RIGID RESORBABLE MATERIALS WITH POLYMER AND ORGANIC FILLERS

Abstract

This invention relates to the composition of flexible resorbable polymers with rigid resorbable fillers. The invention further relates to processing of flexible resorbable polymers with rigid resorbable fillers. The invention relates also to the use of such materials for applications in fast degradation applications. The invention also relates to the composition of flexible resorbable polymers with rigid resorbable for making shape memory materials. This invention also related to the processing of such materials by extrusion, injection molding, thermoforming, solvent mixing, and additive manufacturing. The invention also relates to the use of such materials as bone filler, vascular closure and other hemostasis devices, aneurysms, and stent applications. The invention also relates to the use of such materials as drug delivery platforms.

Claims

1. A resorbable material exhibiting a shape memory effect comprising a flexible resorbable polymer and at least one rigid resorbable filler.

2. The resorbable material of claim 1, wherein the flexible resorbable polymer i) is a semi-crystalline polymer; or ii) is an amorphous polymer; or iii) is a semi-crystalline polymer selected from a polydioxanone, a polycaprolactone, a poly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate), a biodegradable polyurethane, a poly(amino acid), a polyetherester, polyphosphoesters, a polyanhydride, a multi-block copolymer of polydioxanone-b-polycaprolactone, a multi-block copolymer of poly(lactide-b-trimethylene carbonate), a multi-block copolymer of poly(glycolide-b-trimethylene carbonate), a multi-block copolymer of poly(lactide-b-caprolactone), a polyethylene glycol (PEG), a multi-block copolymer of polylactide-b-PEG, a multi-block copolymer of PGA-b-PEG, a multi-block copolymer of PCL-b-PEG, a multi-block copolymer of PDO-b-PEG, a multi-block copolymer of PEG and a polyorthoester, a multi-block copolymer of polyhydrobutyrate-b-polyhydroxyvalerate, and a copolymer, a terpolymer or a mixture thereof; or iv) is an amorphous polymer selected from a random copolymer of polydioxaone-co-polycaprolactone, a random copolymer of poly(lactide-co-caprolactone), a random copolymer of poly(lactide-co-trimethylene carbonate), a random copolymer of poly(glycolide-co-trimethylene carbonate), a random copolymer of polylactide-co-PEG, a random copolymer of PGA-co-PEG, a random copolymer of PCL-co-PEG, a random copolymer of PDO-co-PEG, a random copolymer of polyhydrobutyrate-co-polyhydroxyvalerate, or a mixture thereof; or v) is a mixture of at least one semi-crystalline polymer selected from a polydioxanone, a polycaprolactone, a poly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate), a biodegradable polyurethane, a poly(amino acid), a polyetherester, polyphosphoesters, a polyanhydride, a multi-block copolymer of polydioxanone-b-polycaprolactone, a multi-block copolymer of poly(lactide-b-trimethylene carbonate), a multi-block copolymer of poly(glycolide-b-trimethylene carbonate), a multi-block copolymer of poly(lactide-b-caprolactone), a polyethylene glycol (PEG), a multi-block copolymer of polylactide-b-PEG, a multi-block copolymer of PGA-b-PEG, a multi-block copolymer of PCL-b-PEG, a multi-block copolymer of PDO-b-PEG, a multi-block copolymer of PEG and a polyorthoester, a multi-block copolymer of polyhydrobutyrate-b-polyhydroxyvalerate and at least one amorphous polymer selected from a random copolymer of polydioxaone-co-polycaprolactone, a random copolymer of poly(lactide-co-caprolactone), a random copolymer of poly(lactide-co-trimethylene carbonate), a random copolymer of poly(glycolide-co-trimethylene carbonate), a random copolymer of polylactide-co-PEG, a random copolymer of PGA-co-PEG, a random copolymer of PCL-co-PEG, a random copolymer of PDO-co-PEG, a random copolymer of polyhydrobutyrate-co-polyhydroxyvalerate; and/or vi) is in the form of a continuous matrix.

3. The resorbable material of claim 1 or 2, wherein the rigid resorbable filler i) are in the form of powders, fines, granules, spheres, particles, crystalline whiskers, or a mixture thereof; and/or ii) have regular or irregular shape; and/or iii) have a diameter in the range of 0.01 to 100 μm, preferably in the range of 0.1 to 50 μm, and more preferably in the range of 0.1 to 25 μm; and/or iv) are a polyglycolide, a polylactide, a poly (L-lactide-b-D,L-lactide), a polylactide-b-polyglycolide, a poly(L-lactide-co-D,L-lactide), a polylactide-co-polyglycolide, a polyesteramide, a polylactide stereocomplex, a starch granule, a cellulose microcrystal, a chitin whisker, a collagen, a crosslinked collagen, a silk, or a mixture thereof; and/or v) are more rigid than the flexible resorbable polymer.

4. The resorbable material according to any of claims 1 to 3, wherein i) the volume ratio between the flexible resorbable polymer and the rigid resorbable filler is in the range of 99:1 to 50:50; and/or ii) the resorbable material has improved rigidity compared to the flexible resorbable polymer; and/or iii) the resorbable material has higher crystallinity than the flexible resorbable polymer; and/or iv) the resorbable material has improved mechanical strength than the flexible resorbable polymer; and/or v) the resorbable material has improved yield strain compared to the flexible resorbable polymer.

5. The resorbable material of any of claims 1 to 4 further comprising an active pharmaceutical ingredient.

6. The resorbable material of claim 5, wherein the active pharmaceutical ingredients are dispersed in the flexible resorbable polymer, dispersed in the rigid resorbable filler, or dispersed in both the flexible resorbable polymer and rigid resorbable filler.

7. A process for preparing a resorbable material of any of claims 1 to 6 by solvent mixing, comprising the steps: (a) dissolving the flexible resorbable polymer in a solvent or a solvent mixture to make a solution; (b) dispersing the rigid resorbable fillers in the solution; (c) removing the solvents; and (d) forming the material.

8. A thermal process for preparing a resorbable material of any of claims 1 to 6 by extrusion, comprising the steps: (a) feeding a flexible resorbable polymer, and rigid resorbable filler(s) to an extruder; (b) compounding the flexible resorbable polymer and rigid resorbable fillers using the extruder at a temperature above the melting temperature of the flexible resorbable polymer to form a mixture; (c) extruding the mixture; and (d) forming the mixture into a shape using a die.

9. A thermal process for preparing a resorbable material of any of claims 1 to 6 by injection molding, comprising the steps: (a) feeding a flexible resorbable polymer, and rigid resorbable filler(s) to an injection molding machine; (b) melting the flexible resorbable polymer above the melting temperature of flexible resorbable polymer but below the melting temperature the rigid resorbable fillers to form a mixture; (c) injecting the mixture into a mold cavity; and (d) forming the mixture into a shape using a mold.

10. A thermal process for preparing a resorbable material of any of claims 1 to 6 by thermoforming, comprising the steps: (a) placing sheet(s) of the resorbable material in a mold; (b) heating the sheet(s) to pliable, and (c) forming the sheet(s) into a shape.

11. A process for producing a 3D printed part from a material of any of claims 1 to 6 using a bioplotter; the process comprising: (a) feeding a flexible resorbable polymer, and rigid resorbable filler(s) to a cartridge; (b) melting the flexible resorbable polymer above the melting temperature of flexible resorbable polymer but below the melting temperature of the rigid resorbable fillers to obtain a mixture; (c) printing the mixture through a print head to form multiple layers of the 3D printed part; and (d) setting the 3D printed part.

12. A process for producing a 3D printed part from a resorbable material of any of claims 1 to 6 using binder jetting, comprising the steps of: (a) providing powders of the resorbable material; (b) selectively depositing an amount of a binder onto the powders of material to produce an unfinished layer; (c) repeating steps (a) and (b) to produce a three-dimensional unfinished model; and (d) sintering the unfinished model to produce a three-dimensional 3D printed part.

13. A process for producing a 3D printed part from a resorbable material of any of claims 1 to 6 using FFF, comprising the steps of: (a) feeding the filament of the resorbable material into a temperature-controlled FFF extrusion head; (b) heating the extrusion head for the resorbable material to form a semi-liquid state resorbable material; (c) extruding the resorbable material; (d) depositing the extruded resorbable material onto a fixtureless base; wherein the head directs the material into place forming thin layers of the extruded resorbable material, and (e) solidify the extruded resorbable material by laminating the material to the preceding layer to form a 3D printed part.

14. A process for producing a 3D printed part from a resorbable material of any of claims 1 to 6 using SLS, comprising the steps of: (a) dispersing a thin layer on top of a platform inside the build chamber; (b) the laser scans a cross-section of the 3D model and heats the powder around the melting point of the resorbable material; (c) the platform lowers by one layer into the build chamber, and redispersing a new thin layer of the powder on top, the laser scans the next cross-section of the build, and (d) repeating the steps from (a) to (c) to form a 3D printed part.

15. 3D printed part obtained by a process according to any of claims 11 to 14.

16. Use of the resorbable material according to any of claims 1 to 6 or the 3D printed part of claim 15 as bone filler, vascular closure and other hemostasis devices, aneurysms, stent, fast degradation applications, drug delivery, and drug release applications, or any other medical application requiring implanting into the human body.

Description

EXAMPLES

[0061] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the polymer, particles, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in ° C. or is at ambient temperature, and pressure is at or near atmospheric.

Preparation of Example 1

Processing of Polydioxanone With Starch

[0062] Polydioxanone (PDO, Evonik RESOMER® X 206 S commercially available from Evonik) with fillers, wherein the filler is biodegradable corn starch, with weight ratios between PDO and fillers of 100:0; 98:2; 95:5; 90:10 and 80:20 were compounded by a HAAKE MiniLab twin screw microcompounder. The 3 heating zones for the microcompounder were set at 140° C., respectively. PDO, or PDO with fillers were fed into the microcompounder and recirculated for 3 minutes and discharged to a HAAKE MiniJet cylinder at 145° C. The polymer melt was injection molded to dog-bone specimens following ISO-527-1BB. The melting and mold temperatures were 145° C. and 35° C., respectively. After melting, the material was injected into the mold with an injection pressure of 75 MPa for 8 seconds and a hold pressure of 45 MPa for 4 seconds.

Preparation of Example 2

Annealing of Specimens

[0063] Injection mold specimens of Example 1 were annealed under vacuum at 80° C. for 8 hours. To prevent thermal degradation during annealing after putting the specimens inside a vacuum oven, the chamber was degassed for 30 min at room temperature then heated to 80° C. and holding there for 8 hours.

Preparation of Example 3

Processing of PDO With PGA Particles

[0064] Polyglycolide (PGA, RESOMER® G 205 S commercially available from Evonik) was milled to particles. The PGA particles passed through sieves with diameter of 25 μm. Particle size was analyzed further by laser diffraction. PDO and PGA particles with weight ratios between PDO and PGA particles of 100:0; 95:5; 90:10 and 80:20 were compounded by a HAAKE MiniLab twin screw microcompounder. The 3 heating zones for the microcompounder were set at 140° C., respectively. PDO with PGA particles were fed into the microcompounder and recirculated for 3 minutes and discharged to a HAAKE MiniJet cylinder preheated at 145° C. The polymer melt was injection molded to dog-bone specimens following ISO-527-1BB. The melting and mold temperatures were 145° C. and 35° C., respectively. After melting, the material was injected into the mold with an injection pressure of 75 MPa for 8 seconds and a hold pressure of 45 MPa for 4 seconds.

Testing

[0065] Mechanical properties including tensile strength, elastic modulus, elongation at break were measured on injection molded dog-bone shaped specimens (ISO-527-1BB) by an Instron Universal Testing Machine (Instron 3366) equipped with a 10 kN load cell and pneumatic grips (10 PSI air pressure). The specimens were then tested by tension mode with a crosshead speed of 5 mm/min or 20 mm/min at room temperature. Five replicates were tested, and average values were reported.

[0066] Shape memory property of the resorbable materials were evaluated by a Dynamic Mechanical Analyzer (DMA, Q-800, TA Instruments). Narrow section of injection molded specimens were cut to straight rectangular shape (18×2×1.5 mm), or cut from thermally compressive molded sheet to straight strip (20×3×0.3 mm) and mounted to the DMA with a pair of tensile clamps. The shape memory testing was performed by a controlled force method. The specimens were then heated to 40° C., held at 40° C. for 10 min, then applied 0.3-15 N force on the specimen. Afterwards, the specimens were cooled to −60° C. with applied constant force, held at −60° C. for 30 min, the force was unloaded and the specimen was heated to 40° C. and held at 40° C. for 30 min. Shape recovery rate is determined by Rr(%)=(ε.sub.u−ε.sub.p)/(ε.sub.m−ε.sub.p)×100, where ε.sub.u, ε.sub.p and ε.sub.m represent the fixed strain after unloading, the permanent strain after heat-induced recovery, and the temporal strain achieved by deformation. All these strains were measured and recorded by the DMA.

[0067] FIG. 1. depicts dynamic mechanical analysis of resorbable material containing PDO and PGA. The materials have improved storage modulus with inclusion of PGA particles. The dynamic mechanical properties of the materials with fillers was evaluated by a DMA (Q-800, TA Instruments). Narrow section of injection molded specimens were cut to straight rectangular shape (18×2×1.5 mm) and mounted it to the DMA with a pair of tensile clamps. The specimen was cooled to −60° C. then heated to 90° C. at a heating rate of 3° C./min. The specimens with more PGA particles showed a higher storage modulus. The PDO with 20% PGA particles have doubled storage modulus (840 MPa) compared to neat PDO (410 MPa) at 37° C.

[0068] Results

TABLE-US-00001 TABLE 1 Mechanical properties of materials consisting of resorbable PDO and starch before (i.e., as-made) and after annealing. PDO/starch Yield strength (MPa) Elongation at break (%) Elastic Modulus (MPa) ratio (w/w) As-made annealed As-made annealed As-made annealed 100/0  27.7.8 ± 0.6.sup.  34.9 ± 1.0 215 ± 35 237 ± 61 593 ± 46  968 ± 56 98/2 24.7 ± 1.3 36.5 ± 0.4 266 ± 41 208 ± 51 810 ± 9  1010 ± 27 95/5 25.2 ± 2.1 36.1 ± 0.6 270 ± 27 164 ± 6  834 ± 30 1101 ± 44  90/10 27.4 ± 0.6 36.5 ± 0.4 246 ± 46 146 ± 28 973 ± 44  1205 ± 102  80/20 27.0 ± 2.2 31.7 ± 0.4 243 ± 5  140 ± 66 1065 ± 98  1328 ± 26
Inclusion of starch granules improve elastic modulus of PDO. Annealing as a post treatment process improves yield strength and elastic modulus of PDO and its composites with starch.

TABLE-US-00002 TABLE 2 Mechanical properties of materials consisting of resorbable PDO and PGA before (i.e., as-made) and after annealing. PDO/PGA Yield strength (MPa) Yield strain (%) Elastic Modulus (MPa) ratio (w/w) As-made annealed As-made annealed As-made annealed 100/0  24.8 ± 0.9 34.9 ± 1.0  8.7 ± 0.5  8.8 ± 0.6 593 ± 46 968 ± 56 95/5  35.3 ± 0.1 39.33 ± 0.04 10.8 ± 0.1 11.0 ± 0.3 828 ± 50 849 ± 6  90/10 34.0 ± 0.1 38.7 ± 0.5 10.9 ± 0.3 11.2 ± 0.2 813 ± 14 910 ± 12 80/20 35.1 ± 0.6 39.2 ± 0.4  8.2 ± 0.2  8.2 ± 0.1 1030 ± 51  1009 ± 1 
Inclusion of PGA particles and annealing process improve yield strength and elastic modulus of PDO making it mechanically strong and stiff. Yield strain is improved by inclusion of 5-10% PGA particles.

TABLE-US-00003 TABLE 3 Shape memory effect of the materials consisting of resorbable PDO and starch granules or PGA particles. Composition Shape recover rate (%) PDO 22 PDO/20% starch 50 PDO/10% PGA 43 PDO/20% PGA 70
The presence of rigid PGA particles or the starch granules enhances material's shape recover rate.
Item 1 is a resorbable material exhibiting a shape memory effect comprising a flexible resorbable polymer and at least one rigid resorbable filler.
Item 2 is the flexible resorbable polymer of item 1 is a semi-crystalline polymer.
Item 3 is the flexible resorbable polymer of item 1 is an amorphous polymer.
Item 4 is the flexible resorbable polymer of item 2 is a polydioxanone, a polycaprolactone, a poly(orthoester), a poly(phosphazene), a poly(hydroxybutyrate), a biodegradable polyurethane, a poly(amino acid), a polyetherester, polyphosphoesters, a polyanhydride, a multi-block copolymer of polydioxanone-b-polycaprolactone, a multi-block copolymer of poly(lactide-b-trimethylene carbonate), a multi-block copolymer of poly(glycolide-b-trimethylene carbonate), a multi-block copolymer of poly(lactide-b-caprolactone), a polyethylene glycol (PEG), a multi-block copolymer of polylactide-b-PEG, a multi-block copolymer of PGA-b-PEG, a multi-block copolymer of PCL-b-PEG, a multi-block copolymer of PDO-b-PEG, a multi-block copolymer of PEG and a polyorthoester, a multi-block copolymer of polyhydrobutyrate-b-polyhydroxyvalerate, and a copolymer, a terpolymer or a mixture thereof.
Item 5 is the flexible resorbable polymer of item 3 is a random copolymer of polydioxaone-co-polycaprolactone, a random copolymer of poly(lactide-co-caprolactone), a random copolymer of poly(lactide-co-trimethylene carbonate), a random copolymer of poly(glycolide-co-trimethylene carbonate), a random copolymer of polylactide-co-PEG, a random copolymer of PGA-co-PEG, a random copolymer of PCL-co-PEG, a random copolymer of PDO-co-PEG, a random copolymer of polyhydrobutyrate-co-polyhydroxyvalerate, or a mixture thereof.
Item 6 is the flexible resorbable polymer in item 1 is a mixture of one or more polymers in item 4 and one or more polymers in item 5.
Item 7 is the rigid resorbable filler of item 1 are in the form of powders, fines, granules, spheres, particles, crystalline whiskers, or a mixture thereof.
Item 8 is the rigid resorbable filler of item 7 have regular or irregular shape.
Item 9 is the rigid resorbable filler of item 7 have a diameter in the range of 0.01 to 100 μm, preferably in the range of 0.1 to 50 μm, and more preferably in the range of 0.1 to 20 or 25 μm.
Item 10 is the volume ratio between the flexible resorbable polymer and the rigid resorbable filler of item 1 is in the range of 99:1 to 50:50.

[0069] Item 11 is the rigid resorbable filler of item 7 is a polyglycolide, a polylactide, a poly (L-lactide-b-D,L-lactide), a polylactide-b-polyglycolide, a poly(L-lactide-co-D,L-lactide), a polylactide-co-polyglycolide, a polyesteramide, a polylactide stereocomplex, a starch granule, a cellulose microcrystal, a chitin whisker, a collagen, a crosslinked collagen, a silk, or a mixture thereof.

Item 12 is the flexible resorbable polymer of item 1 is a continuous matrix.
Item 13 is the rigid resorbable filler of item 1 is more rigid than the flexible resorbable polymer of item 1.
Item 14 is the resorbable material of item 1 further comprising an active pharmaceutical ingredient.
Item 15 is the active pharmaceutical ingredient in item 14 is dispersed in the flexible resorbable polymer, dispersed in the rigid resorbable filler, or dispersed in both the flexible resorbable polymer and rigid resorbable filler.
Item 16 is a process for preparing a material of item 1 by solvent mixing:

[0070] (a) dissolving the flexible resorbable polymer of item 1 in a solvent or a solvent mixture to make a solution;

[0071] (b) dispersing the rigid resorbable fillers in the solution;

[0072] (c) removing the solvents; and

[0073] (d) forming the material.

Item 17 is a thermal process for preparing a material of item 1 by extrusion:

[0074] (a) feeding a flexible resorbable polymer, and rigid resorbable filler(s) to an extruder;

[0075] (b) compounding the flexible resorbable polymer and rigid resorbable fillers using the extruder at a temperature above the melting temperature of flexible resorbable polymer;

[0076] (c) extruding the materials; and

[0077] (d) forming the materials into a shape using a die.

Item 18 is a thermal process for preparing a material of item 1 by injection molding:

[0078] (a) feeding a flexible resorbable polymer, and rigid resorbable filler(s) to an injection molding machine;

[0079] (b) melting the flexible resorbable polymer above the melting temperature of flexible resorbable polymer but below the melting temperature the rigid resorbable fillers;

[0080] (c) injecting the materials into a mold cavity; and

[0081] (d) forming the materials into a shape using a mold.

Item 19 is a thermal process for preparing a material of item 1 by thermoforming:

[0082] (a) placing sheet(s) of a material of item 1 in a mold;

[0083] (b) heating the sheet(s) to pliable, and

[0084] (c) forming the sheet(s) into a shape.

Item 20 is a process for producing a 3D printed part from a material of item 1 using a bioplotter; the process comprising:

[0085] (a) feeding a flexible resorbable polymer, and rigid resorbable filler(s) to a cartridge;

[0086] (b) melting the flexible resorbable polymer above the melting temperature of flexible resorbable polymer but below the melting temperature the rigid resorbable fillers;

[0087] (c) printing the material through a print head to form multiple layers of the 3D printed part; and

[0088] (d) setting the 3D printed part.

Item 21 is a process for producing a 3D printed part from a material of item 1 using binder jetting, comprising the steps of:

[0089] (a) providing powders of material of item 1;

[0090] (b) selectively depositing an amount of a binder onto the powders of material to produce an unfinished layer;

[0091] (c) repeating steps (a) and (b) to produce a three-dimensional unfinished model; and

[0092] (d) sintering the unfinished model to produce a three-dimensional 3D printed part.

Item 22 is a process for producing a 3D printed part from a material of item 1 using FFF, comprising the steps of:

[0093] (a) feeding the filament of the material of item 1 into a temperature-controlled FFF extrusion head;

[0094] (b) heating the extrusion head for the materials of item 1 to form a semi-liquid state material;

[0095] (c) extruding the material;

[0096] (d) depositing the material onto a fixtureless base; wherein the head directs the material into place forming thin layers of the material, and

[0097] (e) solidify the material by laminating the material to the preceding layer to form a 3D printed part.

[0098] Item 23 is a process for producing a 3D printed part from a material of item 1 using SLS, comprising the steps of:

[0099] (a) dispersing a thin layer on top of a platform inside the build chamber;

[0100] (b) the laser scans a cross-section of the 3D model and heats the powder around the melting point of the material;

[0101] (c) the platform lowers by one layer into the build chamber, and redispersing a new thin layer of the powder on top. The laser scans the next cross-section of the build, and

[0102] (d) repeating the steps from (a) to (c) to form a 3D printed part.

Item 24 is the material comprising the flexible resorbable polymer of item 1 and rigid resorbable fillers having improved rigidity than the flexible resorbable polymer of item 1.
Item 25 is the material comprising the flexible resorbable polymer of item 1 and rigid resorbable fillers of item 1 is resorbable.
Item 26 is the material comprising the flexible resorbable polymer of item 2 and rigid resorbable filler of item 1 has higher crystallinity than the flexible resorbable polymer of item 2.
Item 27 is the resorbable material in item 1 has improved mechanical strength than the flexible resorbable polymer of item 1.
Item 28 is the resorbable material in item 1 has improved yield strain than the flexible resorbable polymer of item 1.
Item 29 is the resorbable material in item 1 has improved yield strength than the flexible resorbable polymer of item 1.
Item 30 is the material of item 1 can be used for bone filler, vascular closure and other hemostasis devices, aneurysms, stent, fast degradation applications, drug delivery, and drug release applications, or any other medical application requiring implanting into the human body.