Thermoplastic polyurethane admixtures

Abstract

The invention relates to admixtures of thermoplastic polyurethane base polymers that resist surface dulling and fluorinated additives and their use in the manufacture of articles, such as medical devices. For example, the admixtures of the invention are useful in the manufacture of blood dwelling medical devices, such as catheters.

Claims

1. A medical device having a surface comprising an admixture comprising a thermoplastic polyurethane base polymer and a fluorinated additive mixture, wherein said fluorinated additive mixture comprises compounds of formula (I):
G-[B-A].sub.n-B-G  (I), and greater than 0% to 10% (w/w) trimer of formula (II):
G-B-G  (II), wherein A is a soft segment comprising polypropylene oxide, polyethylene oxide, polytetramethylene oxide, hydrogenated polybutadiene (HLBH), poly (2,2 dimethyl-1,3-propylcarbonate) (PCN), polybutadiene (LBHP), diethyleneglycol-orthophthalicanhydride polyester (PDP), poly (hexamethyhlenecarbonate)diol, hydroxyl terminated polydimethylsiloxanes (PrO-PDMS-PrO) block copolymer, hydrogenated-hydroxyl terminated polyisoprene, poly(ethyleneglycol)-block-poly(propyleneglycol))-block-poly(ethylene glycol), 1,12-dodecanediol, hydrogenated polyisoprene (HHTPI), poly(hexamethylene carbonate), or poly(2-butyl-2-ethyl-1,3-propyl carbonate); B is a hard segment comprising terminal urethane linkages; G is an polyfluoroalkyl group; and n is an integer from 1 to 15.

2. The medical device of claim 1, wherein said fluorinated additive mixture comprises between 0.1% and 5% (w/w) trimer of formula (II).

3. The medical device of claim 1, wherein said polyfluoroalkyl group is selected from radicals of the general formula CF.sub.3(CF.sub.2).sub.rCH.sub.2CH.sub.2— wherein r is 2-20, and CF.sub.3(CF.sub.2).sub.s(CH.sub.2CH.sub.2O).sub.χ wherein χ is 1-10 and s is 1-20.

4. The medical device of claim 1, wherein said fluorinated additive mixture is formed by a process that comprises (i) reacting a diisocyanate corresponding to hard segment B with a diol corresponding to soft segment A to form a prepolymer, and (ii) reacting said prepolymer with a polyfluoroalkyl alcohol corresponding to polyfluoroalkyl group G to form a mixture of compounds of formula (I).

5. The medical device of claim 4, wherein said diisocyanate corresponding to hard segment B is selected from the group consisting of 2,4 toluene diisocyanate, 2,6 toluene diisocyanate, methylene bis(p-phenyl) diisocyanate, 1,5 naphthalene diisocyanate, 3,3′ bitoluene diisocyanate, methylene bis (p-cyclohexyl isocyanate), 1,6 hexane diisocyanate, 1,12 dodecane diisocyanate, isophorone diisocyanate, cyclohexyl diisocyanate, lysine diisocyanate, and trimethyl-1,6 diisocyanatohexane.

6. The medical device of claim 4, wherein said diol corresponding to soft segment A is selected from polyalkylene oxide diols, polycarbonate diols, polyester diols, and lactone diols.

7. The medical device of claim 6, wherein said diol corresponding to soft segment A is selected from the group consisting of polyethylene oxide diol, polypropylene oxide diol, and polytetramethylene oxide diol.

8. The medical device of claim 4, wherein said diol corresponding to soft segment A has a theoretical molecular weight of from 400 to 3,000 Daltons.

9. The medical device of claim 4, wherein said diisocyanate corresponding to hard segment B is 1,6 hexane diisocyanate.

10. The medical device of claim 4, wherein said fluorinated additive mixture is formed by a process that comprises (i) reacting about 1 equivalent of said diol corresponding to soft segment A with about 1.4 to 1.8 equivalents of said diisocyanate corresponding to hard segment B to form a prepolymer and (ii) reacting said prepolymer with a polyfluoroalkyl alcohol corresponding to polyfluoroalkyl group G to form said fluorinated additive mixture.

11. The medical device of claim 4, wherein said fluorinated additive mixture is formed by a process that comprises (i) reacting 1 equivalent of polyethylene oxide diol, polypropylene oxide diol, and polytetramethylene oxide diol with about 1.4 to 1.8 equivalents of 1,6-hexamethylene diisocyanate to form a prepolymer; and (ii) reacting said prepolymer with a polyfluoroalkyl alcohol corresponding to polyfluoroalkyl group G to form said fluorinated additive mixture.

12. The medical device of claim 4, wherein said fluorinated additive mixture is formed by a process that further comprises an extraction step for removing some of said trimer of formula (II).

13. The medical device of claim 4, wherein said polyfluoroalkyl alcohol corresponding to polyfluoroalkyl group G is selected from 1H,1H,2H,2H-perfluoro-1-decanol; 1H,1H,2H,2H-perfluoro-1-octanol; 1H,1H,5H-perfluoro-1-pentanol; and 1H,1H, perfluoro-1-butanol, and mixtures thereof.

14. The medical device of claim 1, wherein said fluorinated additive mixture has a polystyrene equivalent weight average molar mass, M.sub.w, of from 2,000 to 26,000 g/mole.

15. The medical device of claim 1, wherein said fluorinated additive mixture has a polystyrene equivalent number average molar mass, M.sub.n, of from 2,000 to 18,000 g/mole.

16. The medical device of claim 1, wherein said fluorinated additive mixture has a polystyrene equivalent molecular weight at highest peak, M.sub.p, of from 2,000 to 26,000 g/mole.

17. The medical device of claim 1, wherein said fluorinated additive mixture has a polydispersity index of between 1.0 and 2.0.

18. The medical device of claim 1, wherein said fluorinated additive mixture has a weight average molar mass, M.sub.w, of from 2,000 to 14,000 g/mole, a number average molar mass, M.sub.n, of from 2,000 to 12,000 g/mole, and comprises between 0.3% and 3% (w/w) trimer of formula (II).

19. The medical device of claim 1, wherein said fluorinated additive mixture has a weight average molar mass, M.sub.w, of from 14,000 to 26,000 g/mole, a number average molar mass, M.sub.n, of from 10,000 to 16,000 g/mole, and comprises greater than 0% to 3% (w/w) trimer of formula (II).

20. The medical device of claim 1, wherein said thermoplastic polyurethane base polymer is a poly (carbonate urethane) base polymer.

21. The medical device of claim 20, wherein said poly (carbonate urethane) base polymer comprises poly(hexamethylene carbonate) and 4,4′-methylene bis(cyclohexyl urethane).

22. The medical device of claim 1, wherein said thermoplastic polyurethane base polymer has a Shore durometer hardness of between 70 A and 95 A.

23. The medical device of claim 1, wherein said admixture comprises from 1% to 8% (w/w) fluorinated additive mixture.

24. The medical device of claim 23, wherein said admixture comprises greater than 0% to less than 1% (w/w) of trimer of formula (II).

25. The medical device of claim 24, wherein said admixture comprises greater than 0% to less than 0.3% (w/w) of trimer of formula (II).

26. The medical device of claim 1, wherein said medical device is a central venous catheter, dialysis catheter, implanted port, or peripherally inserted central catheter.

Description

DRAWINGS

(1) FIG. 1A is an SEM image of a Carbothane™ (Shore Hardness 95 A, with barium sulfate radiopaque filler) film without fluorinated additive at magnifications of 50×, 500×, and 5000×.

(2) FIG. 1B is an SEM image of a Carbothane™ (Shore Hardness 95 A, with barium sulfate radiopaque filler) film with formulation 1 at magnifications of 50×, 500×, and 5000×. At 5000× magnification, a residue is visible for the admixture with formulation 1.

(3) FIG. 1C is an SEM image of a Carbothane™ (Shore Hardness 95 A, with barium sulfate radiopaque filler) film with formulation 7 at magnifications of 50×, 500×, and 5000×. In contrast to FIG. 1B, no residue is observed for the admixture with formulation 7.

DETAILED DESCRIPTION

(4) The methods and compositions of the invention feature admixtures of thermoplastic polyurethane base polymers and fluorinated additive mixtures that resist dulling. The admixtures of the invention are useful in the manufacture of blood dwelling medical devices, such as catheters (i.e., central venous catheter or peripherally inserted central catheter). The medical devices can be fabricated using various processes, including injection molding and extrusion processes resulting from compounded admixture materials.

(5) Applicants have discovered that for admixtures formed from thermoplastic polyurethane base polymers the molecular weight of the fluorinated additive mixture must be (i) low enough to permit migration within, and blooming to the surface of, the base polymer, and (ii) with reduced trimer content to resist dulling. Applicants have discovered that trimer content within fluorinated additive mixtures is associated with dulling of the surface leading to esthetically unpleasing product. Admixtures with reduced trimer content can be prepared as described in the examples.

(6) Thermoplastic Polyurethane Base Polymers

(7) Thermoplastic polyurethanes encompass many different types of materials as well as materials of different durometers. Initial selection of a polyurethane may be based on the performance of the material. Thermoplastic polyurethanes are available with Shore Durometers of from 60 A to 85 D. Thermoplastic polyurethanes come in a variety of different chemical structures, which are selected based upon how the base polymer is being used, and for how long.

(8) Tecoflex medical grade thermoplastic polyurethanes (Grades EG-80A, EG-93A and EG-60D) are a group of aliphatic, polyether based resins that have established credentials for implants including having passed the following standard screening tests: MEM Elution, Hemolysis, USP Class VI, 30 Day Implant, and Ames Mutagenicity.

(9) Tecoflex EG-80A is a medical-grade, aliphatic, polyether-based thermoplastic polyurethane elastomer with a durometer value of 72 A. Tecoflex EG-85A is a medical-grade, aliphatic, polyether-based thermoplastic polyurethane elastomer with a durometer value of 77 A. Carbothane PC-3575A is a medical-grade, aliphatic, polycarbonate-based thermoplastic polyurethane elastomer with a durometer value of 73 A. Carbothane PC-3585A is a medical-grade, aliphatic, polycarbonate-based thermoplastic polyurethane elastomer with a durometer value of 84 A.

(10) Bionate thermoplastic polycarbonate polyurethanes are a family of thermoplastic elastomers formed as a reaction product of a hydroxyl terminated polycarbonate, an aromatic diisocyanate and a low molecular weight glycol to form the soft segment.

(11) These base polymers can be useful in the admixtures of the invention. It is possible that the elastomeric nature of the base polymers renders them both, ideal for use in catheters, but susceptible to dulling when used in combination with fluorinated additive mixtures having high trimer content.

(12) Exemplary poly(carbonate urethanes) that may be included in the admixtures of the invention include, without limitation, CARBOTHANE®, CHRONOFLEX® AL (aliphatic), CHRONOFLEX® AR (aromatic), CHRONOFLEX® C (aromatic), and BIONATE® (aromatic), in a variety of durometers 80 A, 85 A, 90 A, 95 A, 55 D, and 75 D.

(13) 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 methods and compounds claimed herein are performed, 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.

(14) The fluorinated additives of the invention can be prepared by fractionation, washing, and/or by careful design of the reaction conditions (as described in the examples below). These include, but are not limited to, the component reagents mentioned below.

(15) Reagents

(16) HDI=hexamethylene diisocyanate

(17) PTMO=poly(tetramethylene oxide) diol

(18) FOH C8=(CF.sub.3)(CF.sub.2).sub.5CH.sub.2CH.sub.2OH (1H,1H,2H,2H Perfluorooctanol)

Example 1: Formulation 1

(19) To dry reactor glassware was added 1 molar ratio of degassed polytetramethylene oxide diol (M.sub.w 1000) and dimethyl acetamide (DMAC). To the solution was added 2 molar ratio of hexamethylene diisocyanate, and the reaction flask was placed in a water bath. 0.5 mL of dibutyltin dilaurate (DBTDL) was added to the system. The reaction mixture was stirred for 4 hours at 65° C. to produce the desired HDI-PTMO prepolymer.

(20) Once the prepolymer reaction is complete, the reactor contents was cooled to 45° C. and degassed FOH C8 was added to the reactor at a molar ratio of 2.3 to end-cap the pre-polymer. A syringe was used to add ca 1.0 mL dibutyltin dilaurate (DBTDL). The reaction mixture was stirred overnight at 45° C. to produce the desired fluorinated polymers.

(21) The polymer was precipitated in deionized water under constant stirring. The volume of water used for the precipitation should be approximately 3.3 times the volume of the DMAc solvent in the solution.

(22) The polymer was purified by dissolution in boiling isopropanol, followed by cooling to 50-60° C., and precipitation by slow addition of hexane. The precipitated polymer was collected on a filter and washed with hexane. The purified polymer was dried in a convection oven at 50° C. for at least 48 hours to produce Formulation 1 (general formula depicted below).

(23) ##STR00001##

Example 2: Formulations 2 and 3

(24) Formulation 1 was dissolved in tetrahydrofuran and processed through a GPC prep column. Exiting fractions were collected at 0-31 minutes and 31-43 minutes, corresponding to a high molecular weight fraction (Formulation 2) and low molecular weight fraction (Formulation 3), respectively. A rotary evaporator was used to remove the tetrahydrofuran, and the fractions dried under vacuum overnight. About 550 mg of Formulation 2 and about 250 mg of Formulation 3 were isolated from 1 gram of Formulation 1.

Example 4: Formulation 4

(25) Formulation 4 was prepared as described in Example 1, but using a mole ratio of HDI:PTMO of 1.8:1.

Example 5: Formulation 5

(26) Formulation 5 was prepared as described in Example 1, but using a mole ratio of HDI:PTMO of 1.67:1.

Example 6: Formulation 6

(27) Formulation 6 was prepared as described in Example 1, but using a mole ratio of HDI:PTMO of 1.5:1 (950.5 g PTMO, 239.8 g, HDI, and 398.0 g FOH C8).

Example 7: Formulation 7

(28) Formulation 7 was prepared as described in Example 6, but subject to an additional hexane extraction to further reduce the trimer content in the formulation. The solid product of Example 6 was placed in a flask filled with hexane at 50-65° C. with stirring for 2-4 hours. The flask was cooled to 20° C. and the solid contents allowed to settle. The supernatant was siphoned off, and the solids collected on a filter and dried.

Example 8: GPC Analysis of Fluorinated Additives

(29) Gel permeation chromatography (GPC) was used to determine the polymer molecular weight distribution, weight average molecular weight (M.sub.w), number average molecular weight (M.sub.n), and polydispersity index (PDI). GPC was performed on an Agilent 1100 series instrument (Agilent Technologies Inc, Santa Clara, Calif.) with both an refractive index and UV detector and three phenogel columns (10.sup.2 Å, 10.sup.4 Å and 10.sup.5 Å pore sizes, Torrence, Calif.) kept at 50° C. Polymer samples were dissolved at 20 mg/ml in THF containing 0.75 ul/ml benzonitrile internal standard, and 30 μL was injected into the system at a flow rate of 1 mL/min. The M.sub.n, M.sub.w and PDI were calculated relative to polystyrene standards (Fluka, Buchs, Switzerland) using the GPC software (ChemStation Addon Rev. A.02.02). The results for Formulations 1-7 are provided in Table 1, below.

(30) TABLE-US-00001 TABLE 1 Trimer Formu- (w/w lation HDI:PTMO.sup.1 M.sub.w.sup.2 M.sub.n.sup.2 Mp.sup.2 PDI.sup.3 %) 1 .sup. 2:1 11,734 8,214 11,488 1.43 15.7%  2 NA 12,730 9,722 11,628 1.31 .sup. 0% (high MW fraction) 3 NA  4,923 4,201  4,308 1.17 36.5%  (low MW fraction) 4 1.8:1 12,703 8,748 13,150 1.45 8.8% 5 1.67:1  16,093 11,071  17,073 1.45 6.1% 6 1.5:1 20,122 13,544  22,311 1.49 2.8% 7 1.5:1 .sup. 18,822.sup.4 12,753.sup.4  — 1.47.sup.4 0.99%.sup.4  .sup.1Mole ratio of hexamethylenediisocyanate to PTMO diol used to form the prepolymer. .sup.2Polystyrene equivalent (g/mole). .sup.3Polydispersity Index (M.sub.w/M.sub.n). .sup.4Average of 17 batches.

Example 9: Carbothane™ Admixtures

(31) Carbothane™ (Shore Hardness 95 A, with barium sulfate radiopaque filler) was compounded with one or more of formulations 1-7 at 165-210° C. to form an admixture containing 2% (w/w) fluorinated additive. The compounded material was extruded as rods, cut into small pieces, and pressed into films.

(32) The films were placed on plates and incubated at 58-60° C. for 3 days.

(33) Formulations 1 and 3 were observed to form a residue at the surface of the film which leaves a dulling and esthetically unpleasing visual appearance to the product.

(34) In contrast, Formulation 2 formed no residue. With formulations 4 and 5, the amount of the residue was progressively less. In formulations 6 and 7 the residue was not observed.

(35) The results show that the residue at the surface can be reduced or eliminated by reducing the content of trimer in the admixture.

(36) Carbothane™ (Shore Hardness 95 A, with barium sulfate radiopaque filler) films without fluorinated additive (FIG. 1A), compounded with formulation 1 (FIG. 1B), and compounded with formulation 7 (FIG. 1C) were analyzed by scanning electron microscopy (SEM) at magnifications of 50×, 500×, and 5000×. At 5000× magnification, a residue is visible, as asperities, for the admixture with formulation 1. In contrast, no residue is observed for the admixture with formulation 7.

Other Embodiments

(37) All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each independent publication or patent application was specifically and individually indicated to be incorporated by reference.

(38) While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

(39) Other embodiments are within the claims.