MXPA98008072A - Crystalline copolymers and methods to produce such copolime - Google Patents

Abstract

Disclosed are crystalline glycolide and dl-lactidaopically inactive copolymers comprising sixty-two weight percent or less of glycolide, the methods for producing the same and absorbable medical devices manufactured therefrom, which have improved properties.

Description

• í COPO CRYSTAL IMMERS AND METHODS TO PRODUCE SUCH POLAROS TECHNICAL FIELD The present invention relates to copolymer compositions based on glycolide and dl-lactide and more particularly to crystalline cspolymer compositions comprising less than sixty-two weight percent or less of glycolide and the methods for producing such compositions, which are useful in the manufacture of absorbable medical devices.

TECHNICAL BACKGROUND Copolymers of, and surgical devices made from dl-lactide and glycolide are well known.

U.S. Patents relating to such polymers 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 ,395,747; 5,403,713: 5,425,984; 5,431,679; 5,439,884 and ,470,340. The desirable physical properties of medical grade bioabsorbable copolymers, such as those made from dl-lactide and glycolide. They 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 lactide and glycolide, in which portions of lactide predominate, have unexpected desired properties, such as a lower degree of crystallinity. Accordingly, it is well established that such polymers containing thirty-eight percent by weight or more of dl-lactide, which is optically inactive, are characteristically amorphous or lack crystallinity. Similarly, U.S. Patent No. 4,157,437, which describes a crystalline copolymer of lactide and glycolide, requires a larger portion thereof to include optically active lactide, which is known to be crystalline. It does not mention absorbent copolymer medical devices made of optically inactive dl-lactide, and characteristically amorphous glycolide specifically designed to be crystalline to improve the physical properties thereof.

DESCRIPTION OF THE INVENTION The present invention provides novel compositions made from about sixty-two weight percent or less of glycolide and about thirty-eight weight percent or more optically inactive dl-lactide having the unexpected characteristic of being crystalline.

According to the teachings of the prior art such compositions are typically amorphous. However, the compositions of the present invention have a segregated, bioabsorbable 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 the dl-lactide bonds are characteristically non-crystalline or amorphous. The manufacturing process of the compositions of the present invention is a ring-opening copolymerization of two or more steps of highly reactive monomeric bonds using 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 type of catalyst and the level of catalyst employed affect both rates of polymerization and transesterification of the cyclic esters described in this invention. Preferred are tin based catalysts such as stannous chloride dihydrate and stannous octoate. Additionally, the inherent viscosity or molecular weight of the composition objectified is highly influenced by the amount of initiator used during the polymerization. Again, the production methods of the novel compositions of the present invention are described in more detail later. The crystalline compositions of the present invention are useful in the area of medical devices since the compositions are readily bioabsorbable and have superior physical and tensile properties over amorphous copolymers of the same composition. Medical devices manufactured from the objective crystalline compositions are dimensionally stable at ambient conditions in contrast to their amorphous counterparts. This superior physical property is a valuable improvement, both from the economic and commercial point of view due to the elimination of the need for transport and refrigerated warehouses for them. Accordingly, an object of the present invention is to provide novel crystalline copolymer compositions, which are dimensionally stable to ambient conditions and therefore eliminate the need for transport and refrigerated warehouses therefor. Another object of the present invention is to provide novel crystalline copolymer compositions useful in the manufacture of medical devices. Another objective of this invention is to provide absorbable medical devices having improved properties manufactured from the novel crystalline copolymer compositions of the present invention. Another objective of this invention is to provide a novel method for producing the novel crystalline compositions of the present invention. The other objects of the invention are achieved here by providing absorbable medical devices derived from the novel crystalline compositions of the present invention.

BEST MEANS FOR CARRYING OUT THE INVENTION In accordance with the present invention, it has now been found that those desirable physical properties of medical grade bioabsorbable copolymers, such as those made from optically inactive dl-lactide and glycolide are highly influenced. by the degree of crystallinity of the same. However, the 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 objective invention, on the contrary, provides greater crystallinity to the compositions, characteristically amorphous, to achieve improved physical properties. The unexpectedly novel crystalline compositions of the present invention are comprised of about sixty-two percent by weight or less of glycolide and about thirty-eight percent or more of optically inactive dl-lactide, but preferably about fifty percent by weight. weight of glycolide and about fifty weight percent of optically inactive dl-lactide. According to the teachings and manufacturing methods of the prior art such compositions were hitherto characteristically amorphous. The novel processes for manufacturing the novel crystalline compositions of the present invention are copolymerizations that open the ring of two or more steps, but preferably a two step sequential addition copolymerization to increase the crystallinity. The copolymerization is achieved 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 alcoholic initiators include but are not limited to 1-docecanol, 1,4-butanediol, 1,5-pentanediol, 1,6-hexanediol, 1, 10-decanediol, inositol, pentacritritol, mannitol, sorbitol, erythritol, ethylene glycol and 1, 3-propanediol. Preferably, lauryl alcohol, i.e. 1-docecanol, is used as the initiator of choice to increase the characteristics of the polymer block, ie, to increase the length of the sequence 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 greater than 0.5 dl / g at a concentration of 0.5 dl / g in a solvent such as hexafluoroisopropanol at 30 ° C is preferred. However, an inherent viscosity is preferred within the range of 0.3 to 0.8 dl / g but preferably 0.5 or 0.6 dl / g for controlled release devices, where a resistance value is not necessary. For articles of manufacture of formable devices, which do not require high strength, an inherent viscosity is required within the range of 0.05 to 0.3 dl / g, but preferably 0.05 to 0.1 dl / g for adequate formability. An inherent viscosity suitable for fiber applications would be within the range of 0.8 dl / g or greater, such as 2.0 dl / g but more preferably about 1.0 dl / g for suitable tensile properties. To achieve those desired inherent viscosities, the initiator / dl-lactide ratio should be greater than about 1:60 but preferably about 1: 100. A suitable melting point for the crystalline compositions of the present invention is at least 140 ° C but preferably 160 ° C or higher. The polymerization and transesterification rates of the cyclic esters of the present invention are directly influenced by one or more of the catalysts employed. Suitable catalysts include but are not limited to stannous chloride, dibutyl tin laurate, dibutyl tin diacetate, dimethyl tin dichloride, stannic chloride pentahydrate, aluminum isopropoxide, antimony trioxide, stannic fluoride, stannous citrate, stannous acetate, antimony trifluoride, tin tetraisopropoxide, 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 octoate are the preferred catalysts for the production of the compositions herein, because of their superior properties when used in a biological system. Most preferably the stannous chloride dihydrate is used as the catalyst of choice in the present invention to control the required polymerization time. However, other catalysts would be suitable for producing the objective compositions, although it has been found that the tin-based catalysts have bioabsorbable characteristics? superior in_ vivo. The reaction conditions deduced for the presentThe invention includes polymerizations carried out at a temperature of about 0.1 to 160 ° C, but more preferably at a temperature of about 180 ° C to 200 ° C. Polymerizations carried out from this temperature range for a period of about 1 hour to 4 hours, but preferably about 2 to 3 hours achieve the desired degree of crystallinity within the range of 2 to 30 percent, but in a manner preferable about 10 percent. The reaction conditions set forth herein likewise allow the objective compositions to be prepared in an economically and commercially desirable amount and time. A wide variety of implantable medical devices can be manufactured, absorbed in whole or in part from the novel copolymers of the present invention. Such devices include plugs, fasteners, bolts, bone screws and other implantable devices. As stated above, the novel copolymers of the present invention provide dimensional stability at ambient temperatures, thereby eliminating the need for refrigerated transport and storage for such medical implant devices. The elimination of the need for refrigeration makes the copolymers of the present invention economically and commercially desirable. The following examples were used to better describe and better illustrate a few novel crystalline copolymers of the present invention. The following examples are not intended to limit the scope of the novel crystalline compositions covered thereby.

Examples I. Reactions in a Single State: Examples 1 to 6: Copolymers of dl-lactide / glycolide 50/50 to 75/25 Six copolymers were prepared from optically inactive glycolide and dl-lactide. The ring-opening polymerization of glycolide and dl-lactide was conducted using 0.40 mole percent with respect to the total monomer concentration of 1-dodecanol as initiator and 0.001 to 0.005 mole percent with respect to the total monomer concentration of stannous chloride dihydrate as a catalyst. The polymerizations were carried out in a 2CV reactor. When combined, the molten mixture of monomers, initiator and catalyst was charged to a reactor with stirring at 180 ° C, under a nitrogen atmosphere, at 38 to 35 rpm. The temperature of the reaction was raised from 180 ° C to 200 ° C for a period of time of 15 minutes. Stirring and heating was continued for an additional 45 minutes, for a total reaction time of two and a half hours. The reaction time was extended for some polymers. The resulting copolymers were triturated and dried under vacuum at 110 ° C, 0.22 mm Hg, for 16 hours. The analytical results are summarized in Table 1. The molecular weight was characterized by a determination of the inherent viscosity in HFIP (hexafluoroisopropanol) at 30 ° C and a concentration of 0.5 g / dl as referenced in Table 1. Although the Six copolymers were prepared by a single-step reaction, differences in their physical properties were influenced by the composition. The crystalline polymers were obtained with compositions rich in glycolide (Example 5 and Example 6). A deviation of the polymers was observed with respect to the crystallinity of those with amorphous properties with the increase of optically inactive, non-crystalline dl-lactide bonds (Example 1, Example 2, Example 3, Example 4), which are unstable for the present invention.

II. Sequential Addition Copolymers Examples 7 to 14: Copolymers of dl-lactide / gliscolide 50/50 to 25/75 Eight optically inactive glycolide and dl-lactide polymers were prepared using sequential polymerization. The ring-opening polymerization of dl-lactide and glycolide was conducted using 0.40 mole percent, with respect to the total monomer concentration of 1-dodecanol. that is, lauryl alcohol as initiator and 0.005 mole percent with respect to the total monomer concentration, with respect to stannous chloride dihydrate as a catalyst. The copolymers were prepared by first synthesizing an optically inactive glycolide and dl-lactide prepolymer with the desired monomer ratios, followed by a subsequent glycolide addition and then the reaction for a specific period of time. The block length of the crystallizable bonds affecting the crystallinity of the final copolymer was controlled through the proportions of glycolide in the second step. The 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 a nitrogen atmosphere, and stirred at about 28 to 3 revolutions per minute (rpm). The reaction temperature was raised from 180 ° C to 200 ° C for a period of time of b minutes. It was continued stirring and heating for an additional 145 minutes, for a total reaction time of 2 to 2.5 hours. After the prepolymer was converted, molten glycolide was added with continuous 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 triturated and dried under vacuum for 19 hours at 110 ° C / 0.2 Hg. The compositions and properties of the polymer are listed in Table 2. Molecular weight was characterized by determination of the inherent viscosity in HFIP (hexafluoroisopropanol) at 30 ° C and a concentration of 0.5 g / dl. Although the total composition of glycolide to dl-lactide remained 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 addition of the second stage.

A. Example 7 Stage 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 15 minutes and continued for 120 minutes at 200 ° C. Load; glycolide: 97.53 g, dl-lactide: 151.35 g SnCl22H20: 23.69 mg 1-dodecanol: 1.574 g Stage 2: Time: time cuts of 15 minutes (and 30 minutes) Temperature: 200 ° C Load: Glycolide: 24.34 g B. Example 8 Stage 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 15 minutes and continued for 120 minutes at 200 ° C. Loading: glycolide: 97353 g, dl-lactide: 151.35 g SnCl22H20: 23.69 mg 1-dodecanol: 1.574 g Stage 2: Time: 65 minutes Temperature: 210 ° C Loading: Glycolide: 24,334 g C. Example 9 Stage 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 20 minutes and continued for 115 minutes at 200 ° C. Loading: glycolide: 85.53 g, dl-lactide: 151.35 g SnCl22H20: 23.69 mg 1-dodecanol: 1.574 g Stage 2: Time: time cuts of 15 minutes (and 30 minutes) Temperature: 200 ° C Charge: Glycolide: 36.51 g Example 10 Step 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 20 minutes and continued for 115 minutes at 200 ° C. Loading: glycolide: 73.20 g, dl-lactide: 151.35 g SnCl22H20: 23.69 mg 1-dodecanol: 1.574 g Stage 2: Time: time cuts of 15 minutes (and 30 minutes) Temperature: 200 ° C Charge: Glycolide: 48.68 g E. Example 11 Step 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 20 minutes and continued for 115 minutes at 200 ° C. Loading: glycolide: 21.92 g, dl-lactide: 136.27 g SnCl22H20: 21.32 mg 1-dodecanol: 1,409 g Stage 2: Time: 15 minutes (and 30 minutes) time slices Temperature: 200 ° C Load: Glicolida: 87.78 g F. Example 12 Step 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 15 minutes and continued for 120 minutes at 200 ° C. Loading: glycolide: 6.09 g, dl-lactide: 227.02 g SnCl22H20: 22.69 mg 1-dodecanol: 1.574 g Stage 2: Time: 15 minute time slices (and 30 minutes! Temperature: 200 ° C Load: Glycolide: 63.85 g G- Example 13 Stage 1: Time: 2.25 hours Temperature: 180 ° C and then increased to 200 ° C for 20 minutes and continued for 115 minutes at 200 ° C. Loading: glycolide: 13.99 g, dl-lactide: 113.51 g SnCl22H20: 11.85 mg 1-dodecanol: 0.787 g Stage 2: Time: time cuts of 15 minutes (and 30 minutes) Temperature: 200 ° C Load: Glycolide: 10.49 g Table 1 Copolymers of Glycolide-co-dl-Lactide in a Single Stage 00 Table 1 (Continued) Copolymers of Glycolide-co-dl-Lactide in a Single Stage CED (Differential Scanning Calorimetry) l £ > IV (Viscosity Inherent in Hexafluoroisopropanol) 1 NMR5 (Proton NMR) Tm (Polymer melting temperature: maximum peak) Tv (Vitreous transition temperature of the polymer: midpoint of the transition)? H (Heat of Fusion in J / g : measured over the entire endothermic region)% of Crist. (Crystallinity based on Polyglycolic Acid: 206.3 J / g).

Table 2 Crystallinity (Sequential Addition) Copolymers of Glycolide-co-dl-Lactide NJ O Table 2 (Continued) Crystallinity (Sequential Addition) Copolymers of Glycolide-co-dl-Lactide t CED (Differential Scanning Calorimetry) IV (Inherent Viscosity in Hexafluoroisopropanol) 1 NMR (Proton NMR) Tm (Polymer melting temperature: maximum peak) Tv (Vitreous polymer transition temperature: midpoint of the transition) H (Heat of Fusion in J / g: measured over the entire endothermic region)% of Crist. (Crystallinity based on Polyglycolic Acid: 206.3 J / g).

Each of the eight copolymers produced in Examples seven through fourteen, discussed above, are unexpectedly crystalline. Hitherto, copolymers of optically inactive dl-lactide and glycolide in such proportions were known to be characteristically amorphous. Nevertheless, the novel crystalline copolymers, produced as described herein, have desirable physical properties for medical absorbable devices. Additionally, although the preceding examples have been directed to the preparation of specific copolymers of optically inactive dl-lactide and glycolide, those examples are for purposes of illustration only and do not limit 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. Accordingly, it is understood that this invention is not limited to the specific embodiments set forth herein, except as defined in the appended claims.

Claims (31)

CHAPTER CLAIMEDICATORÍO Having described the invention, it is considered as a novelty and, therefore, what is contained in the following is claimed. CLAIMS:

1. A crystalline copolymer composition, characterized in that it comprises about 38 weight percent or more of optically inactive dl-lactide, and about 62 weight percent or less of glycolide.

2. The crystalline composition according to claim 1, characterized in that it has a melting point of about 140 ° C or higher.

3. The crystalline composition according to claim 1, characterized in that it has an inherent viscosity of 0.3 dl / g at 2.0 dl / g.

4. The crystalline composition according to claim 1, characterized in that it was extruded to form a medical absorbable device.

5. The crystalline composition according to claim 1, characterized in that it was molded to form a medical absorbable device.

6. The crystalline composition according to claim 1, characterized in that it was stretched to form a medical absorbable device.

The crystalline composition according to claim 1, characterized in that it has a crystallinity within the range of 2 to 30 percent.

8. A method for preparing a crystalline copolymer of optically inactive dl-lactide and glycolide, containing about 62 weight percent or less of glycolide, characterized in that it comprises: a. preparing a monomer mixture of optically inactive dl-lactide monomer and glycolide monomer; b. polymerizing in a two step sequential polymerization process the monomer mixture to obtain a crystalline copolymer of dl-lactide and glycolide.

9. The method according to claim 8, characterized in that the crystalline copolymer has a melting point of at least 140 ° C.

The method according to claim 8, characterized in that the crystalline copolymer has an inherent viscosity of 0.3 dl / g to 2.0 dl / g,

11. The method according to claim 8, characterized in that the crystalline copolymer has a crystallinity inside. of the range from 2 to 30 percent.

12. The method according to claim 8, characterized in that one or more of the initiators is added to the monomer mixture.

The method according to claim 8, characterized in that 1-dodecanol initiator is added to the monomer mixture.

The method according to claim 8, characterized in that an ethylene glycol initiator is added to the monomer mixture.

15. The method of compliance with the claim 8, characterized in that one or more catalysts are added to the monomer mixture.

16. The method according to claim 8, characterized in that a tin-based catalyst is added to the monomer mixture.

17. The method according to claim 8, characterized in that stannous chloride dihydrate is added to the monomer mixture as a catalyst.

18. The method according to claim 8, characterized in that stannous octoate is added to the monomer mixture as a catalyst.

19. A method for preparing a crystalline copolymer of optically inactive dl-lactide and glycolide, containing about 62 weight percent or less of glycolide, characterized in that it comprises: a. preparing a block copolymer comprising optically inactive dl-lactide and glycolide; and b. mixing with the additional glycolide monomer block copolymer to provide an approximate total of 62 weight percent or less of glycolide in the copolymer-monomer mixture; and c. polymerizing the copolymer-monomer mixture to obtain the crystalline copolymer of optically inactive dl-lactide and glycolide.

20, The method according to the claim 19, characterized in that the crystalline copolymer has an inherent viscosity of 0.3 dl / g at 2.0 dl / g.

21. The method according to claim 19, characterized in that the crystalline copolymer has a crystallinity in the range of 2 to 30 percent.

22. The method according to claim 19, characterized in that one or more of the initiators is added to prepare the block copolymer.

23. The method according to claim 19, characterized in that a 1-dodecanol initiator is added to prepare the block copolymer.

24. The method according to claim 19, characterized in that an ethylene glycol initiator is added to prepare the block copolymer.

25. The method according to claim 19, characterized in that a catalyst is added to prepare the block copolymer.

26. The method according to claim 19, characterized in that a tin-based catalyst is added to prepare the block copolymer.

27. The method according to claim 19, characterized in that stannous chlorine dihydrate is added as a catalyst to prepare the block copolymer.

28. The method according to claim 19, characterized in that stannous chloride is added as a catalyst to prepare the block copolymer.

29. The method according to claim 19, characterized in that the crystalline copolymer has a melting point of at least 140 ° C.

30. An implantable medical device, characterized in that it is comprised of a crystalline copolymer of about 38 weight percent or more of optically inactive dl-lactide and about 62 weight percent or less of glycolide.

31. An implantable medical device, characterized in that at least a portion of which is made from a crystalline copolymer of optically inactive dl-lactide and glycolide containing about 62 weight percent or less of glycolide.