阅读说明：本技术 耐醇硅化聚碳酸酯聚氨酯和掺入所述耐醇硅化聚碳酸酯聚氨酯的医疗装置 (Alcohol resistant siliconized polycarbonate polyurethane and medical devices incorporating the same ) 是由 J·A·缪斯 N·J·弗雷丁 S·文卡塔拉马尼 于 2018-11-17 设计创作，主要内容包括：耐醇硅化聚碳酸酯聚氨酯可包括软链段和硬链段。所述软链段可包含聚碳酸酯多元醇和聚硅氧烷,所述聚硅氧烷可以小于所述聚碳酸酯多元醇的量存在。所述硬链段可包括异氰酸酯和扩链剂。外周置入中心静脉导管(PICC)装置可包括一个或多个组件,所述组件至少部分地由所述硅化聚碳酸酯聚氨酯导管的一种或多种制剂形成。PICC装置可耐受醇锁定,并且在醇锁定事件之前和之后均可以为可功率注入的。(The alcohol resistant siliconized polycarbonate polyurethane may include soft segments and hard segments. The soft segment can comprise a polycarbonate polyol and a polysiloxane, which can be present in an amount less than the polycarbonate polyol. The hard segment may include an isocyanate and a chain extender. Peripherally Inserted Central Catheter (PICC) devices may include one or more components formed at least in part from one or more formulations of the siliconized polycarbonate polyurethane catheter. The PICC device may tolerate alcohol lock and may be power injectable both before and after the alcohol lock event.)

1. An alcohol resistant siliconized polycarbonate polyurethane formed from reactants comprising:

a polycarbonate polyol having a structure according to formula (I):

wherein R is selected from the group consisting of linear or branched, substituted or unsubstituted C₁-C₂₄An alkyl or alkylene group, a is selected from hydrogen (H) or R' OH, and n is an integer from 2 to 30;

a polysiloxane having a structure according to formula (IV):

wherein R1 and R2 are independently selected from linear C1-C6 alkyl groups or hydrogen groups, R3 and R5 are independently selected from C1-C12 alkyl or alkylene groups, R4 and R6 are independently selected from C1-C8 alkyl or alkylene groups, and m is an integer from 2 to 30;

an isocyanate; and

a chain extender which is a mixture of a chain extender,

the siliconized polycarbonate polyurethane comprises:

a hard segment;

a soft segment comprising a polysiloxane in an amount of 5 to 15 wt%; and

an isocyanate index of 1.01 to 1.06.

2. The siliconized polycarbonate polyurethane of claim 1, wherein the polysiloxane has a number average molecular weight (M) of about 925g/mol to about 1025g/mol_n)。

3. The siliconized polycarbonate polyurethane of claim 2, wherein the soft segment comprises the polysiloxane in an amount of 9 to 11 weight percent.

4. The siliconized polycarbonate polyurethane according to claim 3, wherein the isocyanate index is from 1.03 to 1.06.

5. The siliconized polycarbonate polyurethane according to claim 1, wherein the polysiloxane is a carbonyl-modified polydimethylsiloxane having a structure according to formula (V):

wherein m is an integer from 2 to 30.

6. According to the claimsThe siliconized polycarbonate polyurethane of claim 5, wherein the polysiloxane has a number average molecular weight (M) of about 925g/mol to about 1025g/mol_n)。

7. The siliconized polycarbonate polyurethane of claim 6, wherein the polycarbonate polyol has a number average molecular weight (M) of about 1840g/mol to about 2200g/mol_n)。

8. The siliconized polycarbonate polyurethane according to claim 7, wherein the isocyanate index is in the range of 1.03 to 1.06.

9. The siliconized polycarbonate polyurethane of claim 8, wherein the polycarbonate polyol comprises poly (hexamethylene carbonate) diol.

10. The siliconized polycarbonate polyurethane of claim 8, wherein the isocyanate is aromatic.

11. The siliconized polycarbonate polyurethane according to claim 10, wherein the isocyanate comprises methylene diphenyl diisocyanate.

12. The siliconized polycarbonate polyurethane according to claim 10, wherein the chain extender comprises 1, 4-butanediol.

13. The siliconized polycarbonate polyurethane of claim 1, wherein the hard segment is present in an amount between 40 to 50 weight percent and the soft segment is present in an amount between 50 to 60 weight percent.

14. The siliconized polycarbonate polyurethane of claim 13, wherein the siliconized polycarbonate polyurethane has a shore a durometer value of between about 96 to about 100.

15. The siliconized polycarbonate polyurethane of claim 1, wherein the siliconized polycarbonate polyurethane has a weight average molecular weight (Mw) of between 50,000 and 300,000.

16. The siliconized polycarbonate polyurethane of claim 1, wherein R₃And R₅Independently selected from C₁-C₈An alkyl or alkylene group.

17. The siliconized polycarbonate polyurethane of claim 16, wherein R₄And R₆Independently selected from C₁-C₄An alkyl or alkylene group.

18. The siliconized polycarbonate polyurethane of claim 1, wherein R₄And R₆Independently selected from C₁-C₄An alkyl or alkylene group.

19. The siliconized polycarbonate polyurethane of claim 1, wherein the polysiloxane has a number average molecular weight (M) of 300 to 3000_n)。

20. The siliconized polycarbonate polyurethane according to claim 1, wherein the isocyanate is a member selected from the group consisting of: 4, 4' -methylenediphenyl diisocyanate, dibenzylidene diisocyanate, methylenedicyclohexyl diisocyanate, p-phenylene diisocyanate, trans-cyclohexane-1, 4-diisocyanate, 1, 6-diisocyanatohexane, 1, 5-naphthalene diisocyanate, p-tetramethylxylylene diisocyanate, m-tetramethylxylylene diisocyanate, 2, 4-tolylene diisocyanate, isophorone diisocyanate, and combinations thereof.

21. The siliconized polycarbonate polyurethane according to claim 1, wherein the chain extender is a member selected from the group consisting of: 1, 2-propanediol, 1, 3-propanediol, 2-ethyl-2- (hydroxymethyl) propane-1, 3-diol, 1, 4-butanediol, 1, 5-pentanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol, 1, 9-nonanediol, 1, 10-decanediol, 1, 11-undecanediol, 1, 12-dodecanediol, 1, 4-cyclohexanediol, 1, 4-cyclohexanedimethanol, 1, 4-bis (2-hydroxyethoxy) benzene, p-xylenediol, 1, 3-bis (4-hydroxybutyl) tetramethyldisiloxane, 1, 3-bis (6-hydroxyethoxypropyl) tetramethyldisiloxane, and combinations thereof.

22. The siliconized polycarbonate polyurethane of claim 1, further comprising an additive selected from the group consisting of: radiopacifiers, lubricants, catalysts, antioxidants, free radical inhibitors, colorants, fillers, and combinations thereof.

23. The siliconized polycarbonate polyurethane of claim 1 formed by a process comprising:

forming a first mixture comprising the polysiloxane and the isocyanate;

mixing the first mixture for a first period of time;

after completion of the first period of time, forming a second mixture comprising the first mixture and the polycarbonate polyol; and

mixing the second mixture for a second period of time.

24. The siliconized polycarbonate polyurethane according to claim 23, wherein the process further comprises:

after completion of the second period of time, forming a third mixture comprising the second mixture and the chain extender; and

mixing the third mixture for a third period of time.

25. The siliconized polycarbonate polyurethane of claim 24, wherein the third time period terminates when the temperature of the third mixture rises to a threshold value.

26. The siliconized polycarbonate polyurethane according to claim 25, wherein the threshold is in the range of about 200 ° F to about 230 ° F.

27. The siliconized polycarbonate polyurethane of claim 23, wherein the forming the second mixture comprises adding both the polycarbonate polyol and the chain extender to the first mixture.

28. The siliconized polycarbonate polyurethane of claim 27, wherein the second period of time terminates when the temperature of the second mixture rises to a threshold value.

29. The siliconized polycarbonate polyurethane according to claim 28, wherein the threshold is in the range of about 200 ° F to about 230 ° F.

30. The siliconized polycarbonate polyurethane of claim 23, wherein the first period of time is from about 2 minutes to about 30 minutes.

31. The siliconized polycarbonate polyurethane according to claim 30, wherein the second period of time is from about 2 minutes to about 30 minutes.

32. The siliconized polycarbonate polyurethane according to claim 30, wherein the second period of time is from about 2 minutes to about 15 minutes.

33. A medical device comprising at least one component comprising the siliconized polycarbonate polyurethane according to any of claims 1 to 32.

34. The medical device of claim 33, wherein the medical device comprises a catheter.

35. The medical device of claim 33, wherein the medical device comprises a Peripherally Inserted Central Catheter (PICC) device.

36. The medical device of claim 35, wherein the PICC device includes at least one fluid path that is power injectable.

37. The medical device of claim 36, wherein the at least one fluid path of the PICC device is power injectable after (1) having been subjected to an ethanol lock event for a period of time sufficient to disinfect the at least one fluid path and (2) having been flushed after the ethanol lock event and allowed to resume a recovery period.

38. The medical device of claim 37, wherein the recovery period is not less than one hour.

39. The medical device of claim 33, wherein the PICC device includes at least one fluid path capable of maintaining an injection pressure of up to 180psi without rupturing and without leaking.

40. The medical device of claim 39, wherein the at least one fluid path includes a lumen of an extension tube, a passageway through a connection hub coupled to a distal end of the extension tube and coupled to a proximal end of the catheter shaft, and a lumen of a catheter shaft.

41. The medical device of claim 40, wherein the connection hub is overmolded onto the extension tube and the catheter shaft.

42. The medical device of claim 41, wherein the extension tube, the connection hub, and the catheter shaft each comprise a different alcohol-resistant siliconized polycarbonate polyurethane.

43. The medical device of claim 42, wherein the alcohol resistant siliconized polycarbonate polyurethane of the connection hub is harder than the alcohol resistant siliconized polycarbonate polyurethane of the extension tube and the catheter shaft.

44. The medical device of claim 43, wherein the alcohol resistant siliconized polycarbonate polyurethane of the catheter shaft is compounded with a radiopacifier.

45. The medical device of claim 44, wherein the alcohol resistant siliconized polycarbonate polyurethane of the catheter shaft and the extension tube have the same chemistry.

46. A kit, the kit comprising:

a conduit comprising at least one component comprising the siliconized polycarbonate polyurethane according to any of claims 1 to 32. And

instructions for using the catheter, the instructions providing guidance for:

introducing an alcohol into the lumen of the catheter and maintaining the alcohol therein for a clinically effective locking period;

flushing the alcohol from the lumen of the catheter; and

waiting for a recovery period after flushing the alcohol from the lumen, and then using the lumen for injection.

47. The kit of claim 46, wherein the recovery period is one hour.

48. The kit of claim 46, wherein the recovery period is at least one hour.

49. The kit of claim 46, wherein a length of a shaft of the catheter configured to be introduced into a vasculature of a patient defines a 5French outer diameter.

50. The kit of claim 49, wherein the instructions indicate that the catheter is available for use in a patient weighing at least 2.3 kg.

51. The kit of claim 50, wherein the alcohol resistant siliconized polycarbonate polyurethane of the shaft is compounded with a radiopacifier in an amount sufficient to render the shaft radiographically visible when the shaft is in a patient.

52. The kit of claim 51, wherein the radioopaque agent comprises barium sulfate.

53. The kit of claim 46, wherein the injection is a power injection.

Technical Field

Certain embodiments described herein relate generally to polyurethanes, and more particularly to polycarbonate polyurethanes. Another embodiment relates generally to medical devices, such as catheters, incorporating such polycarbonate polyurethanes.

Background

Polyurethane is a versatile plastic material that can be adapted for a variety of applications. For example, polyurethanes have been used in insulation panels, gaskets, hoses, tires, wheels, synthetic fibers, surface coatings, furniture, footwear, adhesives, medical devices, and a variety of other materials and devices. Generally, polyurethanes are formed by reacting a polyol with a diisocyanate or other polyisocyanate in the presence of suitable catalysts, additives, and the like. Because a wide variety of raw materials can be used, a broad spectrum of polyurethane materials can be prepared to meet the needs of a variety of specific applications.

Polycarbonate polyurethanes or polyurethanes formed from polycarbonate polyols are useful in a variety of applications. However, known polycarbonate polyurethanes suffer from various drawbacks or limitations when used in certain medical devices, such as certain catheters. Embodiments disclosed herein overcome the disadvantages of existing polycarbonate polyurethanes in at least this regard, as will be apparent from the discussion below.

Drawings

The written disclosure herein describes non-limiting and non-exhaustive exemplary embodiments. Certain of such exemplary embodiments are described or otherwise described with reference to the accompanying drawings, in which:

FIG. 1 is an exemplary embodiment of a catheter shaft that may suitably be at least partially formed from any of the various embodiments of the siliconized polycarbonate polyurethane disclosed herein;

FIG. 2A is a cross-sectional view of the catheter shaft of FIG. 1 taken along view line 2A-2A in FIG. 1;

FIG. 2B is a cross-sectional view of the catheter shaft of FIG. 1 taken along view line 2B-2B in FIG. 1;

FIG. 3 is a graph of burst pressure exhibited by various catheters including catheter shafts of the form shown in FIGS. 1, 2A and 2B extruded from different embodiments of siliconized polycarbonate polyurethane according to the present disclosure;

4A-4C are graphs of tensile strength exhibited by various portions cut from catheter shafts of the form shown in FIGS. 1, 2A, and 2B extruded from different embodiments of siliconized polycarbonate polyurethane according to the present disclosure;

FIGS. 5A-5C are graphs of strain at break or ultimate elongation exhibited by various portions cut from catheter shafts of the form shown in FIGS. 1, 2A, and 2B extruded from different embodiments of siliconized polycarbonate polyurethane according to the present disclosure;

FIG. 6 is a graph of burst pressure exhibited by various catheters including catheter shafts of the form shown in FIGS. 1, 2A and 2B extruded from embodiments of aliphatic polyether polyurethane, aromatic polycarbonate polyurethane and siliconized polycarbonate polyurethane according to the present disclosure;

fig. 7 is a perspective view of an embodiment of a Peripherally Inserted Central Catheter (PICC) device or assembly including a catheter shaft of the form shown in fig. 1, 2A and 2B connected to an extension leg via a two-part or two-layer overmolded engagement hub, wherein each of the two layers of the catheter shaft, extension leg and engagement hub includes one or more embodiments of a siliconized polycarbonate polyurethane according to the present disclosure;

fig. 8A-8C are schematic plan views showing successive stages in an exemplary method for connecting the catheter shaft and the extension leg of fig. 1 via a two-part engagement hub;

fig. 9 is a graph of the average operating pressure experienced by a set of 40 PICC catheters (such as the catheter shown in fig. 7) during a power injection event over a 10 day period, where each catheter is alcohol locked and allowed to recover for a recovery period of one hour prior to each power injection;

fig. 10 is a graph of the average operating pressure experienced by a set of 40 PICC catheters (such as the catheter shown in fig. 7 and having been subjected to 6 months of accelerated aging conditioning) during a power injection event over a 10 day period, where each catheter is alcohol locked and allowed to recover for a recovery period of one hour prior to each power injection; and

fig. 11 is a graph comparing thrombus formation on the outer surface of three different types of catheter shafts for fifteen separate experimental runs.

Detailed Description

The present disclosure relates generally to alcohol-resistant polymers, which may be particularly useful in medical applications. More particularly, the present disclosure relates to alcohol resistant siliconized polycarbonate polyurethanes or polycarbonate polyurethanes comprising a polysiloxane component that can be formulated to facilitate use in medical devices (e.g., catheters). Siliconized polycarbonate polyurethane may be referred to as siliconized polycarbonate polyurethane; a silicone-containing or silicone-containing polycarbonate polyurethane; polysiloxanes, polycarbonate polyurethanes; or a polyurethane-siloxane copolymer, wherein each such term is intended to identify a polycarbonate polyurethane comprising a polysiloxane component. In particular, these terms name the polyurethane comprising the soft segment into which each of the polycarbonate and polysiloxane components is chemically incorporated.

In some embodiments, a catheter, such as a Central Venous Catheter (CVC), or more specifically, a peripherally inserted central venous catheter (PICC), includes one or more components each formed at least in part from one or more formulations of alcohol-resistant siliconized polycarbonate polyurethane. For example, in some embodiments, the PICC shaft defining at least one lumen comprises a formulation of siliconized polycarbonate polyurethane that enables the lumen of the shaft to be sterilized or disinfected, purged or otherwise treated by alcohol lock (also referred to as ethanol lock), wherein alcohol (typically ethanol) remains within the lumen for a treatment period or exposure period (e.g., at least one hour) to achieve a particular treatment or goal (e.g., sterilization and/or occlusion removal). In various embodiments, the siliconized polycarbonate polyurethane may recover substantially completely from alcohol lock within a recovery period (e.g., no less than one hour) that may be short enough to allow alcohol lock and subsequent power injection of the catheter to occur, for example, in an outpatient clinical setting. In various embodiments, the PICC device may be power injectable both before and after alcohol lock-up (e.g., after a particular recovery period). In another embodiment, the PICC device may be adapted for use as a pediatric PICC or other catheter, including for very small patients (e.g., in neonates weighing as low as 2.3 kg).

In some embodiments, a PICC device includes a shaft comprising a first formulation of a siliconized polycarbonate polyurethane according to the present disclosure, one or more extension tubes comprising a second formulation of a siliconized polycarbonate polyurethane according to the present disclosure, and a connecting hub comprising a third formulation of a siliconized polycarbonate polyurethane according to the present disclosure. One or more of the first, second, and third formulations may be the same as or different from one or more of the remaining formulations of the first, second, and third formulations. The PICC may not substantially leak or rupture before and after the alcohol lock event, during normal use (e.g., at relatively low injection or suction pressures, after multiple openings and closings of the extension tube via a clamp, etc.) and/or during power injection. Numerous other or additional embodiments and advantages are also disclosed.

I. Definitions and disclosure provisions

As used herein, "medical catheter" or "catheter" each refers to a medical device comprising a flexible shaft containing one or more lumens that may be inserted into a subject and/or into any suitable portion of its anatomy or system in any suitable manner for introducing materials, such as fluids, nutrients, drugs, blood products; monitoring the subject, e.g., with respect to pressure, temperature, fluid, analyte, etc.; removing a substance, such as one or more bodily fluids; deploying a balloon, stent, graft, or other device; or any combination thereof. The catheter may also include various accessory components, such as extension tubes, engagement hubs (e.g., hubs overmolded to the shaft and/or extension tubes), fittings, connectors, and the like. The catheter may also have various tip and shaft features including holes, slits, tapers, overmolded tips or lugs, and the like.

As used herein, "vascular access device" refers to a device that provides access to the vascular system of a patient, such as the venous system, or in some particular cases, the central venous circulatory system. This includes, but is not limited to, central venous catheters; peripherally inserted intravenous catheters, such as peripheral venous (PIV) lines; a midline; a port (e.g., an implantable device); a dialysis catheter; and a blood separation catheter. The vascular access device may be held in place from days to years. Typical configurations of vascular access catheters include a flexible shaft having one or more lumens with various tips, slits, tapers, etc. connected by a coupling hub to an extension tube having a luer fitting suitable for attachment to other devices.

As used herein, "central access device" refers to a device that provides direct access to the central venous circulatory system. As used herein, "central venous catheter" or "CVC" refers to a catheter that is configured such that its tip is placed directly into the central venous circulatory system. The term includes any such device that delivers a drug to a central portion of the heart, such as the vena cava, whether fully implanted or partially implanted (e.g., via percutaneous insertion). Central venous catheters are examples of central access devices.

As used herein, "peripherally inserted central catheter" or "PICC" refers to a central venous catheter that is configured to enter the body of a patient percutaneously (i.e., percutaneously) at a peripheral site and extend through the vasculature of the patient such that a distal end thereof is positioned directly in the central venous circulatory system, such as in the superior vena cava. The PICC may also be referred to as a peripherally inserted central line. The PICC may remain in place or within the vasculature for extended periods of time (e.g., days, weeks, months, or years).

As used herein, "pediatric catheter" refers to a catheter configured for use in the vasculature of a patient 18 years of age or younger. Some pediatric catheters may be suitable for use with children, such as children aged 5, 3, or 1 year or younger. Some pediatric catheters may be suitable for use with infants or neonates, such as infants having a weight of no less than, for example, 2.3kg in some cases, and even infants having a weight of less than 2.3kg in other cases.

As used herein, "power injection" is consistent with the generally accepted definition of this term and refers to a pressurized infusion that occurs at high flow rates (such as up to 4.0mL/s or up to 5.0 mL/s); this typically involves injecting a viscous material, such as a material (e.g., contrast media) having a viscosity of 11.8cP +/-0.3 cP; and it occurs at high pressure. In a similar manner, a "power-injectable" catheter is one that is capable of sustaining power injection but does not leak, rupture or swell to a size that is not usable within the vasculature. For example, the power injectable catheter may be a catheter that conforms to the power injection specification of International Standards Organization (ISO) Standard ISO 10555-1. Thus, for example, a power injectable PICC is a PICC configured to maintain power injection. PICCs may also be used for other functions, such as intravenous therapy at lower pressures or standard infusion and aspiration or blood collection.

As used herein, "biocompatible" refers to being compatible with or suitable for use in a patient, such as for an extended period of time (e.g., weeks or months). The term may be used to indicate compliance with generally accepted standards or regulations governing a particular device, such as a catheter. For example, biocompatibility may mean compliance with one or more of ISO standards ISO 10993-1, 4, 5, 6, 10, or 11, and/or compliance with regulations in a particular jurisdiction, such as those described by the Food and drug administration of the United States of America. The biocompatible catheter may be a non-cytotoxic, non-sensitive, non-irritating, non-toxic, non-pyrogenic, non-hemolytic catheter that does not activate the complement system, has minimal effect on partial thromboplastin time, has acceptable interaction with blood (e.g., acceptable clotting activity), and/or may be implanted for a desired period of time without significant adverse effects.

The term "patient" is used broadly herein and is not intended to be limiting. A patient may be, for example, any individual in which a catheter or other medical device discussed herein may be placed, whether in a hospital, clinic, or other environment. The term "patient" includes humans, mammals, or any other animal having an anatomical structure compatible with the embodiments described herein.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a device" may include one or more of such devices, reference to "an isocyanate" may include reference to one or more isocyanates, and reference to "a siliconized polycarbonate polyurethane" may include reference to one or more of such compounds.

The terms "comprising," "including," "containing," and "having" and the like can have the meaning attributed to them by U.S. patent law, and can mean "including," "containing," and the like, and are generally to be construed as open-ended terms. If an item is referred to as a list comprising, including, etc., one or more components, structures, steps, or other items, then that list may be non-exclusive or non-exhaustive, or it may alternatively be exclusive or exhaustive. The term "consisting of" is a closed term and includes only the components, structures, steps, etc. specifically listed in connection with such term, as well as the terms according to U.S. patent law. "consisting essentially of" has the meaning generally assigned to them by U.S. patent law. In particular, such terms are generally intended to be inclusive terms that allow for the inclusion of additional items, materials, components, steps, or elements that do not materially affect the basic and novel characteristics or functions of the item or items with which they are used. For example, if present in the language "consisting essentially of", trace elements present in the composition that do not affect the properties or characteristics of the composition may be permissible even if not expressly shown in the listing of items following such term. In this written description, when open-ended terms such as "comprising" or "including" are used, it is to be understood that direct support is also provided for the language "consisting essentially of and" consisting of, as if explicitly stated, and vice versa.

The terms "first," "second," "third," "fourth," and the like in the description and in the claims, if any, are used for distinguishing between similar elements and not necessarily for describing a particular sequential, chronological, preferred or other order. It is to be understood that any terms so used are interchangeable under appropriate circumstances such that the embodiments described herein are, for example, capable of operation in sequences other than those illustrated or otherwise described herein. Similarly, if a method is described herein as including a series of steps, the order of such steps as shown herein is not necessarily the only order in which such steps may be performed, and some of the steps may be omitted and/or some other steps not described herein may be added to the method.

The terms "left", "right", "front", "back", "top", "bottom", "over", "under", and the like in the description and in the claims, if any, are used for descriptive purposes and not necessarily for describing permanent relative positions. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the embodiments described herein are, for example, capable of operation in other orientations than those illustrated or otherwise described herein. The term "coupled," as used herein, is defined as connected, directly or indirectly, in any suitable manner. Objects described herein as "adjacent" to one another can be in physical contact with one another, in dosage proximity to one another, or in the same general area or zone as one another, as appropriate for the context in which the phrase is used.

As used herein, and unless otherwise expressly defined, the term "substantially" refers to the complete or nearly complete range or degree of an action, property, state, structure, item, or result. For example, an object that is "substantially" enclosed may mean that the object is completely or nearly completely enclosed. In some cases, the exact allowable degree of deviation from absolute completeness may depend on the particular context. However, in general, near-perfect will have the same overall result as when absolute and overall-perfect is obtained. The use of "substantially" is equally applicable to refer to the complete or near complete absence of an action, property, state, structure, item, or result when used in a negative sense. For example, a composition that is "substantially free of particles" will be completely free of particles, or therefore, almost completely free of particles, such that the effect may be the same as if it were completely free of particles. In other words, a composition that is "substantially free" of an ingredient or element can still actually contain such an item as long as there is no measurable effect thereof.

As used herein, the term "about" is used to provide flexibility to the numerical range endpoints by assuming that the given value can be "slightly above" or "slightly below" the endpoint. Unless otherwise indicated, the use of the term "about" in reference to a particular number or numerical range should also be understood to provide support for such numerical terms or ranges without the term "about". For example, for convenience and brevity, a numerical range of "about 50 angstroms to about 80 angstroms" should also be understood to provide support for the range of "50 angstroms to 80 angstroms". Further, it should be understood that in this specification, even when the term "about" is used in conjunction with an actual numerical value, support is provided for that actual numerical value. For example, an expression of "about" 30 should be understood to provide support not only for values slightly above and below 30, but also for actual values of 30.

As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list was individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.

Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. By way of example, a numerical range of "about 1 to about 5" should be understood to include not only the explicitly recited values of about 1 to about 5, but also individual values and subranges within the indicated range. Accordingly, included within this numerical range are individual values (e.g., 2, 3, and 4) and subranges (such as 1 to 3, 2 to 4, and 3 to 5, etc.) as well as individual values of 1, 2, 3, 4, and 5.

The same principle applies to ranges reciting only one numerical value as either a minimum or maximum value. Moreover, such interpretation should apply regardless of the breadth of the range or the characteristics being described.

Reference may be made in this application to compositions, systems or methods that provide "improved" or "enhanced" performance. It is understood that such "improvement" or "enhancement" is a measure of the benefit obtained based on comparison to prior art compositions, systems or methods, unless otherwise indicated. Further, it is to be understood that the degree of improved or enhanced performance may vary between disclosed embodiments, and that no equivalence or conformity in the amount, degree, or implementation of the improvement or enhancement is assumed to be universally applicable.

Reference throughout this specification to "an example" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the example or embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in an example" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment.

It should also be noted that various features are sometimes grouped together in a single embodiment, figure, or description thereof for the purpose of streamlining the disclosure. This method of description, however, is not intended to require that any given claim include more features than those expressly recited in that claim. Rather, as reflected in the claims following the present disclosure, inventive aspects may be presented in combinations of fewer than all of the features presented in any single example disclosed herein.

Exemplary unmet needs addressed by various embodiments

As noted above, polyurethanes are typically formed by reacting a polyol (meaning a compound containing multiple hydroxyl functional groups available for organic reactions) with a diisocyanate or other polyisocyanate. Further, the polyurethane may include both hard and soft segments. The hard segments may generally comprise the isocyanate component of the polyurethane in combination with a chain extender. The soft segment may generally include a polyol component of a polyurethane. In some examples, the type of polyol employed may depend on the environment in which the polyurethane will be used. For example, where the polyurethane is intended for use in an aqueous environment, it may be advantageous to use a polyether-based polyol. In other examples, where the polyurethane is intended for use in a hydrocarbon environment, it may be desirable to use a polyester-based polyol. In addition, the molecular weight, compositional ratio, chemical type, and other characteristics of the hard and soft segments can be varied to achieve the desired characteristics of the polyurethane.

However, many polyurethane materials configured for use in aqueous environments do not have suitable resilience to organic solvents or resistance to organic solvents. For example, some polyurethane materials configured for use in aqueous environments (such as biological environments) may undergo swelling, cracking, a decrease in hardness, a decrease in mechanical strength, and the like, when exposed to organic solvents. Thus, it can be challenging to prepare polyurethane materials that are resilient in both aqueous and organic environments. In some cases, polyurethanes improved in this manner or to enable widespread use in aqueous environments and to resist occasional exposure to organic solvents may have particular utility in certain medical devices, such as catheters.

For example, certain catheters may be introduced into a patient's vasculature (e.g., the venous system) for various purposes. For example, catheters may be introduced into the vasculature for the purpose of delivering fluids, nutrients, blood, glucose solutions, drugs, diagnostic agents, and the like. Catheters may also be introduced for the purpose of, for example, drawing blood from the vascular system, for treating blood, for making a diagnosis of blood, etc.

Catheter shafts, including those used for central venous catheters, are typically made of polymers. Suitable polymers are generally biocompatible, can be formed into tubing having a variety of diameters, including some diameters that are small enough to reside within the vasculature, and can be flexible enough to be navigated through the vasculature without causing injury to the patient. When formed as tubing, the selected polymer may also advantageously provide sufficient strength to ensure that the lumen does not collapse in the vasculature and resist repeated bending. The shaft material may advantageously provide chemical resistance, burst resistance, radiopacity, durability, and/or additional properties. Polymers based on silicone or polyurethane are typically employed to meet these criteria, however polyurethane catheters may be preferred because of their generally stronger mechanical strength. In some cases, thermoplastic polyurethane may be advantageously used for the catheter. Thermoplastic polyurethanes may be melt processable and may be extruded and/or molded using thermal processing, whereas thermoset polyurethanes may be cast molded.

During the course of performing medically necessary or desired tasks, or during the dwell period between such tasks, the catheter may become colonized by microorganisms (such as bacteria or fungi) that may harm the patient. In addition, the catheter may be completely or partially occluded by lipids, for example, in the case of delivery of nutrients. The presence of microbial and/or lipid occlusions can be particularly problematic for central venous catheters that may reside in a patient for extended periods of time.

Certain methods of reducing or eliminating microbial or lipid occlusion may involve direct and prolonged exposure of the catheter to an alcohol, such as isopropanol or ethanol. One such method of exposing a catheter to alcohol is known to clinicians as alcohol locking. Alcohol locking of a catheter generally refers to a technique or procedure in which alcohol is introduced into a lumen of the catheter and held in the lumen for a treatment period (e.g., greater than about 10 minutes, greater than about 30 minutes, greater than about one hour, or about one hour or more) with an alcohol (e.g., ethanol) concentration between 25% and 100% (e.g., 70%) for the purpose of disinfecting or sterilizing and/or eliminating lipid occlusions. The practice of alcohol lock-up or other internal or external application of liquid alcohol is herein referred to individually as direct and prolonged alcohol exposure.

Silicone catheters are commonly used as central venous catheters when direct and prolonged exposure to alcohol is to be achieved. However, silicone catheters may suffer from certain disadvantages, such as inferior mechanical strength and durability, compared to polyurethane catheters. However, it is also well known by clinicians and manufacturers that the mechanical properties of polyurethane catheters can be adversely affected when the polyurethane catheter is subjected to direct and prolonged exposure to alcohol. Thus, when direct and prolonged exposure to alcohol is not used or not expected, clinicians generally prefer to use polyurethane catheters over their silicone counterparts due to the increased durability achievable with polyurethane, particularly when high flow rates and associated high pressure power injection applications are required.

Certain thermoplastic polyurethanes can undergo swelling in the presence of alcohols, water, and other polar solvents. For example, when central venous catheters formed from such thermoplastic polyurethanes are exposed to these agents, the catheters may soften, swell, and lose their mechanical properties, such as modulus of elasticity and tensile strength. This effect can also be accelerated at body temperature (e.g., 37 ℃). The resulting loss of these mechanical properties can lead to central venous catheter failure including, but not limited to, tip instability, tip dislocation, excessive swelling and/or bursting during power injection, lumen collapse during fluid aspiration, cyclic fatigue failure due to repeated bending or clamping, and leakage from the extension leg or catheter shaft at the joint hub. Thus, in many applications, medical device manufacturers are required to design or specify conditions under which polyurethane central venous catheters may be used for safety reasons. In many cases, manufacturers explicitly warn or prohibit (e.g., provide warnings in instructions for use) the use of alcohols and other materials with catheters to prevent these failures. In other words, polyurethane central venous catheters are generally incompatible with alcohol locking because the catheters can degrade rapidly to the point where they can no longer be used as intended, particularly where the catheters are power-injectable.

As another example, certain catheters made from polyurethane (e.g.,

orEach of which is available from Lubrizol Advanced Materials, Cleveland, Ohio;

orEach purchased from Biomerics, LLC, Salt Lake City, Utah;purchased from Advan Source Biomaterials Corp., Wilmington, Massachusetts; etc.) may degrade or otherwise suffer performance degradation during or after prolonged exposure to alcohol. For example, such conduits may rupture during power injection or leak due to cyclic kinking. This loss of performance is directly related to the decrease in mechanical properties associated with the alcohol, such as increased swelling, decreased stress crack resistance, and loss of certain mechanical properties (such as hardness, modulus, and strength). Thus, in many cases, ofManufacturers of cardiac venous catheters expressly prohibit the use of their catheters for direct and prolonged exposure to alcohol.

With respect to alcohol locking, polycarbonate polyurethanes may be preferred over polyether polyurethanes because polycarbonate polyurethanes generally do not degrade too much. In addition, the aromatic type of any polyurethane is generally preferred over the aliphatic type. Thus, alcohol lock-up can result in different amounts of degradation for the following materials, which are generally listed in order of maximum degradation to minimum degradation: aliphatic polyether polyurethanes, aromatic polyether polyurethanes, aliphatic polycarbonate polyurethanes, aromatic polycarbonate polyurethanes. However, even aromatic polycarbonate polyurethanes, when formed into catheter shafts, typically cannot withstand the stringent requirements of power injection after an alcohol lock event or after many such alcohol lock events.

The present disclosure relates to alcohol-resistant aromatic polycarbonate polyurethanes comprising polysiloxane in their soft segments. Embodiments of the siliconized polycarbonate polyurethane may exhibit improved alcohol resistance compared to, for example, polycarbonate polyurethane. Also disclosed herein are alcohol-resistant conduits comprising the alcohol-resistant siliconized polycarbonate polyurethanes disclosed herein. In some embodiments, the catheter exhibits reduced swelling, improved stress crack resistance, and/or greater retention of certain mechanical properties (such as hardness, modulus, and strength) when exposed to alcohol as compared to other polyurethanes. Embodiments of the catheter are power injectable. Furthermore, the catheter can recover well after alcohol lock and can be suitable for long term use by patients. For example, some embodiments include PICC devices that may be suitable for long-term use in patients (including pediatric patients).

Certain embodiments of conduits comprising siliconized polycarbonate polyurethane may also perform well when compounded additives are retained therein. For example, the catheter may retain radiopacifiers, such as barium sulfate, sufficiently well to allow the catheter to be used with small children and even newborns. In other words, when the material is extruded into a catheter shaft, the material may produce relatively small amounts of extractables when the shaft is positioned within a patient. One or more of the foregoing advantages and/or other advantages of embodiments of the siliconized polycarbonate polyurethane and/or devices into which these materials may be incorporated are discussed further below and/or will be apparent from the present disclosure.

Siliconized polycarbonate polyurethane

The present disclosure describes, among other things, embodiments of siliconized polycarbonate polyurethanes that are suitable for use in aqueous environments and have good resistance or resilience to a variety of organic solvents, such as alcohols (e.g., ethanol). The siliconized polycarbonate polyurethane may include soft segments and hard segments. The soft segment can include a polycarbonate polyol and a polysiloxane. In some cases, the polycarbonate polyol can be present in an amount greater than or equal to the amount of polysiloxane. In some embodiments, formulations in which the polysiloxane forms a specific percentage of soft segments are particularly well suited for use in catheters, such as power injectable PICC catheters. The hard segment may include an isocyanate and a chain extender.

In more detail, a plurality of polycarbonate polyols or a combination of polycarbonate polyols may be used to prepare the soft segment of the polyurethane. In some examples, the polycarbonate polyol can be or include a polycarbonate diol. In some examples, the polycarbonate polyol can have a structure according to formula (I):

wherein R is selected from the group consisting of linear or branched, substituted or unsubstituted C₁-C₂₄An alkyl or alkylene group, A is selected from hydrogen (H) or R' OH, and n is an integer from 2 to 30. In some specific examples, a may be H. In other examples, a may be R' OH. In some such cases, R and R' may be the same. In other cases, R and R' may be different. In either case, R' may be selected from linear or branched, substituted or unsubstituted C₁-C₂₄An alkyl or alkylene group. In some examples, R and R' may be independently selected from C₄-C₁₂A linear or branched, substituted or unsubstituted alkyl or alkylene group. In some examples, R, R' or both may be straight chain alkyl or alkylene groupsAnd (4) clustering. Thus, in some examples, the polycarbonate polyol can have a structure similar to or according to formula (II):

in other examples, R, R' or both may be a branched alkyl or alkylene group. When R, R' or both include branches, any suitable number of branches may be present. In some specific examples, one or two branches may be present per R group, R' group, or both. In some examples, the branched chain may include a substituted or unsubstituted C₁-C₆An alkyl or alkylene group. In some particular examples, the branches may include methyl, ethyl, propyl, or butyl groups, or combinations thereof. Thus, for example, in some cases, the polycarbonate polyol can have a structure similar to or according to formula (III):

in some specific examples, one or more carbon groups of R, R' or both may be substituted. When R, R' or both are substituted, the substitution can include oxygen, nitrogen, sulfur, hydroxyl, amino, nitro, thiol, carboxyl, another suitable substituent, or a combination thereof. In some specific examples, R and R' are independently selected from linear unsubstituted C₄-C1₀An alkyl group. In some examples, R and R' may be independently selected from pentyl, hexyl, or heptyl groups. In some examples, n may be an integer from 5 to 25, or from 10 to 15.

Polycarbonate polyols can have a variety of molecular weights depending on the desired material properties of the siliconized polycarbonate polyurethane. For example, in some cases, increasing the molecular weight of the polycarbonate polyol can reduce the mechanical strength of the siliconized polycarbonate polyurethane and reduce the stiffness of the material. Conversely, in some cases, decreasing the molecular weight of the polycarbonate polyol may increase the viscosity of the siliconized polycarbonate polyurethaneMechanical strength and rigidity. In some examples, the polycarbonate polyol can have a number average molecular weight (M) of about 500g/mol to about 5000g/mol_n). In other examples, the polycarbonate polyol can have an M of about 500g/mol to about 2500g/mol, about 1000g/mol to about 4000g/mol, about 1500g/mol to about 2500g/mol, about 1800g/mol to about 2200g/mol, or about 1840g/mol to about 2200g/mol_n。

Generally, the polycarbonate polyol can constitute greater than 50 weight percent of the soft segment. In some examples, the polycarbonate polyol can constitute greater than or equal to 80, 85, 88, 89, or 90 weight percent of the soft segment. In some specific examples, the soft segment can comprise about 50% to about 98% by weight of the polycarbonate polyol, although other amounts can be used as desired. In some examples, the soft segment can include about 70 wt% to about 96 wt%, about 75 wt% to about 85 wt%, about 85 wt% to about 95 wt%, about 88 wt% to about 94 wt%, about 88 wt% to about 92 wt%, about 89 wt% to about 91 wt% of the polycarbonate polyol.

In contrast, the polysiloxane can generally constitute less than 50 weight percent of the soft segment. In some examples, the polysiloxane can constitute less than or equal to 20, 15, 12, 11, or 10 weight percent of the soft segment. In some specific examples, the soft segment can comprise from about 2% to about 50% by weight polysiloxane, although other amounts can be used as desired. In some examples, the soft segment can comprise about 4 wt% to about 30 wt%, about 15 wt% to about 25 wt%, about 5 wt% to about 15 wt%, about 6 wt% to about 12 wt%, about 8 wt% to about 12 wt%, about 9 wt% to about 11 wt%, or about 9.5% to about 10.5% polysiloxane.

A variety of polysiloxanes or combinations of polysiloxanes can be used to prepare the soft segment of the siliconized polycarbonate polyurethane. In some examples, the polysiloxane can have a structure according to formula (IV):

wherein R is₁And R₂Independently selected from straight chain C₁-C₆Alkyl or hydrogen radicals, R₃And R₅Independently selected from C₁-C₁₂Alkyl or alkylene groups, R₄And R₆Independently selected from C₁-C₈An alkyl or alkylene group, and m is an integer from 2 to 30. In some examples, R₁And R₂One or more of which may be different. In other examples, R₁And R₂Each of which may be the same. In some examples, R₁And R₂One or more of which may be hydrogen. In some examples, R₁And R₂One or more of which may be a methyl group. In some specific examples, R₁And R₂Each of which may be a methyl group. In some examples, R₃And R₅Can be independently selected from C₁-C₈An alkyl or alkylene group. In some examples, R₃And R₅Can be independently selected from C₂-C₈An alkyl group. In some specific examples, R₃And R₅Both may be ethyl, propyl or butyl groups. In some examples, R₄And R₆Can be independently selected from C₁-C₄An alkyl or alkylene group. In some examples, R₄And R₆Can be independently selected from C₁-C₄An alkyl group. In some specific examples, R₄And R₆Both may be methyl, ethyl or propyl groups. In some examples, m may be an integer from 2 to 20, or from 6 to 14.

The polysiloxane can have a variety of molecular weights depending on the specific material properties desired for the siliconized polycarbonate polyurethane. In some examples, the polysiloxane can have an M of about 300g/mol to about 3000g/mol_n. In some examples, the polysiloxane can have an Mn of about 500g/mol to about 1500g/mol, about 800g/mol to about 1200g/mol, about 1500g/mol to about 2500g/mol, or about 700g/mol to about 2300 g/mol.

The polycarbonate polyol and polysiloxane can be present in the soft segment in a variety of weight ratios. In some examples, the polycarbonate polyol and polysiloxane can be present in a weight ratio of polycarbonate polyol to polysiloxane of from about 20: 1 to about 1: 1. In other examples, the polycarbonate polyol and polysiloxane can be present in a weight ratio of polycarbonate polyol to polysiloxane of from about 20: 1 to about 4: 1, from about 20: 1 to about 8: 1, from about 19: 1 to about 9: 1, from about 11: 1 to about 8: 1, from about 11: 1 to about 9: 1, from about 10: 1 to about 9: 1, or from about 10: 1 to about 8: 1.

The amount of soft and hard segments in the siliconized polycarbonate polyurethane can be adjusted to achieve the desired material properties. For example, while a relatively large hard segment generally increases the hardness of a material and vice versa, other material properties can also be affected by varying the relative percentages of hard and soft segments. In some examples, the siliconized polycarbonate polyurethane may comprise from about 30% to about 80% by weight soft segment. In other examples, the siliconized polycarbonate polyurethane may comprise from about 30% to about 60% by weight soft segment. In other examples, the siliconized polycarbonate polyurethane may comprise from about 40% to about 70% by weight soft segment. In other examples, the siliconized polycarbonate polyurethane may comprise from about 30% to about 40%, from about 35% to about 45%, from about 40% to about 50%, from about 45% to about 55%, from about 50% to about 60%, from about 55% to about 65%, from about 54% to about 58%, from about 60% to about 70%, or from about 65% to about 75% by weight soft segments. In various embodiments, the siliconized polycarbonate polyurethane may comprise about 69 wt.%, about 56 wt.%, or about 50 wt.% soft segment.

In contrast, the siliconized polycarbonate polyurethane may comprise from about 10% to about 60% by weight of hard segments. In other examples, the siliconized polycarbonate polyurethane may comprise from about 10% to about 30% by weight, or from about 20% to about 40% by weight, of the hard segment. In other examples, the siliconized polycarbonate polyurethane may comprise about 30% to about 50% by weight of the hard segment. In other examples, the siliconized polycarbonate polyurethane may comprise about 20% to about 30%, about 25% to about 35%, about 30% to about 40%, about 35% to about 45%, about 42% to about 46%, about 40% to about 50%, about 45% to about 55%, or about 50% to about 60% by weight of the hard segment. In various embodiments, the siliconized polycarbonate polyurethane may comprise about 31 wt.%, about 44 wt.%, or about 50 wt.% hard segments.

The siliconized polycarbonate polyurethane may comprise soft segments and hard segments in various weight ratios. In some examples, the soft segment and the hard segment can be present in a weight ratio of soft segment to hard segment of about 5: 1 to about 1: 3. In other examples, the soft segment and the hard segment can be present in a weight ratio of soft segment to hard segment of about 3: 1 to about 1: 2. In other examples, the soft segments can be present in a weight ratio of soft segments to hard segments of about 3: 1 to about 1: 1, about 3: 1 to about 3: 2, about 2: 1 to about 1: 2, or about 2: 1 to about 1: 1.

As previously mentioned, the hard segment may include an isocyanate and a chain extender. It should be noted that as used herein, "isocyanate" or "isocyanate compound" refers to a compound having multiple isocyanate groups. Thus, "isocyanate" or "isocyanate compound" may refer to a diisocyanate or other polyisocyanate. Thus, the isocyanate may include a diisocyanate, other polyisocyanate, or a combination thereof. A variety of isocyanates may be used in the siliconized polycarbonate polyurethane. Non-limiting examples may include 4, 4' -methylene diphenyl diisocyanate, dibenzylidene diisocyanate, methylene dicyclohexyl diisocyanate, p-phenylene diisocyanate, trans-cyclohexane-1, 4-diisocyanate, 1, 6-diisocyanatohexane, 1, 5-naphthalene diisocyanate, p-tetramethylxylylene diisocyanate, m-tetramethylxylylene diisocyanate, 2, 4-toluene diisocyanate, isophorone diisocyanate, other diisocyanates or polyisocyanates, or combinations thereof. In some specific examples, the isocyanate may be or include 4, 4' -methylene diphenyl diisocyanate. In some cases, the isocyanate may be an aromatic isocyanate.

The hard segments may include different amounts of isocyanate depending on the desired material properties of the siliconized polycarbonate polyurethane. In some examples, the hard segment may comprise about 50% to about 90% by weight of the isocyanate. In some further examples, the hard segment may comprise about 60% to about 90% by weight of the isocyanate. In some specific examples, the hard segment may comprise about 70% to about 80%, about 75% to about 85%, or about 80% to about 90% by weight of the isocyanate.

A variety of chain extenders may be included in the hard segments of the siliconized polycarbonate polyurethane. Non-limiting examples may include 1, 2-propanediol, 1, 3-propanediol, 2-dimethylpropane-1, 3-diol, 2-ethyl-2- (hydroxymethyl) propane-1, 3-diol, 1, 4-butanediol, 1, 5-pentanediol, 1, 6-hexanediol, 1, 7-heptanediol, 1, 8-octanediol (1, 8-octainediol), 1, 9-nonanediol, 1, 10-decanediol, 1, 11-undecanediol, 1, 12-dodecanediol, 1, 4-cyclohexanediol, 1, 4-cyclohexanedimethanol, 1, 4-bis (2-hydroxyethoxy) benzene, p-xylylene glycol, 1, 3-bis (4-hydroxybutyl) tetramethyldisiloxane, 1, 3-bis (4-hydroxybutyl), 1, 3-bis (6-hydroxyethoxypropyl) tetramethyldisiloxane, trimethylolpropane, and combinations thereof. In some particular examples, the chain extender may be or include 1, 4-butanediol.

The chain extender may be included in the hard segment in various amounts depending on the desired material characteristics of the siliconized polycarbonate polyurethane. In some examples, the hard segment may comprise about 10 wt.% to about 50 wt.% of the chain extender. In some further examples, the hard segment may comprise about 10 wt.% to about 40 wt.% of the chain extender. In some specific examples, the hard segment may comprise about 20 wt.% to about 30 wt.%, about 15 wt.% to about 25 wt.%, about 10 wt.% to about 20 wt.%, or about 20 wt.% to about 22 wt.% of the chain extender.

The isocyanate and the chain extender may be present in the hard segment in a variety of weight ratios. In some examples, the isocyanate and the chain extender may be present in the hard segment in a weight ratio of isocyanate to chain extender of from about 10: 1 to about 1: 1. In other examples, the isocyanate and the chain extender may be present in the hard segment in a weight ratio of isocyanate to chain extender of from about 5: 1 to about 1: 1. In further examples, the isocyanate and the chain extender may be present in a weight ratio of isocyanate to chain extender of from about 10: 1 to about 5: 1, from about 7: 1 to about 3: 1, or from about 4: 1 to about 2: 1.

In some embodiments, one or more crosslinking agents may be used such that the siliconized polycarbonate polyurethane comprises crosslinked chains, resulting, for example, in greater mechanical and/or thermal stability compared to an otherwise identical siliconized polycarbonate polyurethane in which no crosslinking agent is employed. Non-limiting examples of crosslinking agents can include trimethylolpropane, castor oil, poly (vinyl alcohol), glycerol, one or more of the aforementioned polyisocyanates, or combinations thereof.

Unless otherwise indicated, the siliconized polycarbonate polyurethane may also contain a variety of other additives that are not generally considered part of the hard or soft segments. For example, in some cases, the siliconized polycarbonate polyurethane may include radiopacifiers, lubricants, catalysts, antioxidants, free radical inhibitors, colorants, fillers, nucleating agents (e.g., fumed silica), and the like, or combinations thereof.

In some particular examples, the siliconized polycarbonate polyurethane may include a radiopacifier. Generally, radiopacifiers are dense fillers that are added to the polymer to enable the resulting medical device (including catheter shafts), for example, to be radiographically observed while in vivo. Non-limiting examples of radiopacifiers may include barium sulfate, tungsten metal, tungsten carbide, bismuth metal, bismuth oxide, bismuth oxychloride, bismuth subcarbonate, platinum, palladium, gold, zirconium oxide, and the like, or combinations thereof. Where a radiopacifier is used, it may generally be included in the siliconized polycarbonate polyurethane in an amount of from about 5% to about 45%, from about 10% to about 30%, from about 15% to about 40%, or from about 25% to about 35% by weight. In various embodiments, the radiopacifier may be present in an amount of no less than 20%, 25% or 30%.

In some cases, the addition of higher amounts of filler and/or denser filler may increase the radiopacity of the resulting medical catheter shaft, but may also degrade the mechanical properties of the material (e.g., elongation, tensile strength, burst strength, biocompatibility, modulus, and chemical resistance). Thus, the amount of filler added to the catheter material may depend on the specific application requirements of the material. For example, in small diameter thin walled catheters (which may become difficult to see radiographically), the appropriate amount of filler can be highly dependent on the parameters of the device and the intended use of the device. Furthermore, for catheters that may remain in a patient for extended periods of time, such as PICC devices, it may be desirable to reduce the amount of radiopaque agent that seeps into the blood. Reduction in extractables can be achieved by reducing the amount of radiopacifier compounded into the polymeric material, but this can make the catheter darkened or otherwise less readily visible under radiography. However, embodiments disclosed herein may advantageously retain the radiopacifier (e.g., barium sulfate) within the polymer, thereby reducing the amount of radiopacifier extractables, without sacrificing high radiopacifier content with good imaging visibility.

In some additional specific examples, the siliconized polycarbonate polyurethane may include a lubricant, such as a lubricant or a mold release agent that may be used for extrusion. Non-limiting examples of suitable lubricants can include polyethylene, fluorocarbon polymers (e.g., polytetrafluoroethylene), silicone resins, organic waxes (e.g., stearate waxes, bisamide waxes, including Ethylene Bisstearamide (EBS), etc.), and the like, or combinations thereof. An exemplary example of a suitable lubricant is GLYCOLUBE^TMVL, available from Lonza, Switzerland. Where a lubricant is used, the lubricant may be present in the siliconized polycarbonate polyurethane in an amount of from about 0.05% to about 5%, or from about 0.1% to about 0.5% by weight.

In other specific examples, the polyurethane polycarbonate can include a colorant. The colorant can include any suitable dye or pigment or combination thereof and can impart any suitable color to the siliconized polycarbonate polyurethane. Where a colorant is used, it may be present in the siliconized polycarbonate polyurethane in an amount of from about 0.1% to about 10% by weight, or from about 0.3% to about 3% by weight.

The siliconized polycarbonate polyurethane may have a variety of molecular weights. Typically, the siliconized polycarbonate polyurethane may have a weight average molecular weight (Mw) of from about 50,000g/mol to about 300,000 g/mol. In some examples, the siliconized polycarbonate polyurethane may have a Mw of about 70,000g/mol to about 300,000 g/mol. In other examples, the siliconized polycarbonate polyurethane may have a Mw of about 120,000g/mol to about 250,000 g/mol. In other examples, the siliconized polycarbonate polyurethane may have a Mw of about 50,000 to about 150,000g/mol, about 150,000 to about 220,000g/mol, about 160,000 to about 200,000g/mol, about 150,000 to about 190,000g/mol, or about 170,000 to about 210,000 g/mol.

The siliconized polycarbonate polyurethane may also have any of a variety of isocyanate indices. In some examples, the siliconized polycarbonate polyurethane may have an isocyanate index (i.e., moles of isocyanate groups/moles of hydroxyl groups) of from about 0.98 to about 1.10, such as from about 1.00 to about 1.10. In other examples, the siliconized polycarbonate polyurethane may have an isocyanate index of about 1.00 to about 1.08, about 0.98 to about 1.00, about 1.00 to 1.02, about 1.02 to about 1.05, about 1.03 to about 1.08, about 1.04 to about 1.10, about 1.01 to about 1.06, about 1.02 to about 1.04, about 1.03 to about 1.04, about 1.04 to about 1.08, or about 1.045 to about 1.055.

The siliconized polycarbonate polyurethane may also have a range of durometer values. In some examples, the siliconized polycarbonate polyurethane may have a shore a durometer value of about 65 to about 100. In other examples, the siliconized polycarbonate polyurethane may have a shore a durometer value (including a hardness slightly deviating from the upper limit of the shore a scale, or harder than 100) of about 70 to about 90, about 75 to about 85, about 91 to about 100, about 94 to about 98, about 96 to about 100, about 95 to about 99, about 96 to about 98, or about 97 to about 100. In other examples, the siliconized polycarbonate polyurethane may have a shore D durometer value of about 15 to about 85, about 60 to about 80, or about 65 to about 75.

The invention also discloses a method for preparing the silicified polycarbonate polyurethane. In some examples, the method may include mixing or combining a polycarbonate polyol, a polysiloxane, an isocyanate, and a chain extender to produce a siliconized polycarbonate polyurethane. The polycarbonate polyol can be present in an amount greater than or equal to the amount of polysiloxane.

In some examples, one or more of the raw materials may be melted or otherwise pre-treated prior to combination with the other components of the siliconized polycarbonate polyurethane. For example, in some cases, the polycarbonate polyol may be melted prior to combining with the other components of the siliconized polycarbonate polyurethane. For example, certain polycarbonate polyols can be pre-melted at a temperature of about 160 ° F to about 200 ° F. In other cases, such as in the case of certain polycarbonate diols, the pre-melt temperature may be lower, such as from about 90 ° F to about 150 ° F. In some examples, the polycarbonate polyol can be stored at a temperature of about 160 ° F to about 175 ° F, with or without melting as previously described, prior to combining with one or more other components. In some further examples, the polycarbonate polyol may be stored under a nitrogen atmosphere, argon atmosphere, or other suitable atmosphere to protect against moisture prior to being combined with one or more other components.

In some examples, the polysiloxane can also be stored at elevated temperatures, for example, from about 140 ° F to about 160 ° F, prior to combining with one or more other components. In some further examples, the polysiloxane can be stored under a nitrogen atmosphere, argon atmosphere, or other suitable atmosphere to protect against moisture prior to combination with one or more other components.

In some examples, the isocyanate may melt at a temperature of about 125 ° F to about 160 ° F. In some additional examples, the isocyanate may be decanted from insoluble dimers that precipitate out of the liquid phase. In some such cases, the decanted isocyanate can be stored at about 125 ° F to about 140 ° F for subsequent use. In some additional examples, the isocyanate may be titrated to determine the percentage isocyanate content. This may allow formulation adjustments as needed to maintain an appropriate or desired isocyanate index. In some examples, the chain extender may also be melted prior to mixing, as desired.

The polycarbonate polyol, polysiloxane, isocyanate and chain extender may be combined or mixed in various ways and/or in one or more steps. For example, in some cases, the polycarbonate polyol, polysiloxane, isocyanate, and chain extender all may be added together in a common container and mixed simultaneously, or in other words, may be combined in one mixing process. In some cases, the components are mixed and held for a set period of time, such as in the range of about 30 seconds to about 20 minutes. In other or additional instances, the components are mixed until a threshold, target, or predetermined temperature is reached. For example, the reaction may be exothermic, and the temperature of the mixture may increase from about 120 ° F to about 230 ° F or more as mixing continues. In some cases, it may be desirable to stop mixing and pour the mixture from the container when a threshold temperature is reached. In various instances, the threshold temperature may be in a range of about 200 ° F to about 230 ° F.

In some cases, the temperature of the mixture may be controlled during mixing, such as by introducing heat to the mixture from an external source or by removing heat from the mixture in a controlled manner. In other cases, such as those just described, the temperature of the mixture is not controlled as the reaction proceeds. For example, while the starting temperature of the various reactants may be maintained at a desired starting point, once the reactants are added to the mixture, no further control of their temperature can be externally applied. Rather, while the temperature of the mixture may subsequently change, the change occurs naturally (e.g., increases) due to the thermal nature of the reaction (e.g., exothermicity) and heat dissipation to the surrounding environment. The temperature may be monitored, such as via any suitable temperature monitoring device. The method of temperature monitoring and the use of such temperature monitoring devices are equally applicable to other parts of the present disclosure involving the determination of temperatures of various mixtures. In various embodiments, whether or not the temperature is controlled during the reaction, it can be said that mixing of the mixture occurs at a temperature of, for example, about 120 ° F to about 250 ° F. This convention, which means that mixing occurs "at" a certain temperature or temperature range, is used throughout this disclosure and claims regardless of whether the temperature is actively controlled to remain at a specified temperature or within a specified temperature range.

In some examples, the mixing of the components may be performed in a multi-step process. For example, in some cases, the polysiloxane and polycarbonate polyols may be mixed prior to the addition of the isocyanate and chain extender. In some such cases, the polysiloxane and polycarbonate polyol can generally be added together to the first mixture and mixed at a temperature of from about 120 ° F to about 200 ° F for a suitable mixing period, such as from about 30 seconds to about 15 minutes. In other words, rather than controlling or maintaining the temperature of the mixture during mixing, the temperature of the mixture may naturally increase in the range of about 120 ° F to about 200 ° F as mixing proceeds. In some examples, the polysiloxane and polycarbonate polyols may be mixed under vacuum for 12 to 48 hours to remove moisture and dissolved gases. In some examples, the isocyanate may then be added to the mixture of polycarbonate polyol and polysiloxane before the chain extender is added. In other words, after the mixing of the first mixture is completed, the second mixture may be formed by adding the isocyanate to the first mixture, and subsequently, the third mixture may be formed by adding the chain extender to the second mixture. The mixture of polycarbonate polyol, polysiloxane, and isocyanate (i.e., the second mixture) may be mixed and continued for a suitable mixing period, such as from about 2 minutes to about 30 minutes. In some cases, the temperature at which mixing occurs is not specifically or actively controlled, or in other words, not maintained within a specific or predetermined range. For example, in some cases, the isocyanate (in a pre-heated state, as described above) is added to and mixed with the mixture of polycarbonate polyol and polysiloxane, but no further heat is applied to the mixture. Any temperature changes that may occur during mixing at this stage may be due to heating due to the exothermic nature of the reaction and cooling due to heat transfer from the reaction vessel. After the polycarbonate polyol, polysiloxane, and isocyanate are mixed (i.e., after the second mixture is mixed), the chain extender may be added to the mixture (i.e., a third mixture may be formed) and mixed. As mixing continues, the temperature of the third mixture may range from about 160 ° F to about 230 ° F. In some cases, the mixing is carried out for a suitable or predetermined mixing period of time, such as from about 30 seconds to about 15 minutes. In other or additional cases, mixing is performed until the target temperature is reached. In various instances, the target temperature may be in a range of about 200 ° F to about 250 ° F.

The first mixture may be said to be mixed for a first period of time. After the first period of time is complete, a second mixture is formed and mixed for a second period of time. After the second period of time is complete, a third mixture is formed and mixed for a third period of time. The term "after completion" means at the termination point, or any point thereafter. For example, the first time period can be terminated at the same time as the second mixture is formed, such as by introducing an isocyanate into the polycarbonate/polysiloxane mixture. In other cases, an amount of time may elapse between completion of the first mixing period and formation of the second mixture. This convention of indicating that some events occur "after completion" of the mixing period is used throughout this disclosure and claims, whether the event occurs immediately upon expiration of the mixing period or at some point thereafter.

In other examples, the diisocyanate and the chain extender may be added simultaneously to a mixture of the polycarbonate polyol and the polysiloxane. In other words, the first mixture may include a polycarbonate polyol and a polysiloxane, and the second mixture may be formed by adding both an isocyanate and a chain extender to the first mixture. In some cases, the components (i.e., components of the second mixture) are then mixed, and as mixing continues, the temperature of the mixture may range from about 120 ° F to about 230 ° F. In some cases, the mixing is carried out for a suitable or predetermined mixing period of time, such as from about 30 seconds to about 15 minutes. In other or additional cases, mixing is performed until the target temperature is reached. In various instances, the target temperature may be in a range of about 200 ° F to about 230 ° F.

In other examples, the polysiloxane and isocyanate may be mixed prior to adding the polycarbonate polyol and the chain extender. In other words, the first mixture may comprise a polysiloxane and an isocyanate. In certain such cases, the polysiloxane and isocyanate can be mixed, for example, at a temperature of about 120 ° F to about 180 ° F for a suitable mixing period, such as about 2 minutes to about 30 minutes.

In some examples, the polycarbonate polyol may then be added to the mixture of polysiloxane and isocyanate before the chain extender is added. In other words, the second mixture may be formed by adding the polycarbonate polyol to the first mixture, and subsequently, the third mixture may be formed by adding the chain extender to the second mixture. The mixture of polysiloxane, isocyanate, and polycarbonate polyol (i.e., the second mixture) can be mixed at a temperature of 130 ° F to 190 ° F for a suitable mixing period of time, such as about 2 minutes to about 30 minutes. The chain extender may then be added to the mixture of polysiloxane, isocyanate, and polycarbonate polyol (i.e., a third mixture may be formed) and mixed at a temperature of 160 ° F to 230 ° F for a suitable mixing period of time, such as about 30 seconds to about 15 minutes. In other or additional cases, mixing is performed until the target temperature is reached. In various instances, the target temperature may be in a range of about 200 ° F to about 250 ° F.

In other examples, the polycarbonate polyol and the chain extender may be added simultaneously to the mixture of polysiloxane and isocyanate. In other words, the second mixture may be formed by adding both the polycarbonate polyol and the chain extender to the first mixture comprising the polysiloxane and the isocyanate. The second mixture may be mixed at a temperature of 130 ° F to 230 ° F for a suitable mixing period, such as about 2 minutes to about 15 minutes. In other or additional cases, mixing is performed until the target temperature is reached. In various instances, the target temperature may be in a range of about 200 ° F to about 230 ° F.

Mixing such as described in the preceding paragraph may be achieved via any suitable mixing device. For example, in some cases, an overhead stirrer may be used. In some such cases, an overhead stirrer may be used with a gate blade or other suitable attachment and may operate at moderate speeds.

In some examples, lubricants, antioxidants, catalysts, or other suitable additives, or combinations thereof, may be added to a suitable mixture of polycarbonate polyol, polysiloxane, isocyanate, and chain extender to provide a siliconized polycarbonate polyurethane having desired characteristics. In some examples, the additive may be added in an amount of about 0.05 wt% to about 5 wt%, or about 0.1 wt% to about 0.5 wt% of the siliconized polycarbonate polyurethane.

In some examples, a mixture of polycarbonate polyol, polysiloxane, isocyanate, chain extender, and optional additives may be cured. Curing can generally be carried out at temperatures of about 210 ° F to about 250 ° F, although other curing temperatures can also be used with some formulations or where desired. Further, curing may generally be carried out for a curing period of about 12 hours to about 36 hours, although other curing periods may be used if desired.

Curing can be carried out to produce a cured siliconized polycarbonate polyurethane, which can optionally be further compounded or otherwise processed to produce a siliconized polycarbonate polyurethane, as desired. For example, in some cases, the cured siliconized polycarbonate polyurethane may be pelletized. In certain such cases, the siliconized polycarbonate polyurethane may be pelletized to have an average particle size of, for example, from about 1 millimeter to about 10 millimeters, or from about 2 millimeters to about 8 millimeters.

In some examples, the particulate siliconized polycarbonate polyurethane may be further compounded with a radiopacifier, a colorant, a wax and/or a lubricant, a nucleating agent, or other suitable compounding agent, or combinations thereof, to produce the siliconized polycarbonate polyurethane. In some examples, the compounding agent, the particulate siliconized polycarbonate polyurethane, or both may be dried prior to compounding. The compounding agent can be added in various amounts depending on the type of compounding agent and the desired characteristics of the siliconized polycarbonate polyurethane. In some examples, the compounding agent may be added in an amount of about 5 wt% to about 45 wt%, about 10 wt% to about 30 wt%, about 15 wt% to about 40 wt%, or about 25 wt% to about 35 wt%. In other examples, the compounding agent may be added in an amount of about 0.1 wt% to about 10 wt%, or about 0.3 wt% to about 3 wt%.

In some further examples, the particulate siliconized polycarbonate polyurethane, optionally mixed with a compounding agent, may be further extruded and pelletized for subsequent use. Any suitable extrusion device is envisaged. Two illustrative examples are models LSM30.34 and ZSE 27, available from Leistritz, Germany. In some cases, extrusion is achieved via twin screw or single screw extrusion. In certain such embodiments, the temperature of the various extruder zones may be set, for example, between about 300 ° F and about 600 ° F. In some cases, the extruder zone temperature may be in the range of about 340 ° F to about 520 ° F. In further cases, screw speeds of about 50RPM to about 500RPM may be employed for any suitable length/diameter (L/D) ratio of the screw conveyor or conveyors. For example, in various embodiments, the screw conveyor diameter may be in the range of about 25 millimeters to about 35 millimeters, and the L/D ratio may be in the range of about 25 to about 55. In some cases, the screw speed may be about 100RPM, with one or more screw conveyors each having, for example, a diameter of 34 millimeters and an L/D ratio of 30, or each having a diameter of 27 millimeters and an L/D ratio of 50. In each case, the extrudate can be strand pelletized or underwater pelletized to obtain pellets for subsequent use.

Another embodiment of a siliconized polycarbonate polyurethane and an exemplary method of forming the same will now be described, followed by a more specific example.

Any of the above polycarbonate polyols is provided in liquid form or melted prior to use. In some cases, the polycarbonate polyol melts at a temperature of about 160 ° F to about 200 ° F. The polycarbonate polyol may optionally be stored prior to use. In some cases, the polycarbonate polyol is stored at a temperature in the range of about 160 ° F to about 175 ° F until use. In some cases, the polycarbonate polyol is protected from moisture (e.g., under nitrogen or other gases) during storage prior to use. Illustrative examples of polycarbonate polyols include poly (hexamethylene carbonate) diol according to formula (II) above, including but not limited to number average molecular weight (M)_n) At about 18Those in the range of from 40g/mol to about 2200 g/mol.

Any of the above polysiloxane polyols are used at room temperature or stored at a temperature in the range of about 140 ° F to about 160 ° F until use. In some cases, the silicone polyol is protected from moisture (e.g., under nitrogen or other gas) during storage prior to use. An illustrative example of a polysiloxane polyol is a carbinol-modified polydimethylsiloxane according to the following formula (V), including but not limited to having a number average molecular weight (M) in the range of about 925g/mol to about 1025g/mol_n) Which exhibits reactivity at both ends.

As previously described above with respect to formula (IV), m is an integer from 2 to 30. The polysiloxane polyols exhibit relatively high reactivity, which in some cases may advantageously allow them to be easily incorporated into polyurethane chains. The polysiloxane polyols may likewise exhibit good miscibility with other polyols, which may be advantageous in some cases. For example, such increased miscibility can improve the absorption of the resulting polycarbonate polyurethane by the polysiloxane. In other examples, the polysiloxane polyol can have a structure similar to formula (V) above, but with a different linkage between the polydimethylsiloxane center and the terminal hydroxyl functional group of the chain.

Any of the above isocyanates is provided in liquid form or melted prior to use. In some cases, the isocyanate melts at about 140 ° F. In other cases, the molten isocyanate is decanted to remove insoluble dimer that precipitates out of the liquid phase. The decanted (e.g., clear) portion can be stored at an elevated temperature until use, such as in the range of about 125 ° F to about 140 ° F. In some cases, the isocyanate is protected from moisture (e.g., under nitrogen or other gas) during storage prior to use. A sample of the decanted liquid can be taken for titration for use in adjusting the bulk formulation. In particular, the percentage of NCO can be determined by titration. An illustrative example of an isocyanate is methylene diphenyl diisocyanate (MDI).

Any of the chain extenders described above are provided in liquid form or melted prior to use. The chain extender may be stored at an elevated temperature, such as at about 80 ° F, prior to use. In some cases, the chain extender is protected from moisture (e.g., under nitrogen or other gas) during storage prior to use. An exemplary chain extender is 1, 4-Butanediol (BDO).

The amount of each of the above components (polycarbonate polyol, polysiloxane polyol, isocyanate, chain extender) can be selected to achieve a desired isocyanate index that can fall within any of the above ranges. For example, the isocyanate index may be in the range of about 1.00 to about 1.10. In other words, the formulation of the siliconized polycarbonate polyurethane may be adjusted or fine-tuned prior to combining any of the components. In the formulation adjustment, the number of hydroxyl groups and H of each of the polyols may be used₂Percentage of O, percentage of NCO of isocyanate and H of chain extender₂Percentage of O. In some cases, adjusting the isocyanate index may represent a very small change in the mass ratio of the various components, but may have a significant effect on the properties of the final siliconized polycarbonate polyurethane.

In some cases, the isocyanate and polysiloxane polyol are poured into a common container and mixed and held for a suitable period of time, such as described above. For example, mixing may be carried out for a period of time in the range of about 2 minutes to about 30 minutes. In some cases, mixing may be performed for about 5 minutes. In some cases, first combining the isocyanate and the polysiloxane may result in a more thorough and/or uniform distribution of the polysiloxane in the final siliconized polycarbonate polyurethane material.

In some cases, the polycarbonate polyol is then added to the mixture. The mixture may be mixed for an additional period of time, such as from about two minutes to about fifteen minutes. In other cases, the mixing period is about 5 minutes.

The chain extender may then be added to the mixture of polysiloxane, isocyanate, and polycarbonate polyol and mixed at a temperature of 160 ° F to 230 ° F for a suitable mixing period of time, such as about 30 seconds to about 15 minutes. Alternatively, the temperature of the mixture may be monitored, and the mixing may be terminated when the temperature reaches a threshold value, which may correspond to the point at which the mixture begins to thicken. In various embodiments, the threshold may be in the range of about 200 ° F to about 230 ° F. In some particular instances, the mixing time is in a range of about 1 minute to about 2 minutes and/or the temperature threshold is in a range of about 200 ° F to about 210 ° F.

Upon completion of mixing, the mixture can be poured into a tray or sheet of any suitable size and configuration (e.g., teflon coated). The mixture may then be cured in an oven, for example, at about 230 ° F for about 16 hours to about 24 hours.

In some cases, the cured cake is removed from the pan and cut into smaller tiles. The bricks are then ground or pelletized to a size small enough to be fed into the compounder. Any of the above granulation sizes are contemplated.

In some cases, the pelletized siliconized polycarbonate polyurethane is dried, for example, at a temperature in the range of about 140 ° F to about 180 ° F. In other cases, it may be desirable to compound the radiopacifier with siliconized polycarbonate polyurethane. In some such cases, the radiopacifier may also be dried. For example, in some embodiments, barium sulfate is dried prior to compounding.

In some cases, the particulate and dry siliconized polycarbonate polyurethane is compounded with any of the above-described additives, such as one or more radiopacifiers and/or colorants. In some embodiments, the siliconized polycarbonate polyurethane, radiopacifier (e.g., barium sulfate), and colorant are weighed and then introduced into a bag, such as a large polymeric bag. The bag can be closed and tumbled (e.g., in a cement mixer) to effect blending.

After blending, the mixed materials are fed into a preheated extruder, such as a twin screw extruder. The extrudate can be pelletized into any of the pellet sizes such as described above. In other cases, the pellets may then be introduced into a separate extruder to form a medical component, such as a catheter shaft.