Adjustable polyisobutylene polyurethane

Abstract

A polymer material having polyisobutylene polyurethane. The polyisobutylene has a soft segment containing polyisobutylenediamine residues and a hard segment containing biscyclic carbonate residues.

Description

Technical Field

[0001] The present disclosure relates to polymer materials. More specifically, the present disclosure relates to polyisobutylene-polyurethane block copolymers, methods for making polyisobutylene-polyurethane block copolymers, and medical devices comprising polyisobutylene-polyurethane block copolymers.

Background Art

[0002] Polymer materials are widely used in the field of medical devices. For example, polymer materials such as silicone rubber, polyurethane, and fluoropolymers are used as coatings and / or insulating materials for medical leads, stents, catheters, and other devices.

[0003] Thermoplastic polyurethane (TPU) can be used in either short-term or long-term implantable devices (such as catheters, polymer disks, and coatings). A block copolymer is a polymer material consisting of alternating sections of polymerized monomers. Polyisobutylene polyurethane is a TPU formed from hard segments (such as diisocyanates) and soft segments (hydroxyl-terminated polymers such as polyethers, polycarbonates, poly-ε-caprolactone, and polyisobutylene). The mechanical (such as hardness and stretchability) and thermal (such as crystallinity and glass transition) properties of polyisobutylene polyurethane can be adjusted, for example, by varying the weight percentages of the hard and soft segments.

[0004] However, one problem associated with existing polyisobutylene polyurethane manufacturing processes is the formation of undesirable urea linkage groups, which can cause unpredictable variations in the molecular weight of the polyurethane and its thermal and / or mechanical properties.

[0005] In addition, non-covalent coatings have been used on polyisobutylene polyurethane to reduce or prevent biofilm buildup on polymer surfaces. However, covalent coatings also prevent biofilm buildup while providing improved coating and sufficient lubricity. [Overview of the project]

[0006] Example 1 is a polymer material having polyisobutylene polyurethane. The polyisobutylene has a soft segment containing a polyisobutylenediol residue and a hard segment containing a bis-cyclic carbonate residue.

[0007] Example 2 is the polymer material of Example 1, and the polyisobutylene polyurethane does not contain urea bonds. Example 3 is the polymer material of Example 1, wherein the hard segment further contains ethanol side chains.

[0008] Example 4 is the polymer material of Example 1, and the hard segment further comprises modifying groups covalently bonded to the polymer backbone. Example 5 is the polymer material of Example 4, wherein the modifying group is derived from bromine-terminated polyethylene glycol (PEG-Br), quaternary ammonium bromine-terminated derivatives (small molecule or polymer-based), bromine-terminated polyvinylpyrrilidone (PVP-Br), or bromine-terminated poly(2-methyl-2-oxazoline).

[0009] Example 6 is the polymer material of Example 4, wherein the modifying group is derived from 8-bromo-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane, bromine-terminated polytetrafluoroethylene (PTFE-Br), or bromine-terminated polydimethylsiloxane (PDMS-Br).

[0010] Example 7 is a medical device having a polymer material. This polymer material has a soft segment containing polyisobutylenediamine residues and a hard segment containing biscyclic carbonate residues.

[0011] Example 8 is a medical device of Example 7, wherein the hard segment further comprises modifying groups covalently bonded to the polymer backbone. Example 9 is a medical device of Example 8, in which the modifying group is present only on the surface of the polyisobutylene polyurethane.

[0012] Example 10 is a medical device of Example 8, in which the modifying group is present throughout the polyisobutylene polyurethane. Example 11 is a method for producing a polymer material, which includes forming an amino-terminated polyisobutylene from a hydroxyl-terminated polyisobutylene and forming a polyisobutylene polyurethane by performing ring-opening polymerization using a biscyclic carbonate and an amino-terminated polyisobutylene.

[0013] Example 12 is the same method as in Example 11, and involves forming an amino-terminated polyisobutylene by adding methanesulfonyl chloride and ammonia to the hydroxyl-terminated polyisobutylene.

[0014] Example 13 is the same method as in Example 11, in which biscyclic carbonate and amino-terminated polyisobutylene are present in equimolar amounts during ring-opening polymerization. Example 14 is the method described in Example 11, and is S with polyisobutylene polyurethane. N The process further comprises carrying out two reactions to form a modified polyisobutylene polyurethane.

[0015] Example 15 is the method of Example 14, S N The two reactions involve bromine-terminated polyethylene glycol (PEG-Br), quaternary ammonium bromine-terminated derivatives (small molecule or polymer-based), bromine-terminated polyvinylpyrrolidone (PVP-Br), or bromine-terminated poly(2-methyl-2-oxazoline).

[0016] Example 16 is the method of Example 14, S N The two reactions involve 8-bromo-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane, bromine-terminated polytetrafluoroethylene (PTFE-Br), or bromine-terminated polydimethylsiloxane (PDMS-Br).

[0017] Example 17 is the method described in Example 14, further comprising forming polyisobutylene polyurethane into a medical device. Example 18 is the method of Example 17, and S N The second reaction takes place before forming the medical device.

[0018] Example 19 is the method of Example 17, S N The second reaction takes place after the medical device has been formed. Example 20 is the method of Example 19, S N The 2 reaction involves a polymer or molecule having a leaving group and a modifying group, wherein the leaving group is selected from the group consisting of bromides, iodides, chlorides, tosylates, and mesylates, and the modifying group is selected from the group consisting of polyacrylates, acrylic acid copolymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyoxazolines, quaternary ammonium functionalized polymers or molecules, glycosaminoglycans, and peptides.

[0019] While several examples are disclosed, further examples provided herein will become apparent to those skilled in the art from the following detailed description illustrating and explaining exemplary embodiments. Therefore, the drawings and detailed description should be considered illustrative and not restrictive. [Brief explanation of the drawing]

[0020] [Figure 1] A schematic diagram illustrating a process for producing polyisobutylene polyurethane according to some embodiments of the present disclosure. [Figure 2]Schematic diagram showing the second (optional) step of a process for producing polyisobutylene - polyurethane according to some embodiments of the present disclosure.

BRIEF DESCRIPTION OF THE INVENTION

[0021] Although the present disclosure admits of various modifications and alternative forms, specific embodiments are shown by way of example in the drawings and are hereinafter described in detail. However, the intention is not to limit the present disclosure to the particular embodiments described. Rather, the present disclosure is intended to cover all modifications, equivalents, and alternatives falling within the scope of the present disclosure as defined by the appended claims.

[0022] According to various aspects of the present disclosure, a polyisobutylene - polyurethane block copolymer (also generically referred to herein as "PIB - PUR") and a method for producing the same are disclosed. Also disclosed are medical devices that are implantable or insertable into a patient's body and contain a polyisobutylene urethane copolymer. PIB - PUR is a thermoplastic polyurethane (TPU) that includes hard segments and soft segments. PIB - PUR can be biocompatible and can have enhanced biostability compared to currently used thermoplastic polyurethanes. Since PIB - PUR is hydrolytically stable and has good oxidation stability, it is useful in many applications including medical devices used for insertion or implantation into patients. Exemplary medical devices include guidewires, stents, drainage catheters, pacemaker leads, left atrial appendage closure devices, percutaneous nephrolithotomy (PCNL) procedures, hydrogels, implantable meshes, and artificial heart valves.

[0023] Traditionally, polyisobutylene polyurethanes have been synthesized from polyfunctional isocyanates (e.g., diisocyanates containing both aliphatic and aromatic diisocyanates) and polyols (e.g., macroglycols). However, isocyanates are hydrosensitive and can be converted to primary amines, which can react with free isocyanates to form undesirable urea-bonded structures (CO(NH2)2). That is, isocyanates can form urea-bonded structures instead of the desired urethane formation. Urea-bonded structures can lead to unpredictable variations in molecular weight and thermal and mechanical properties, making quality control difficult.

[0024] Disclosed herein is a novel synthesis method for polyisobutylene polyurethane that avoids the formation of urea-bonded structures, yields a naturally hydrophilic coating to provide lubricity on the outer surface of the polymer, and provides an opportunity to covalently bond functional groups, such as polymers or molecules, to the polymer to further modify the properties of the polyisobutylene polyurethane.

[0025] Figure 1 is a schematic diagram illustrating a process for producing polyisobutylene polyurethane according to several embodiments of the present disclosure. Hydroxyl-terminated polyisobutylene (PIB-OH) is used as a starting material. This starting material is combined with methanesulfonyl chloride and ammonia (NH3) to convert the hydroxyl-terminated group to an amino-terminated group to form amino-terminated polyisobutylene (PIB-NH3). In some embodiments, p-toluenesulfonyl chloride can be used instead of methanesulfonyl chloride.

[0026] In the second step, amino-terminated polyisobutylene (PIB-NH3) is used as a micromolecular initiator for ring-opening polymerization with a biscyclic carbonate to produce polyisobutylene polyurethane. In some embodiments, PIB-NH3 and the biscyclic carbonate are combined in equimolar amounts. In some embodiments, the ratio of functional groups of PIB-NH3 and the biscyclic carbonate is maintained at a ratio of 1:1 or close to 1:1, for example, 0.995:1 or 0.995:0.995.

[0027] As shown in Figure 1, the resulting polyisobutylene polyurethane has a soft segment containing polyisobutylenediamine residues and a hard segment containing biscyclic carbonate residues and ethanol side chains. These ethanol side chains can provide a naturally hydrophobic coating on the polyisobutylene surface to provide lubricity. The ethanol side chains can also provide an antifouling or antimicrobial surface. In some embodiments, the ethanol side chains can provide a surface that can be adjusted by surface functionalization.

[0028] The resulting polyisobutylene polyurethane does not involve urea formation or urea bond formation. In some embodiments, this synthesis results in more predictable and less variability in the molecular weight and thermal and mechanical properties of the polyisobutylene polyurethane, partly due to the absence of urea side reactions. In addition, the low oxygen content on the polyisobutylene polyurethane backbone avoids or reduces further in vivo oxidative degradation.

[0029] The weight ratio of soft segments to hard segments in polyisobutylene polyurethane in various embodiments can be varied to achieve a wide range of physical and mechanical properties, as well as a range of desirable functional performance. For example, the weight ratio of soft segments to hard segments in the polymer can vary from 99:1 to 95:5 to 90:10 to 75:25 to 50:50 to 25:75 to 10:90 to 5:95 to 1:99, more specifically from 95:5 to 90:10 to 80:20 to 70:30 to 65:35 to 60:40 to 50:50, and even more specifically from about 80:20 to about 50:50. In some embodiments, the soft segment component may be about 40% to about 70% by weight of the copolymer, and the hard segment component may be about 30% to about 60% by weight of the copolymer.

[0030] In some embodiments, the polyisobutylene polyurethane copolymer may comprise about 60% to about 100% by weight of polyisobutylene in the soft segment and about 0% to about 40% by weight of polyether, polyester, or polycarbonate in the soft segment. For example, the copolymer may comprise about 40% to about 70% by weight of soft segment, of which polyisobutylene is present in about 60% to about 100% by weight of the soft segment and polyether is present in about 0% to about 40% by weight of the soft segment. In another embodiment, the copolymer may contain soft segments in an amount of about 40% to about 70% by weight of the copolymer, of which polyisobutylene (e.g., polyisobutylenediamine residues) are present in an amount of about 70% to about 95% by weight of the soft segments, and polyether (e.g., polytetramethylene oxidediol residues) are present in an amount of about 5% to about 40% by weight of the soft segments.

[0031] As used herein, “polymer segment” or “segment” refers to a part of a polymer. As used herein, “soft segment” and “hard segment” are relative terms for describing the properties of polymer materials containing such segments. Without limiting the foregoing, soft segments may exhibit glass transition temperatures (Tg) below body temperature, more typically 35°C–20°C–0°C–-25°C–-50°C or lower. Hard segments may exhibit Tg above body temperature, more typically 40°C–50°C–75°C–100°C or higher. Tg can be measured by differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), and / or thermomechanical analysis (TMA).

[0032] In some embodiments, the surface of the polyisobutylene polyurethane can be further modified. More specifically, the ethanol side chains provide an opportunity to modify the hydrophilicity or hydrophobicity of the surface, which can affect the lubricity of the polyisobutylene polyurethane surface and / or prevent or reduce bacterial adhesion. Figure 2 is a schematic diagram showing a second (optional) step in the process for producing polyisobutylene polyurethane, in which the surface of the polyisobutylene polyurethane is modified.

[0033] As shown in Figure 2, the polyisobutylene polyurethane of Figure 1, which includes an ethanol side chain, can be combined with polymers or molecules containing modifying groups. N Through two reactions (nucleophilic substitution proceeding via a bimolecular mechanism), the modifying group covalently bonds to the polymer backbone of the polyisobutylene polyurethane to form the modified polyisobutylene polyurethane. As shown in Figure 2, the polyisobutylene polyurethane can be combined with a polymer or molecule containing bromide ions (Br) and the desired modifying group. Bromide is S N It is a good leaving group for reaction 2. Other suitable leaving groups include iodide (I), chloride (Cl), tosylates (OTs), and mesylates (OMs).

[0034] In some embodiments, modified polyisobutylene polyurethanes have improved hydrophilicity. Suitable modifying groups for improving hydrophilicity include, but are not limited to, polyacrylates, acrylic acid copolymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyoxazolines, quaternary ammonium functionalized polymers or molecules, and glycosaminoglycans (including natural ones such as hyaluronic acid (HA) or heparin, or synthetic ones such as sulfonated polymers). Suitable polymers or molecules containing modifying groups for improving hydrophilicity include, but are not limited to, bromine-terminated polyethylene glycol (PEG-Br), quaternary ammonium bromine-terminated derivatives (small molecule or polymer-based), bromine-terminated polyvinylpyrrolidone (PVP-Br), and bromine-terminated poly(2-methyl-2-oxazolines).

[0035] Suitable modifying groups for improving the hydrophobicity of modified polyisobutylene polyurethane include, but are not limited to, polydimethylsiloxane (PDMS), polytetrafluoroethylene (PTFE), 2-perfluorohexylethylthiol, and polyisobutylene (PIB). Suitable polymers or molecules containing modifying groups for improving the hydrophobicity of modified polyisobutylene polyurethane include, but are not limited to, 8-bromo-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane, bromine-terminated polytetrafluoroethylene (PTFE-Br), and bromine-terminated polydimethylsiloxane (PDMS-Br).

[0036] In some embodiments, a prodrug is prepared by reacting an ethanol side chain with an active compound. The release rate of the active compound can be controlled by hydrolysis. In some embodiments, drug release can be extended over a significant period, providing long-term benefits. In some embodiments, the active compound or drug contains a carboxylic acid such as ibuprofen. The carboxylic acid group from the active compound is bonded to a polyisobutylene polyurethane by an ester bond. The ester bond gradually decomposes in vivo, releasing the active compound such as ibuprofen.

[0037] Modification of polyisobutylene polyurethane (e.g., Figure 2) can be carried out before or after forming the final medical device from the polyisobutylene polyurethane. When the polyisobutylene polyurethane is modified before the medical device is formed (i.e., bulk polyisobutylene polyurethane is modified according to Figure 2), the bound moiety is dispersed throughout the bulk polymer. This may be suitable for adjusting mechanical properties such as water absorption or for modifying drug release kinetics. In one embodiment, a solution suspension is used by combining an organic solvent with a specific moiety such as polyvinylpyrrolidone-bromine (PVP-Br) or polyethylene glycol-bromine (PEG-Br) and the polyisobutylene polyurethane. A precipitation procedure can then be performed.

[0038] When polyisobutylene polyurethane is modified after the medical device has been formed, only the surface properties of the polyisobutylene polyurethane are altered. This may be suitable when adapting the surface properties of the polyisobutylene polyurethane, such as hydrophobicity or hydrophilicity. When a polyisobutylene polyurethane medical device is modified according to Figure 2, the modifying groups covalently bond to the surface of the polyisobutylene polyurethane, forming a coating. The covalently bonded coating does not fall apart or peel off after implantation. A covalent bond is a chemical bond in which electrons are shared between atoms. In contrast, a non-covalent bond is a weaker bond compared to a covalent bond because a chemical reaction does not occur in part (i.e., there is no formation or breakdown of chemical bonds).

[0039] Polyisobutylene polyurethane according to embodiments of the present disclosure may be incorporated into medical devices that can be implanted or inserted into a patient's body. Examples of medical devices include, but are not limited to, structural cardiac applications including vascular grafts, electrical leads, catheters, leadless cardiac pacemakers (LCPs), pelvic floor repair support devices, shock coil covers, covered stents, urethral stents, enteral feeding tubes / balloons, and valve leaflets; ophthalmic applications including suture sleeves, breast implants, intraocular lenses, and glaucoma tubes; and intervertebral disc repair. Exemplary electrical leads may include, but are not limited to, implantable electrical stimulation or diagnostic systems including neurostimulation systems such as spinal cord stimulation (SCS) systems, deep brain stimulation (DBS) systems, peripheral nerve stimulation (PNS) systems, gastric nerve stimulation systems, cochlear implant systems, and retinal implant systems; and cardiac systems including, in particular, implantable cardiac rhythm management (CRM) systems, implantable cardioverter-diffibrillators (ICDs), and cardiac resynchronization therapy and defibrillation (CRDT) devices.

[0040] Prediction Example 1 Polyisobutylene polyurethane material (e.g., extruded or injection-molded polyisobutylene polyurethane tubes or films) is immersed in a polar aprotic solvent (e.g., THF, ether, or acetone) with sodium carbonate or potassium carbonate, or under basic conditions (i.e., pH 8-12), in a first container for about 30 minutes. A solution of Br-terminated PEG or other hydrophilic material is prepared in a polar aprotic solvent in a second container. The contents of this second container are combined with the polyisobutylene polyurethane in the first container. After about 30 minutes, the polyisobutylene polyurethane is removed from the solution and washed three times with deionized (DI) water. The polyisobutylene polyurethane is then dried. The dried polyisobutylene polyurethane has a hydrophilic coating on its surface via an Sn2 reaction.

[0041] Prediction Example 2 Polyisobutylene polyurethane material, such as extruded or injection-molded polyisobutylene polyurethane tubes or films, is immersed in a sodium acetate / ethyl acetate solution in a first container for approximately 30 minutes. A second solution is formed in the second container by dissolving a Br-terminated hydrophilic polymer, such as Br-PEG, in ethyl acetate. The contents of the second container are added to the polyisobutylene polyurethane in the first container. After approximately 30 minutes, the polyisobutylene polyurethane is removed from the solution and washed three times with deionized (DI) water. The polyisobutylene polyurethane is then dried. The dried polyisobutylene polyurethane has a hydrophilic coating on its surface via an Sn2 reaction.

[0042] Prediction Example 3 The polyisobutylene polyurethane material (e.g., an extruded or injection-molded polyisobutylene polyurethane tube or film) is immersed in an aqueous solution of sodium acetate (or sodium carbonate or potassium carbonate may be used) in a first container for about 30 minutes. The second solution is formed in a second container by dissolving a Br-terminated hydrophilic polymer, such as Br-PEG, in water. The contents of the second container are added to the polyisobutylene polyurethane in the first container. After about 30 minutes, the polyisobutylene polyurethane is removed from the solution and washed three times with deionized (DI) water. The polyisobutylene polyurethane is then dried. The dried polyisobutylene polyurethane has a hydrophilic coating on its surface via an Sn2 reaction.

[0043] Various modifications and additions can be made to the embodiments described without departing from the scope of this disclosure. For example, while the embodiments described above refer to specific features, the scope of this disclosure also includes embodiments having different combinations of features, and embodiments that do not include all of the described features. Accordingly, the scope of this disclosure shall encompass all such substitutes, modifications, and variations that fall within the claims, along with all their equivalents.

Claims

1. Soft segment containing polyisobutylenediamine residue and A hard segment containing a biscyclic carbonate residue and A polymer material containing polyisobutylene polyurethane.

2. The polymer material according to claim 1, wherein the polyisobutylene polyurethane does not contain urea bonds.

3. The polymer material according to claim 1 or claim 2, wherein the hard segment further comprises an ethanol side chain.

4. The polymer material according to any one of claims 1 to 3, wherein the hard segment further comprises a modifying group covalently bonded to the polymer backbone.

5. The polymer material according to claim 4, wherein the modifying group is derived from bromine-terminated polyethylene glycol (PEG-Br), quaternary ammonium bromine-terminated derivative (small molecule or polymer-based), bromine-terminated polyvinylpyridone (PVP-Br), or bromine-terminated poly(2-methyl-2-oxazoline).

6. The polymer material according to claim 4, wherein the modifying group is derived from 8-bromo-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane, bromine-terminated polytetrafluoroethylene (PTFE-Br), or bromine-terminated polydimethylsiloxane (PDMS-Br).

7. Soft segment containing polyisobutylenediamine residue and A hard segment containing a biscyclic carbonate residue and A medical device containing polymer materials, including polyisobutylene polyurethane.

8. The medical device according to claim 7, wherein the hard segment further comprises a modifying group covalently bonded to the polymer backbone.

9. The medical device according to claim 8, wherein the modifying group is present only on the surface of the polyisobutylene polyurethane.

10. The medical device according to claim 8, wherein the modifying group is present throughout the entire polyisobutylene polyurethane.

11. A method for producing polymer materials. The step of forming an amino-terminated polyisobutylene from a hydroxyl-terminated polyisobutylene, The steps include: carrying out ring-opening polymerization using a biscyclic carbonate and the amino-terminated polyisobutylene to form a polyisobutylene polyurethane; A method that includes this.

12. The method according to claim 11, wherein the step of forming the amino-terminated polyisobutylene includes the step of adding methanesulfonyl chloride and ammonia to the hydroxyl-terminated polyisobutylene.

13. The method according to claim 11 or claim 12, wherein the biscyclic carbonate and the amino-terminated polyisobutylene are present in equimolar amounts during the ring-opening polymerization.

14. The aforementioned polyisobutylene polyurethane and S Ｎ The method according to any one of claims 11 to 13, further comprising carrying out a 2 reaction to form a modified polyisobutylene polyurethane.

15. The aforementioned S Ｎ The method according to claim 14, wherein the second reaction comprises bromine-terminated polyethylene glycol (PEG-Br), a quaternary ammonium bromine-terminated derivative (small molecule or polymer-based), bromine-terminated polyvinylpyridone (PVP-Br), or bromine-terminated poly(2-methyl-2-oxazoline).

16. The aforementioned S Ｎ The method according to claim 14, wherein the second reaction comprises 8-bromo-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane, bromine-terminated polytetrafluoroethylene (PTFE-Br), or bromine-terminated polydimethylsiloxane (PDMS-Br).

17. The method according to claim 14, further comprising the step of forming the polyisobutylene polyurethane into a medical device.

18. The aforementioned S Ｎ The method according to claim 17, wherein the reaction is carried out before the step of forming the medical device.

19. The aforementioned S Ｎ The method according to claim 17, wherein the second reaction is carried out after the medical device has been formed.

20. The aforementioned S Ｎ The method according to claim 19, wherein the second reaction comprises a polymer or molecule having a leaving group and a modifying group, the leaving group being selected from the group consisting of bromides, iodides, chlorides, tosylates and mesylates, and the modifying group being selected from the group consisting of polyacrylates, acrylic acid copolymers, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), polyoxazolines, quaternary ammonium functionalized polymers or molecular glycosaminoglycans and peptides.

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