CA2446702A1

CA2446702A1 - Resorbable polymer compositions

Info

Publication number: CA2446702A1
Application number: CA002446702A
Authority: CA
Inventors: Timo Pohjonen; Harri Happonen; Pertti Helevirta; Auvo Kaikkonen; Jan Nieuwenhuis; Piet Haers; Hermann Sailer
Original assignee: Individual
Current assignee: Inion Ltd
Priority date: 2001-05-17
Filing date: 2002-05-17
Publication date: 2002-11-21
Also published as: ES2292751T3; BR0209810A; KR100730432B1; WO2002092691A8; DE60222415T2; ATE373048T1; JP2004533512A; US6607548B2; WO2002092691A1; EP1401958B1; CN100491467C; KR20040014522A; EP1401958A1; US20020173595A1; DE60222415D1; CN1509315A

Abstract

A novel polymer composition is provided which includes a base material including a biodegradable polymer or copolymer, and a copolymer additive including one or more monomers imparting a tensile strength to the polymer composition at room temperature that is lower than a tensile strength at roo m temperature for the base material.

Description

RESORBABLE POLYMER. COMPOSITIONS
BACKGROUND OF THE INVENTION
1. Field of the Invention Embodiments of the present invention relate generally to novel polymer compositions which are useful uz the manufacture of medical implants. More particularly, embodiments of the present invention relate to blended polymer compositions havilzg an additive ingredient, which produces a blend having a lower tensile strength when compared to the polymer composition without the additive ingredient. The blended polymer compositions are biodegradable or bioresorbable.
Methods of lowering the tensile strength of a copolymer are also disclosed.
The novel polymer compositions can be fashioned into medical implants for implantation in the body.

2. Description of Related Art Biodegradable polymer materials and blends thereof used for the production of implants, and implants themselves, are lrnown. See for e~.ample US Patent Nos.
5,700,901; 5,502,159; 5,868,746; 5,569,250; 6,093,201; 5,314,989; 5,403,347;
5,372,598; 4,905,680; 5,468,242; and 5,690,631 each of wluch are hereby incorporated by reference in their entireties for all purposes. However, blends of polymers with copolymers which result in reduced teilsile strength of the implant fashioned therefrom and resulting cold-bendable propez-ties have not been disclosed.

SUMMARY OF THE INVENTION
Embodiments of the present invention relate generally to novel polyner compositions which are useful in the manufacture of medical implants. The polymer compositions are biocompatible and bioresorbable. According to one embodiment of the present invention, a lactic acid or glycolic acid based polymer or copolymer is blended with one or more copolymer additives. The resulting blend is used to form an implant, for example, by well ltnown methods such as melt blending and injection molding and the life. The resulting implant exhibits a lower tensile strength and a lv.gher ductility when compared to an implant formed from a polymer or copolymer laclting the one or more copolymer additives. A copolymer additive according to the present invention includes a bioresorbable monomer and a monomer capable of lowering the tensile strength of the overall polymer composition. As a result, implants fashioned from the novel polymer compositions of the present invention exhibit advantageous properties of being cold-bendable, i.e. bendable at room 1 S temperature without crazing or craclting. In addition, the implants of the present invention are capable of being rejuvenated, i.e. cold-bendable properties which may be reduced over long periods of time can be restored by warming the implalzt.
Embodiments of the present invention also include methods of malting implants and the resulting implants themselves which exhibit reduced tensile strength due to the incorporation of the copolymer additive into a bioresorbable polymer or copolymer either before or during the extrusion process. According to the method, a bioresorbable polymer or copolymer is provided. The bioresorbable polymer or copolymer can be mixed with the copolymer additive and then the mixture melt-blended. Alternatively, the individual components can be melted separately or sequentially and then blended together prior to an injection molding process.
Embodiments of the present invention are still further directed to methods of recovering initial physical properties of implants formed from the polyner compositions of the present ilzvention. According to the present invention, physical properties of implants fonned from the present invention are allowed to change through, for example, the passage of time as can be associated with shelf life. The implant is then heated, for example, on a temperature controlled heating plate for a time period sufficient to restore approximately the ilutial physical properties of the implant.
Accordingly, it is an object of the present invention to provide polymer compositions having reduced tensile strength and increased ductility. It is another object of the present invention to provide polymer compositions useful in the production of biodegradable or bioresorbable implants. It is yet another obj ect of the present invention to provide a method of altering the tensile strength of implants to accommodate a particular implant use. It is still yet another object of d2e present invention to provide a biodegradable or bioresorbable implant which is cold bendable, i.e. bendable at room temperature without crazing or craclcing. It.
is a further object of the invention to eliminate the need fox the preheating of implants prior to implantation into the body. It is a yet fm-ther object of the present invention to provide a method of restoring approximately the initial physical properties of the implant. These and other objects, features and advantages of the present invention will become apparent from the following description taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a table showing different polymer compositions used to manufacture inj ection molded plate test pieces.
Fig. 2 is graph of the elongation at brew of 25 implants produced by different polymer compositions at room temperature and at 37°C.
Fig. 3 is a graph of tensile force at break of 25 implants produced by different polymer compositions at room temperature and at 37°C.
Fig. 4 is a graph of tensile force in newtons of a prior al-t device known as LACTOSORB.
Fig. 5 is a graph of tensile force in newtons of a prior art device known as BIOSORB F~.
Fig. 6 is a graph of tensile force in newtons versus elongation for various implants at room temperature.
Fig. 7 is a graph of tensile force in newtons versus elongation at 37°C.
Fig. 8 is a graph of tensile strength in newtons of implaxlts versus weight percent of the copolymer additive of the present invention in the implant at room temperature and at 37°C.
Fig. 9 is a graph of elongation at break in mln of implants versus weight percent of the copolymer additive of the present invention in the implant at room temperature and at 37°C.

Fig. 10 is a graph of tensile strength and elongation.at break of various implants after production and after 12 weeks storage.
Fig. 11 is a graph showing the recovery of initial tensile properties of various aged implants by 5 minute heat treatment at 50°C.
DETAILED DESCRIPTION
OF CERTAIN PREFERRED EMBODIMENTS
The principles of the present invention may be applied with particular adva~.ztage to provide novel implants formed from polymer compositions that exhibit advantageous tensile properties. In a particular aspect, a melt-blended polyrner composition is provided that includes a base material including a biodegradable polymer or copolymer, and a copolymer additive including one or more monomers imparting, providing or otherwise altering a tensile strength to or of the melt-blended polymer composition at room temperature that is lower than a tensile strength at room temperature for the base material. The polymer compositions of the present invention can be used to form implants having desirable properties by processing steps including injection molding, extrusion, pressure melting, hot pressing and other lilce methods known to those skilled in the art. The terms "inj ection molding" and "inj ection molded" should in no way be interpreted as the only meaxis for producing the implants of the present invention. One aspect of the invention, rather, relates to implants which have been produced or modified by thermoplastic deformation.
According to the present invention, a biodegradable polymer or copolymer is provided as an initial base material and is then combined with one or more copolymer additives to alter the tensile properties of the biodegradable polymer or copolymer. According to one embodiment of the present invention, the biodegradable polymer or copolymer, i.e. base material, is a poly~.ner or copolymer of lactic acid, L-lactide, D-lactide, D,L-lactide, meso-lactide, glycolic acid, glycolide and the like and optionally other cyclic esters which are copolymerizable with lactide. Additional co-monomers may also be present to impart desired properties as needed such as alpha-, beta- or gamma-hydroxybutyric acid, alpha-, beta- or gaanma-hydroxyvaleric acid and other hydroxy fatty acids (C11 to C25) such as stearic acid, pahnitic acid, oleic acid, lauric acid and the like. Accordingly, base material of the present invention include polylactides, polyglycolides, poly(L-Iactide), poly (D-Iactide), poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-meso-lactide), poly(L-lactide-co-glycolide), poly(L-lactide-co-epsilon-caprolaetone), poly(D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide-co-epsilon-caprolactone), poly(meso-lactide-co-glycolide), poly(meso-lactide-co-epsilon-caprolactone) and the like. When the base material is a copolymer, the monomer units are present in a ratio of 50:50, 60:40, 70:30, 80:20, 85:15 axed all suitable ratios in between. For example, suitable base materials include poly(L-Iactide-co-D,L-lactide) 70:30, poly(L-lactide-co-D,L-Iactide) 80:20, poly(L-lactide-co-glycolide) 85:15, and poly(L-lactide-co-glycolide) 80:20. Copolymers that contain L-lactide as a component preferably contain at least 70% of the L-lactide component and more preferably between about 70% and about 95% of the L-lactide component. Polymers or copolymers useful as base materials are commercially available from many sources or can be readily manufactured using methods well-known to those skilled in the art.
In accordance with the present invention, the copolymer additive of the present invention is based on a biodegradable monomer and a monomer that alters the tensile property of the resu1ti11g implant. The monomers that are included into the copolymer additive can be in any sequence. For example, the copolymer additive includes both random copolymers and block copolymers. According to one embodiment of the present invention, the copolymer additives are those including one or more of lactic acid, L-lactide, D-lactide, D,L-lactide, meso-lactide, glycolic acid, glycolide and the like along with one or more of trilnethylene carbonate and dioxanone. Certain advantageous copolymer additives witlun the scope of the present invention include poly(L-lactide-co-trimethylene carbonate), poly(D,L-lactide-co-trimethylene carbonate), poly(meso-lactide-co-tl-imethylene carbonate), poly(glycolide-co-trimethylene carbonate), poly(L-lactide-eo-dioxanone), poly(D,L-Iactide-co-dioxanone), poly(meso-lactide-co-dioxanone), and poly(glycolide-co-dioxanone) and the Iike. Polymers or copolymers useful as base materials are commercially available from many sources or can be readily manufactured using methods well-knomz to those spilled in the art.
According to the present invention, incorporation of copolymer additives including trimethylene carbonate and/or dioxanone to the base materials results in implants and other devices fashioned therefrom havitzg an increased elongation at brealc and also.a lowered tensile strength. It is particularly advalitageous in the implants of the present invention to exhibit lowered tensile strength as the resulting unplants are cold bendable, i.e. bendable at room temperature without visual confirmation of crazing or cracl~ing. The advantageous cold-bendable implants of the present invention allow the user greater mobility in contouring the implants to uneven or curved surfaces without tulduly stressing the implant itself.
Accordingly, it is a particularly useful aspect of the present invention to lower the tensile strength of implants formed from biodegradable polymers or copolymers alone by blending base materials with the polymer additives of the present invention. The resulting cold-bendable implaxlts avoid the use of heating systems to preheat otherwise brittle implants to a ductile state prior to implantation onto a contoured surface in the body.
In accordance with another aspect of the present invention, a method is provided to produce an implant having a resulting crystallinity that is lower than the crystallinities of the individual polymers or copolymers which are blended together to produce the implant. Accordingly, a base polymer or copolymer having a certain crystallinity is blended with a copolymer additive having a certain crystalliW ty. The resulting blend which may be in the form of am implant has a crystallinity that is lower than the crystallinity of either fhe base polymer or the copoly.~ner additive. The lower crystallinity results in the blend having a lower tensile strength as compared to the base polymer alone. In accordance with this aspect of the invention, a blend is produced wherein the blend is characterized as being in a continuous phase or alternatively in a discontinuous phase.

In accordance with another aspect of the present invention, a method is provided to produce an inplant of a blend of a base polymer or copolymer and an additive copolymer having a resulting glass transition temperature that is lower than the glass transition temperature of the base polymer or copolymer alone.
Accordingly, a base polymer or copolymer having a certain glass transition temperature is blended with a copolymer additive. The resulting blend which may be in the farm of an implant has a glass transition temperature that is lower than the glass transition temperature of the base polymer or copolyner. The lower glass transition temperature results in the blend having a Iower tensile strength as compaxed to the base polymer alone.
According to certain aspects of the present invention, the mixtures or blends of the present invention include the base material in an amount betyveen about SO% and about 99%. Lilcewise, the polymer or copolymer additive is present in an amount between about 1% and about 50% depending upon the initial amowlt of the base material chosen and the desired reduction in tensile strength.
Fig. 1 identifies 25 different compositions that have been formulated and used to create an injection molded plate test piece. The base materials included poly(L-lactide-co-D,L-lactide) 70:30, poly(L-lactide-co-D,L-lactide) 80:20, poly(L-lactide-co-glycolide) 85:15, and poly(L-lactide-co-glycoside) 80:20 in the percentage amounts indicated in Fig. 1. The polpner additive was poly(L-lactide-co-trimethylene carbonate) 70:30 in the percentage a~.nounts indicated in Fig.
1.
The following examples are intended to illustrate certain embodiments of the present invention and are not intended to be limiting in any manner.

E~~AMPLE I
Preparation of Polymer Compositions In general, the polymer compositions identified in Fig. 1 were prepared by manually mixing commercially available base materials with ' commercially available copolymer additives. The resulting mixture was then melt blended and inj action molded into plate test pieces. The plate test pieces were then tested for elongation at break, tensile force at break and tensile strength according to the following protocols.
More specifically, the polymer compositions were prepared by dry mixing commercially available granular materials with commercially available copolymer additives. The components were weighed according to the desired weight ratio into a container which was then rotated in a Turbula T2F shaper mixer for 30 minutes until a homogenous dry mixture was obtained. The resulting mixture was subsequently dried in vacuum at 60°C for 6 hours and thereafter melt blended and injection molded into plate test pieces. The plate test pieces were then tested for elongation at break, tensile force at brealc and tensile strength according to the following protocols. The injection-molding machine used was a fully electric Fmuc Roboshot Alpha i30A -injection molding machine with a mould clamping force of 300 kN. The injection unit was equipped with high speed (mar.
66 cm3/s - 330 mm/s), high pressure (mar. 2500 bar) injection options. The barrel diameter was l6mm and was equipped with three band heater zones, a standard profile anticorrosion screw, and a standard open nozzle with a 2,5 mm hole.
The extruder melt blending and homogenization conditions of the material during meteri~ag phase of the process included a back pressure of 40-60 bar, a screw speed of 60-100 rpm, and barrel temperatures of 160-230°C. The injection molding conditions included a nozzle temperature of 180-230°C, an injection speed of 80-300 mnz/s, a maximum injection pressure of 2500 bar, a pack pressure of 1000-bar for 3 to 8 seconds, a cooling time of 10 to 22 seconds and a mould temperature of 20-30°C.
The total cycle time was 20 to 40 seconds consistilzg of the following phases during one injection molding process cycle: closing of the mould, injection of the molten polymer i~lto the mould, pack pressure, cooling (extruder metering for the next cycle during cooling phase), opening the mould, and ejection of the plate.
EXAMPLE II
Determining Elongation at Break According to the following protocol, the elongations at break of various injection molded plates were determined.
A Zwick Z020/TH2A unversal materials testhlg machine with 10 1cN load cell was used to determine elongation at break of the test plates. Gamma sterilized plates were tested at room temperature just after opelung the sterile package or at 37°C in water bath after 30 minutes of preconditioning in water at 37°C. Plates were fixed with tluee pins through the holes of the plate in both ends of the plate.
Plates were loaded with the constant speed of 5 mm/min until brealc of the plate.
Elongation at break was determined in millimeters (mm) according the standard (ASTM D638M). Crosshead movement of the universal materials testing machine was used to measure extension of the specimen.
EXAMPLE III
Determining Tensile Force at Break According to the following protocol, the tensile force at break of various injection molded plates were determined.
A Zwick Z020/TH2A universal materials testing machine with 10 kN load cell was used to detemine tensile force at break of the test plates. Gamma sterilized plates were tested at room temperature just after opening the stel-ile paclcage or at 37°C in water bath after 30 minutes preconditioning in water at 37°C. Plates were fixed with three pins through the holes of the plate in both ends of the plate. Plates were loaded with the constant speed of 5 mmlmin until break of the plate. Tensile force at break was determined in Newtons (N~
according the standard (ASTM D638M).
EXAMPLE IV
Determining Tensile Strength According to the following protocol, the tensile strength of vaxious illj ection molded plates were determined.
Zwiclc Z020/TH2A universal materials testing machine with 10 1cN load cell was used to deteiznine tensile strength of the test plates. Gamma sterilized plates were tested at room temperature just after opening the sterile package or at 37°C in water bath after 30 minutes preconditioning in water at 37°C. Plates were fixed with three pins through the holes of the plate in both ends of the plate.
Plates were loaded with the constant speed of 5 mm/min until break of the plate.
Maximum Ioad was measured in Newtons (NJ and tensile strength was determined according the standard (ASTM D63gM).
F max 6~
A min Where 6 = Tensile strength (MPa) F max = Maximum load (N' A min = Minimum cross section area of the plate (nnna) EXAMPLE V
Testing Data Fig. 2 is a graph of the elongations at break of various injection molded test plates of Fig. 1 at room temperature (RT) and at 37°C. R1LF-1 is a commercially available polymer composition for use in certain cranial-maxillo-facial plating systems. As can be seen in Fig. 2, the elongation at breal~ at room temperature and at 37°C generally increases as the amount of copolymer additive increases. The low elongation at break for the commercially available material represented by R1LF-1 wluch lacks the copolymer additive indicates that the test plate is brittle at room temperature and is not cold-bendable. According to the present invention, a test piece is cold-bendable when the test piece exhibits an elongation at break of greater than 5%.

Fig. 3 is a graph of tensile force at brealc for the test plates of Fig. 1. As can be seen in Fig. 3, tensile force at break at room temperature and at 37°C
generally decreases as the amount of copolymer additive increases. In addition, the tensile force at break increases after annealing indicating improved stability of the test plates.
Fig. 4 is a graph of the tensile force versus elongation for a commercially available plate known under the trade name LACTOSORB formed from a bloclc copolymer of 82% glycolide and 18% L-lactide at room temperature and at 37 °C.
The data demonstrates that the LACTOSORB plate which lacks a copolymer additive of the present invention is brittle at room temperature and not cold bendable.
Fig. 5 is a graph of the tensile force versus elongation for a commercially available plate known under the trade name BIOSORB formed from reinforced poly(L-lactide-co-glycolide) 70:30 at room temperature and at 37 °C.
The data IS demonstrates that the BIOSORB plate is not as brittle as the LACTOSORB
plate, however, the BIOSORB plate is self reinforced wluch detracts from bending strength. Further, the BIOSORB plate camlot be shaped once heated in water and also shriW~s in size after heating.
Fig. 6 is a graph of tensile force versus elongation at room temperature for a test plate which excludes a copolymer additive of the present invention and test plates which include copolymer additives of the present invention. The test piece which excludes the copolymer additive has a failure at 1.5 mm sixain indicating that the material is not cold bendable.

Fig. 7 is a graph of tensile force versus elongation at 37°C for the test plate of Fig. 6 which excludes a copolymer additive of the present invention and the test plates of Fig.. 6 which include copolymer additives of the present i~lvention. The fast piece wlnich excludes the copolymer additive shows desirable tensile force at 37°C, however, it remains brittle at room temperature.
In contrast, the test plates of the present invention are bendable at both room temperature and 37°C.
Fig. 3 is a graph of tensile strength versus weight percent of copolymer additive which further demonstrates the brittle nature at room temperature of the test piece which lacks the copolymer additive.
Fig. 9 is a graph of elongation at break versus weight percent of copolymer additive which further demonstrates the brittle nature at room temperature of the test piece which laclcs the copolymer additive.
Fig. 10 is graph of tensile strength and elongation at break of vauous 1 S implants after production and after 12 weeks storage. The elongation at break becomes lower as shelf life increases due the effects of aging. It is believed that the polymer chains reorgaiuze over time to decrease free volume and to increase the glass transition temperature of the test plate and to thereby increase the tensile strength of the test plate, thereby reducing the cold-bending ability of the test plate. However, Fig. 11 is a graph showing the recovery of initial tensile properties of various aged implants by immersing the test plate in water at 50°C
for 5 minutes. When the test plate is heated, the polymer chains return to their origilnal confirmation and the free volume increases to thereby decrease the tensile strength of the test plate. According to this aspect of the invention, therefore, a method of recovering initial physical properties of implants, such as lower tensile strength, formed from the polymer compositions of the present invention is presented wherein, the tensile strength of the implant is allowed to increase, such as for example, at room temperature. The implant is then heated above room temperature for a time period sufficient to lower the tensile strength at room temperature of the implant. According to the present invention, the test piece including the copolymer additive maintains its lowered tensile strength when rejuvenated for a longer period of time, i.e. several hours to several days, as compared to test pieces which do not include the copolymer additive, i.e. a few second to a few nvnutes.
It is to be understood that the embodiments of the invention, which have been described, are merely illustrative of some applications of the principles of the invention. Numerous modifications may be made by those spilled 11 the art without departing from the tx-ue spirit and scope of the invention.

Claims

What is claimed is:

1. A melt-blended polymer composition compring:
a base material including a biodegradable polymer or copolymer, and a copolymer additive including one or more monomers imparting a tensile strength for the melt-blended polymer composition at room temperature that is lower than a tensile strength at room temperature for the base material, wherein the tensile strength of the composition is first allowed to increase, and thereafter the composition is heated in a manner to decrease the tensile strength of the composition for a time period greater than a few minutes.

2. The melt-blended polymer composition of claim 1 wherein the base material is a polymer or copolymer including a lactide.

3. The melt-blended polymer composition of claim 2 wherein the base material is selected from the group consisting of polylactides, polyglycolides, poly(L-lactide), poly (D-lactide), poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-meso-lactide), poly(L-lactide-co-glycolide), poly(L-lactide-co-epsilon-caprolactone), poly(D,L-lactide-co-meso-lactide), poly(D,L-lactide-co-glycolide), poly(D,L-lactide-co-epsilon-caprolactone), poly(meso-lactide-co-glycolide), poly(meso-lactide-co-epsilon-caprolactone).

4. The melt-blended polymer composition of claim 1 wherein the copolymer additive includes trimethylene carbonate or dioxanone.

5. The melt-blended polymer composition of claim 1 wherein the base material is selected from the group consisting of poly(L-lactide-co-D,L-lactide) 70:30, poly(L-lactide-co-D,L-lactide) 80:20, poly(L-lactide-co-glycolide) 85:15, and poly(L-lactide-co-glycolide) 80:20.

6. The melt-blended polymer composition of claim 1 wherein the copolymer additive is selected from the group consisting of poly(L-lactide-co-trimethylene carbonate), poly(D,L-lactide-co-trimethylene carbonate), poly(meso-lactide-co-trimethylene carbonate), poly(glycolide-co-trimethylene carbonate), poly(L-lactide-co-dioxanone), poly(D,L-lactide-co-dioxanone), poly(meso-lactide-co-dioxanone), and poly(glycolide-co-dioxanone).

7. The melt-blended polymer composition of claim 1 wherein the copolymer additive is poly(L-lactide-co-trimethylene carbonate).

8. The melt blended polymer composition of claim 1 wherein the base material is present in an amount of between about 50% and 99% and the copolymer additive is present in an amount between 1% and 50%.

9. A method of making implants comprising melt-blending a mixture of a base material and a copolymer additive to form a melt-blended mixture, forming an implant from the melt-blended mixture, wherein the implant has a tensile strength at room temperature that is lower than a tensile strength at room temperature for an implant formed from the base material excluding the copolymer additive, allowing the tensile strength of the implant to increase, and heating the implant in a manner to decrease the tensile strength of the implant for a time period greater than a few minutes.

10. An implant formed from a melt-blended polymer composition comprising:
a base material including a biodegradable polymer or copolymer, and a copolymer additive including one or more monomers imparting a tensile strength for the implant at room temperature that is lower than a tensile strength at room temperature for an implant formed from the base material excluding the copolymer additive, wherein the tensile strength of the composition is first allowed to increase, and thereafter the composition is heated in a manner to decrease the tensile strength of the composition for a time period greater than a few minutes.

11. A method of making implants comprising melt-blending a mixture of a base material and a copolymer additive to form a melt-blended mixture, forming an implant from the melt-blended mixture, wherein the implant has a glass transition temperature at room temperature that is lower than a glass transition temperature for an implant formed from the base material excluding the copolymer additive, allowing the tensile strength of the implant to increase, and heating the implant in a manner to decrease the tensile strength of the implant for a time period greater than a few minutes.
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