CRYSTALLINE COPOLYMERS AND METHODS OF PRODUCING SUCH COPOLYMERS

Abstract: Crystalline copolymers of glycolide and optically inactive dl-lactide comprising sixty-two weight percent or less glycolide, methods of producing the same and absorbable medical devices manufactured therefrom having improved properties are disclosed.

Description: CRYSTALLINE COPOLYMERS AND METHODS OF PRODUCING SUCH COPOLYMERS TECHNICAL FIELD The present invention relates to glycolide and dl - lactide based copolymer compositions and more particularly to crystalline copolymer compositions comprising less than sixty-two weight percent or less glycolide and methods of producing such compositions which are useful in the manufacture of absorbable medical devices. BACKGROUND ART Copolymers of, and surgical devices made from dl-lac ¬ tide and glycolide are well known. U.S. Patents relating to such copolymers and the like include: 3,620,218; 3,636,956; 3,9102,497; 3,918,455; 3,937,223; 4,137,921; 4,157,437; 4,243,775; 4,443,430; 4,835,139; 5,013,553; 5,198,220; 5,242,910; 5,229,469; 5,317,065; 5,320,624; 5,384,133; 5,395,747; 5,403,713; 5,425,984; 5,431,679; 5,439,884 and 5,470,340. The desirable physical properties of medical grade bioabsorbable copolymers such as those made from dl - lactide and glycolide are strongly influenced by the degree of crystallinity thereof. Prior patents such as U.S. Patent No. 5,320,624 disclose that compositions derived from lac¬ tide and glycolide in which the lactide moieties predominate have unexpected desired properties such as a decreased degree of crystallinity. Accordingly, it is well established that such copolymers which contain thirty-eight weight percent or more dl-lactide which is optically inactive are characteristically amorphous or lack crystallinity. Likewise, U.S. Patent No. 4,157,437 which discloses a crystalline copolymer of lactide and glycolide, requires a major portion thereof to include optically active lactide which is known to be crystalline. No mention is made of absorbable copolymeric medical devices made of optically inactive and characteristically amorphous dl-lactide and glycolide specifically designed to be crystalline to improve the physical properties thereof. DISCLOSURE OF INVENTION The present invention provides novel compositions made of approximately sixty-two weight percent or less glycolide and approximately thirty-eight weight percent or more optically inactive dl-lactide having the unexpected characteristic of being crystalline. According to prior art teachings such compositions are characteristically amorphous. However, the compositions of the present invention have a bioabsorbable, segmented molecular architecture comprising a plurality of dl-lactide and glycolide linkages and mixtures thereof which are unexpectedly crystalline. The crystallinity of such compositions is unexpected since dl-lactide linkages are characteristically non-crystalline or amorphous. The process of manufacturing the compositions of the present invention is a two or more stage ring-opening copolymerization of highly reactive monomer linkages utilizing an initiator. A catalyst is also employed in the suitable methods used to produce the crystalline compositions described in detail below. It is important to note that the catalyst type and the level of catalyst employed affect both the polymerization and transesterification rates of the cyclic esters described in this invention. Tin based catalysts such as stannouε chloride dihydrate and stannous octoate are preferred. Additionally, the inherent viscosity or molecular weight of the subject composition is strongly influenced by the amount of initiator used during polymerization. Again, the methods of producing the novel compositions of the present invention are described in great detail below. The crystalline compositions of the present invention are useful in the area of medical devices in that the compositions are readily bioabsorbable and have superior physical and tensile properties over amorphous copolymers of the same composition. Medical devices fabricated from the subject crystalline compositions are dimensionally stable at ambient conditions in contrast to amorphous counterparts. This superior physical property is a valued improvement from both an economical and a commercial point of view due to the elimination of the need for refrigerated shipping and storage thereof. Accordingly, it is one object of the present invention to provide novel crystalline copolymer compositions which are dimensionally stable at ambient conditions and thereby eliminate the need for refrigerated shipping and storage thereof . It is another object of the present invention to provide novel crystalline copolymer compositions useful in the manufacture of medical devices. It is another object of this invention to provide absorbable medical devices having improved properties manufactured from the novel crystalline copolymer compositions of the present invention. It is another object of this invention to provide a novel method of producing the novel crystalline compositions of the present invention. Other objects of the invention are achieved herein by providing absorbable medical devices derived from the novel crystalline compositions of the present invention. BEST MODE FOR CARRYING OUT THE INVENTION In accordance with the present invention, it has now been found that desirable physical properties of medical grade bioabsorbable copolymers such as those made from optically inactive dl-lactide and glycolide are strongly influenced by the degree of crystallinity thereof. However, teachings to date indicate that a decrease in crystallinity improves the physical properties of a synthetic composition to be used in the manufacture of a medical device. The subject invention to the contrary provides for the increased crystallinity of characteristically amorphous compositions to achieve improved physical properties. The novel unexpectedly crystalline compositions of the present invention are made up of approximately sixty-two weight percent or less glycolide and approximately thirty-eight weight percent or more optically inactive dl-lactide but preferably approximately fifty weight percent glycolide and approximately fifty weight percent optically inactive dl- lactide. According to prior art teachings and methods of manufacture such compositions were heretofore characteristically amorphous. The novel processes of manufacturing the novel crystalline compositions of the present invention are two or more stage ring-opening copolymerizations but preferably a two stage sequential addition copolymerization to increase crystallinity. The copolymerization is achieved by using one or more initiators and one or more catalysts. Suitable initiators for the manufacture of the crystalline copolymers of the present invention include but are not limited to alcohols. Suitable alcohol initiators include but are not limited to 1-docecanol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1, 10-decanediol, inositol, pentacrythritol, mannitol, sorbitol, erythritol, ethylene glycol and 1,3- propane diol. Preferably, lauryl alcohol, i.e., 1-docecanol is used as the initiator of choice to increase the polymer block characteristics, i.e., to increase sequence length and thereby increase the degree of crystallinity, of the copolymer . The inherent viscosity or molecular weight of a copolymer is directly influenced by the initiator and the amount of initiator used during the polymerization. For the novel crystalline copolymers of the present invention, an inherent viscosity of greater than 0.5 dl/g at a concentration of 0.5g/dl in a solvent such as hexafluoroisopropanol at 30°C is preferred. However, an inherent viscosity within the range of 0.3 to 0.8 dl/g but preferably 0.5 or 0.6 dl/g is preferred for controlled release devices where a strength value is not necessary. For articles of manufacture of formable devices which do not require high strength, an inherent viscosity within the range of 0.05 to 0.3 dl/g but preferably .05 to 0.1 dl/g is required for adequate formability. A suitable inherent viscosity for fiber applications would be within the range of 0.8 dl/g or higher such as 2.0 dl/g but most preferably approximately l.Odl/g for adequate tensile properties. In order to achieve these desired inherent viscosities the initiator/dl-lactide ratio should be greater than approximately 1:60 but preferably approximately 1:100. A suitable melting point for the crystalline compositions of the present invention is at least 140°C but preferably 160°C or greater . The polymerization and transesterification rates of the cyclic esters of the present invention are directly influenced by the one or more catalysts employed. Suitable catalysts include but not limited to stannous chloride, dibutyl tin dilaurate, dibutyl tin diacetate, dibutyl tin dichloride, stannic chloride pentahydrate, aluminum isopropoxide, antimony trioxide, stannic fluoride, stannous citrate, stannous acetate, antimony trifluoride, tin teteraisopropoxide, lead oxide, tetraisopropyl titanate, titanium acetyl acetonate, tetraoctylene glycol titanate, boron trifluoride etherate, aluminum trichloride, stannous chloride dihydrate and stannous octoate. Stannous chloride dihydrate and/or stannous actoate are preferred catalysts for the production of the present compositions due to their superior properties when utilized in a biological system. Most preferably stannous chloride dihydrate is used as the catalyst of choice in the present invention in order to control the required polymerization time. However, other catalysts would be suitable to produce the subject compositions although the tin based catalysts have been found to have superior bioabsorbable characteristics in vivo. Suitable reaction conditions for the present invention include polymerizations carried out at a temperature of approximately 160°C to 240°C but most preferably at a temperature of approximately 180°C to 200°C. The polymerizations are carried out within this temperature range over a period of approximately 1 hour to 4 hours but preferably approximately 2 to 3 hours to achieve the desired degree of crystallinity within the range of 2 to 30 percent, but preferably approximately 10 percent. The reaction conditions set forth herein likewise allows the subject compositions to be prepared in an economically and commercially desirable amount of time. A wide variety of absorbable, implantable medical devices can be manufactured in whole or in part from the novel copolymers of the present invention. Such devices include plugs, fasteners, pins, bone screws and other implantable devices. As expressed above, the novel copolymers of the present invention provide dimensional stability at ambient temperatures thereby eliminating the need for refrigerated shipping and storage of such medical implant devices. The elimination of the need for refrigeration makes the copolymers of the present invention economically and commercially desirable. The examples below are used to further describe and further illustrate a few of the novel crystalline copolymers of the present invention. The following examples are in no way intended to limit the scope of the novel crystalline compositions covered herein. Examples: I. Single State Reactions: Examples 1 through 6: 50/50 to 75/25 Copolymers of dl- lactide/glycolide Six copolymers were prepared from glycolide and optically inactive dl-lactide. Ring opening polymerization of glycolide and dl-lactide were conducted using 0.40 mole percent with respect to the total monomer concentration of 1-dodecanol as the initiator and 0.001 to 0.005 mole percent with respect to total monomer concentration of stannous chloride dihydrate as catalyst. The polymerizations were carried out in a 2CV reactor. When combined, the molten mixture of monomers, initiator and catalyst was charged to a stirred reactor at 180°C, under nitrogen atmosphere, at 28 to 35 rpm. The reaction temperature was raised from 180°C to 200°C over a 15 minute time period. Stirring and heating was continued for an additional 45 minutes, for a total reaction time of two and one half hours. The reaction time was extended for some polymers. The resulting copolymers were ground and dried under vacuum at 110°C, 0.2 mm Hg, for 16 hours. Analytical results are summarized in Table 1. Molecular weight was characterized by a determination of the inherent viscosity in HFIP (Hexafluorisopropanol) at 30°C and a concentration of 0.5 g/dl as referenced in Table 1. Although all six copolymers were prepared by a single stage reaction, differences in their physical properties were influenced by composition. Crystalline polymers were obtained with glycolide-rich compositions (Ex. 5 and Ex. 6) . A shift from polymers with crystalline to those with amorphous properties is observed with the increase of noncrystalline optically inactive dl-lactide linkages (Ex. 1, Ex. 2, Ex. 3 Ex. 4) which are unsuitable for the present invention. II. Sequential Addition Copolymers: Examples 7 through 1 : 50/50 to 25/75 copolymers of dl- latide/glycolide Eight polymers of glycolide and optically inactive dl- lactide were prepared using sequential addition polyme ization. Ring opening polymerization of dl-lactide and glycolide were conducted using 0.40 mole percent with respect to total monomer concentration of 1-dodencanol, i.e., lauryl alcohol as initiator and 0.005 mole percent with respect to total monomer concentration of stannous chloride dihydrate as catalyst. Copolymers were prepared by first synthesizing a prepolymer of glycolide and optically inactive dl-lactide with the desired monomer proportions, followed by a subsequent glycolide addition and continuation of the reaction for a specific length of time. The block length of the crystalizable linkages affecting the crystallinity of the final copolymer, was controlled through the glycolide proportions in the second stage. Polymerization was carried out in a 2 CV reactor. The molten mixture of monomers, initiator and catalyst was charged to the reactor at 180°C, under nitrogen atmosphere, and stirred at approximately 28 to 35 revolutions per minute (rpm) . The reaction temperature was raised from 180°C to 200°C over a 15 minute time period. Stirring and heating was continued for an additional 60 to 145 minutes, for a total reaction time of 2 to 2.5 hours. After the prepolymer was converted, molten glycolide was added with continued stirring to provide a homogeneous distribution of the glycolide in the prepolymer. The reaction was allowed to continue for 15 to 45 minutes. The resulting polymers were ground and dried under vacuum for 19 hours at 110°C/0.2 Hg. Compositions and polymer properties are listed in Table 2. The molecular weight was characterized by determination of inherent viscosity in HFIP (Hexaflurorisopropanol) at 30°C and a concentration of 0.5 g/dl . Although the overall composition of glycolide to dl- lactide was kept the same for examples 7-11 and for examples 12-14, respectively, it is clear, that the use of a two stage polymerization process produces copolymers with different levels of crystallinity. It was also observed that the melting temperature and crystallinity of the final copolymer increased proportionally with the increase of the glycolide fraction in the second stage addition. A. Example 7 Stage 1 : Time : 2.25 hrs Temperature: 180°C then increased to 200°C over 15 min . and continued for 120 mins at 200°C. Charge : glycolide: 97.53 g, dl-lactide: 151.35 g SnCl 2 2H 2 0: 23.69 mg 1-dodecanol: 1.574 g Stage 2 : Time : 15 min (and 30 min time cuts Temperature 200°C Charge : Glycolide: 24.34 g B. Example 8 Stage 1 : Time: 2.25 hrs Temperature 180°C then increased to 200°C over 15 min. and continued for 120 mins at 200°C. Charge : glycolide: 97353 g, dl-lactide: 151.35 g SnCl 2 2H ? 0: 23.69 mg 1-dodecanol: 1.574 g Stage 2 : Time : 65 min Temperature: 210°C Charge: Glycolide: 24.334 g C. Example 9 Stage 1: Time: 2.25 hrs Temperature: 180°C then increased to 200°C over 20 min and continued for 115 mins at 200°C. Charge : glycolide: 85.53 g, dl-lactide: 151.35 g SnCl 2 2H 2 0: 23.69 mg 1-dodecanol: 1.574 g Stage 2 : Time: 15 min (and 30 min) time cuts Temperature: 200°C Charge: Glycolide: 36.51 g D. Example 10 Stage 1: Time: 2.25 hrs Temperature : 180°C then increased to 200°C over 20 min. and continued for 115 mins at 200"C. Charge: glycolide: 73.20 g, dl-lactide: 151.35 g SnCl 2 2H 2 0: 23.69 mg 1-dodecanol: 1.574 g Stage 2 : Time : 15 min (and 30 min) time cuts Temperature 200°C Charge : Glycolide: 48.68 g E. Example 11 Stage 1 : Time: 2.25 hrs Temperature: 180°C then increased to 200°C over 20 min. and continued for 115 mins at 200°C. Charge: glycolide: 21.92 g, dl-lactide: 136.27 g SnCl 2 2H 2 0: 21.32 mg 1 -dodencanol : 1.409 g Stage 2 : Time: 15 min (and 30 min) time cuts Temperature 200°C Charge : Glycolide: 87.78 g F. Example 12 Stage 1 : Time: 2.25 hrs Temperature : 180°C then increased to 200°C over 15 min and continued for 120 mins at 200°C. Charge : glycolide: 6.09 g, dl-lactide: 227.02 g SnCl 2 2H 2 OL 22.69 mg 1-dodecanol: 1 5 -7-4 g Stage 2 : Time: 15 min (and 30 min time cuts Temperature 200°C Charge: Glycolide: 63.85 g G. Example 13 Stage l: Time: 2.25 hrs Temperature : 180°C then increased to 200°C over 20 min and continued for 115 mins at 200°C. Charge : glycolide: 13.99 g, dl-lactide: 113.51 g SnCl 2 2H 2 OL 11.85 mg 1-dodecanol: 0.787 g Stage 2 : Time: 15 min (and 30 min) time cuts Temperature 200°C Charge: Glycolide: 10.49 g Table 1 Single Stage GlycoIide-co-dl-Lacttde Copolymers to Table 2 Crystalline (Sequential Addition) GlycoIide-co-dt-Lactide Copolymers DSC ( Differential Seannlog Caloilmltiy) IV (Inherent Viscosity In Hexafluorolsopropanol) 1 NMR (Proton NMR) Tm (Polymer melt: peak maximum) Tg (Polymer glass transition: midpoint of bwiition) ▲H (Heat of Faslon in J/j: measured o?er enlite endolherm region) % Cryst (Cryjtalliαlty bised on crystalline Polygtycollc Acid: 206.3 J/g) Each of the eight copolymers produced in Examples seven through fourteen set forth above are unexpectedly crystalline. Heretofore, copolymers of optically inactive dl-lactide and glycolide in such proportions were known to be characteristically amorphous. However, the novel crystalline copolymers produced as disclosed herein have desirable physical properties for absorbable medical devices . Additionally, while the preceding examples have been directed to the preparation of specific copolymers of optically inactive dl-lactide and glycolide, these examples are for purposes of illustration only and are not limiting of the invention. Many different embodiments of this invention will be apparent to those skilled in the art and may be made without departing from the spirit and scope thereof. It is accordingly understood that this invention is not limited to the specific embodiments set forth herein except as defined in the appended claims .

Claims: CLAIMS 1. A crystalline copolymer composition comprising approximately 38 weight percent or greater optically inactive dl-lactide and approximately 62 weight percent or less glycolide. 2. The crystalline composition of claim 1 having a melting point of approximately 140°C or greater. 3. The crystalline composition of claim 1 having an inherent viscosity of 0.3 dl/g to 2.0 dl/g. 4. The crystalline composition of claim 1 extruded to form an absorbable medical device. 5. The crystalline composition of claim 1 molded to form an absorbable medical device. 6. The crystalline composition of claim 1 drawn to form an absorbable medical device. 7. The crystalline composition of claim 1 having crystallinity within the range of 2 to 30 percent. 8. A method of preparing a crystalline copolymer of optically inactive dl-lactide and glycolide containing approximately 62 weight percent or less glycolide comprising: a. preparing a monomer mixture of optically inactive monomer dl-lactide and the monomer glycolide; b. polymerizing in a two stage sequential polymerization process said monomer mixture to obtain a crystalline copolymer of dl-lactide and glycolide . 9. The method of claim 8 wherein said crystalline copolymer has a melting point of at least 140°C. 10. The method of claim 8 wherein said crystalline copolymer has an inherent viscosity of 0.3 dl/g to 2.0 dl/g 11. The method of claim 8 wherein said crystalline copolymer has a crystallinity within the range of 2 to 30 percent . 12. The method of claim 8 wherein one or more initiators are added to said monomer mixture. 13. The method of claim 8 wherein a 1-dodecanol initiator is added to said monomer mixture. 14. The method of claim 8 wherein an ethylene glycol initiator is added to said monomer mixture. 15. The method of claim 8 wherein one or more catalyst is added to said monomer mixture. 16. The method of claim 8 wherein a tin based catalyst is added to said monomer mixture. 17. The method of claim 8 wherein stannous chloride dihydrate is added to said monomer mixture as a catalyst. 18. The method of claim 8 wherein stannous octoate is added to said monomer mixture as a catalyst. 19. A method of preparing a crystalline copolymer of optically inactive dl-lactide and glycolide containing approximately 62 weight percent or less glycolide comprising: a. preparing a block copolymer comprising optically inactive dl-lactide and glycolide; and b. admixing with said block copolymer additional glycolide monomer to provide an approximate total 62 weight percent or less glycolide in the copolymer -monomer mixture; and c. polymerizing said copolymer -monomer mixture to obtain said crystalline copolymer of optically inactive dl-lactide and glycolide. 20. The method of claim 19 wherein said crystalline copolymer has an inherent viscosity of 0.3 dl/g to 2.0 dl/g. 21. The method of claim 19 wherein said crystalline copolymer has a crystallinity within the range of 2 to 30 percent . 22. The method of claim 19 wherein one or more initiators are added to prepare said block copolymer. 23. The method of claim 19 wherein a 1-dodecanol initiator is added to prepare said block copolymer . 24. The method of claim 19 wherein a ethylene glycol initiator is added to prepare said block copolymer. 25. The method of claim 19 wherein a catalyst is added to prepare said block copolymer . 26. The method of claim 19 wherein a tin based catalyst is added to prepare said block copolymer . 27. The method of claim 19 wherein stannous chloride dihydrate is added as a catalyst to prepare said block polymer . 28. The method of claim 19 wherein stannous chloride is added as a catalyst to prepare said block polymer . 29. The method of claim 19 wherein said crystalline copolymer has a melting point of at least 140°C. 30. An implantable medical device comprised of a crystalline copolymer approximately 38 weight percent or greater optically inactive dl-lactide and approximately 62 weight percent or less glycolide. 31. An implantable medical device, at least a portion of which is fabricated from a crystalline copolymer of optically inactive dl-lactide and glycolide containing approximately 62 weight percent or less glycolide.

Inventors: KRAMER HILDEGARD I, LICHKUS ANDREW M, KRAMER, HILDEGARD, I., LICHKUS, ANDREW, M.
Applicants: AMERICAN CYANAMID CO, KRAMER HILDEGARD I, LICHKUS ANDREW M, AMERICAN CYANAMID COMPANY, KRAMER, HILDEGARD, I., LICHKUS, ANDREW, M.
Application year: 1997
Main classification: A61F2
IPC codes: A61F2, A61L17, A61L27, A61L31, C08G63