         9      3      --                              
11     MA   1.6   6         9      3                                      
12     MA   --    6         6      --                                     
13     MA   --    3         9      --     --                              
14     TA   0.8   7        10      3      35                              
15     TA   1.1   5        10      4      --                              
16     TA   1.6   9        10      4      --                              
Comparative                                                               
Example                                                                   
 1     --   --    7        7       4      --                              
 2     --   --    2        10      --     --                              
 3     --   --    8        7       --     --                              
 4     --   --    6        8       --     --                              
 5     --   --    10       8       --     --                              
 6     --   --    8        8       3      --                              
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 *CA = citric acid, MA = mallic acid and TA = tartaric acid.              
 
    
     As the foregoing data show, sutures coated with the copolymers of this invention possess performance characteristics that are equal or superior to those of the Comparative Example. In particular, the knot reposition characteristics of sutures coated with the copolymers of this invention (Examples 4-16) are excellent, i.e., a rating of 10 successful passes out of 10 attempts was obtained for 9 out of 13 coated sutures which were tested.