NOVEL THERMOPLASTIC POLYURETHANES, USE OF THESE MATERIAL FOR THE PREPARATION OF T-FRAMES FOR INTRAUTERINE SYSTEMS AND T-FRAMES MADE OUT OF THIS MATERIAL

Abstract

The present invention relates to a novel thermoplastic polyurethane (TPU) elastomer, T-frames made thereof as well as the use of the new TPU in manufacturing of T-frames for intrauterine systems for contraception and therapy.

Claims

1. A thermoplastic polyurethane elastomer made of a) 1,6-Hexamethylene diisocyanate with a content of 10 to 40 weight-%, b) at least one polycarbonate diol with a number average molecular weight between 800 and 2500 g/mol with a content of 25 to 65 weight-%, c) 1,6-Hexanediol, 1,8-Octanediol, 10 Decanediol and/or 1,12-Dodecanediol as chain extender, d) optionally monofunctional alcohols as chain terminators, in the presence of e) one or more catalysts, with the addition of f) inorganic fillers in the range of 0 to 35 wt.-%, based on the weight of the thermoplastic polyurethane made of components a) to d), g) an antioxidant in the range of 0.05 to 2.0 wt.-%, h) optionally, further additives and/or auxiliary substances under the proviso that the ratio of the isocyanate groups of a) to isocyanate-reactive groups of b), c) and optionally d) is from 0.9:1 to 1.1:1 and the thermoplastic polyurethane elastomer has a flexural modulus above 90 MPa without an inorganic filler and with a flexural modulus above 100 MPa containing an inorganic filler.

2. A thermoplastic polyurethane elastomer according to claim 1, wherein the catalyst is a bismuth catalyst or a titanium catalyst.

3. A thermoplastic polyurethane elastomer according to claim 1, wherein the polycarbonate diol has a number average molecular weight of 1000 to 2100 g/mol.

4. A thermoplastic polyurethane elastomer according to claim 1, wherein the chain extender is 1,8-Octanediol, 1,10-Decanediol, and/or 1,12-Dodecanediol.

5. A thermoplastic polyurethane elastomer according to claim 1, wherein Barium sulfate is used as an inorganic filler.

6. A thermoplastic polyurethane elastomer according to claim 1, wherein Licowax, Irganox® MD 1024, and/or Irganox® 1010 are used as additives or auxiliary substances.

7. A thermoplastic polyurethane elastomer according to claim 1, wherein the elastomer is made of a) 1,6-Hexamethylene diisocyanate with a content of 19.5 to 21.5 weight-%, b) a polycarbonate diol based on 1,6-Hexane diol with a number average molecular weight between 1900 and 2100 g/mol with a content of 60.0 to 62.0 weight-%, c) 1,12-Dodecanediol with a content of 16.5 to 18.5 weight-%, in the presence of e) TIPT catalysts, with the addition of f) BaSO.sub.4 in the range of 0 to 35 wt.-%, based on the weight of the thermoplastic polyurethane made of components a) to c), g) Pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), h) optionally, further additives and/or auxiliary substances.

8. A thermoplastic polyurethane elastomer according to claim 1, wherein the elastomer is made of a) 1,6-Hexamethylene diisocyanate with a content of 19 to 21 weight-%, b) A polycarbonate diol based on a mixture of 1,4-Butane diol and 1,6-Hexane diol with a number average molecular weight between 1900 and 2100 g/mol with a content of 58 to 60 weight-%, c) 1,12-Dodecanediol with a content of 18.8 to 20.8 weight-%, in the presence of e) TIPT catalysts, with the addition of f) BaSO.sub.4 in the range of 0 to 35 wt.-%, based on the weight of the thermoplastic polyurethane made of components a) to d), g) Pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate), h) optionally, further additives and/or auxiliary substances.

9. A T-frame for Intrauterine Systems characterized in that the frame is made of a thermoplastic polyurethane elastomer according to claim 1.

10. A T-frame for Intrauterine Systems according to claim 9, wherein the T-frame contains locking parts on the vertical stem to hold the capsule with the active compound.

11. A T-frame for Intrauterine Systems according to claim 9, wherein the T-frame contains a metal ring to enhance ultrasound visibility.

12. Use of a thermoplastic polyurethane elastomer according to claim 1 for manufacture of T-frames for Intrauterine Systems.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0082] FIG. 1/8/(Table 1) shows the mechanical properties of the thermoplastic polyurethane (TPU) materials of the examples 1 to 10 according to the current invention. With the exception of the MRV data all data have been measured at room temperature [RT]. The MRV values have been measured at 200° C.

[0083] All TPU materials as described in the current invention (examples 1-7) have a flexural e-modulus of >90 MPa). Examples 8-10 (TPU's mixed with 20% BaSO.sub.4 have a flexural e-modulus of >102 MPa).

[0084] The inorganic filler BaSO.sub.4 is added to enhance X-ray visibility but is also known to increase stiffness of polymer material.

[0085] Bariumsulfate containing example 8 is based on a TPU prepared according to example 3) and bariumsulfate containing example 9), based on the TPU of example 4.

[0086] As explained above the flexural e-modulus value can be regarded as a specific characteristic (surrogate parameter) for frame stiffness/flexibility. According to the present invention TPU materials with a flexural e-modulus value above 90 MPa (N/mm.sup.2) at room temperature are suitable for T-frames, whereby this value refers to the basic (pure) TPU without BaSO.sub.4 as additive.

[0087] TPUs suitable for T-frames compounded with ≧20% Bariumsulfate the e-modulus value should be above 102 MPa at room temperature.

[0088] FIG. 2/8 (Table 2) shows the mechanical properties at room temperature of the thermoplastic polyurethane (TPU) materials of the comparison examples 2 and 3 according to WO2011/039418.

[0089] For the unblended TPU as prepared according to comparion example 2, a value below 90 MPa, namely 88 MPa has been measured.

[0090] Comparison example 3 of WO2011/039418 refers to a blend of TPU with (20%) BaSO.sub.4. A value of 100 MPa has been measured for this composition.

[0091] It should be remarked that unblended TPU, as used in comparision example 3, was prepared as described in example 1 of WO2011/039418 . For this (example 1) a value of 66 MPa was measured.

[0092] FIG. 3/8 compares the material stiffness.sup.5 of different frame materials at 38° C. in dependency of exposure with moisture (0 days, vs. 7 and 21 days moisture exposure). It has to be remarked that “dry” in the context of this invention and as used in FIG. 3/8 means a TPU material after exposure to air. This material contains ˜1% water. .sup.5Stiffness is the counterpart to flexiblility. If material aren't flexibile it is stiff and visa versa.

[0093] In this comparison experiment TPU frames according to the present invention (TPU1 and TPU2), a TPU frame as disclosed in WO2011/039418, Carbothane and Polyethylene/BaSO4 frames have been compared in terms of stiffness/flexibility. It should be remarked that all test materials have been compounded with ˜20% BaSO.sub.4.

[0094] The light blue “star” curve refers to PE/BaSO4 material, the blue “diamond” curve (named “old TPU) refers to a TPU as described in WO2011/039418 (similar to example 3) and the red “square” curve (named as expulsed TPU) refers to an aliphatic Carbothane® containing 20% BaSO.sub.4 (Carbothane PC-3595A-BA20).

[0095] The green “triangle” curve” (named TPU1) and the violet “cross” curve (named TPU2) refer to the new TPUs according to the invention [TPU1=example 8; TPU2=example 9).

[0096] As the data show, TPU's in general are relative insusceptible against moisture in comparison to PE.

[0097] However, although the effect of moisture on TPU materials is negligible the old TPU as well as Carbothane® show a stiffness under in-vivo conditions which is too low to be used in T-frames.

[0098] Contrary to that the new TPUs according to the invention (examples 8 and 9) show an elastic modulus of 98 MPa at +38° C. in wet medium which is an increase of 48% compared to the TPU as disclosed in WO2011/039418 and an increase of 100% compared to Carbothane® PC-3595A-BA20.

[0099] FIG. 4/8 compares the “Memory Effect”, Opening force and “Breaking force” of the different materials. The “dotted” bar gives the values for Polyethylene, the “faciated” bar for a Carbothane®. The “white” and “black” bar shows the data for the TPUs according to the current invention (examples 8 and 9).

[0100] The breaking forces for TPU's, in particular for Carbothane® show increased values (23) in comparison to PE (14).

[0101] Also the memory effect of the TPU materials is comparable or even better compared to PE (5,8).

[0102] However, it should be remarked that for this comparison experiment closed frames with a pentagon shape have been investigated, thus the data measured for the memory effect have only exploratory character and are not directly transferable to T-frames as the results in FIG. 5/8 show.

[0103] The memory effect reflects the capability of the frame to return into its old shape after the frame is released from the insertion tube.

[0104] The opening force of TPU's according to the current invention is compared with PE/BaSO.sub.4 respectively Carbothane®. It is a force the frame tries to open up itself back to original shape when being collapsed in to a slot (insertion tube/cervix). The opening force is therefore an important parameter.

[0105] In other words, if the frame has a good memory its effect will be lost if the frame has no opening force to “utilize” the good memory in uterine cavity.

[0106] This parameter (opening force) is of clinical relevance as this force acts on the cervix channel when the Intrauterine System is removed from the uterus through the cervix channel at the end of its wearing time. Low forces go along with less pain but bear also a higher risk of expulsion during the wearing time of the IUS.

[0107] Opening force and Memory has been measured for frames with a pentagon shape, thus the absolute values are not directly transferable to T-frames. However, the ratio between the values of the different materials will remain essentially unchanged , thus although for T-frames lower opening forces and a similar memory as compared to PE can be foreseen.

[0108] A relative high opening force is needed for PE (0.52 N) (“dotted” bar in FIG. 4/8), which could cause pain during removal of the IUS.

[0109] Carbothane® (“fascinated” bar) shows a value of only 0.1 N which is favorable if the IUS is removed but by far too low to ensure that the IUS is stable fixed in the uterus. Thus high expulsion rates can be expected with this material.

[0110] The materials according to the invention show values of 0.3 N (“white” bar; example 8) respectively 0.26 N (“black” bar; example 9), which is a good compromise between comfort during removal and avoidance of expulsion.

[0111] The memory effect for the new TPU's according to the invention is lower compared to PE but still in an acceptable range.

[0112] FIG. 5/8 compares the “Memory Effect”, Flexibility and “Breaking force” for PE in comparison to the TPU's according to the current invention (examples 8 and 9). The investigations have been made with T-frames. Results are essentially in line with the results as shown in FIG. 4/8 measured for frames with a closed pentagon shape design. All TPU materials show improved values in terms of flexibility and breaking force in comparison to PE as used in the market products Mirena® and Jaydess®. The memory effect of TPU's is slightly worse compared to Polyethylen (PE). However, as the memory effect has less clinical relevance than flexibility or opening force, this marginal disadvantage is negligible.

[0113] FIG. 6/8 shows the temperature effect on the elastic modulus of the material. Flexibility/stiffness at room temperature (26° C.) and body temperature (38° C.) have been investigated. Whereby the temperature effect is significant, when looking at PE and Carbothane®, a neglectable effect is observed for the new TPU materials according to the current invention. Although the stiffness is lower as for PE it is still in a range which makes the material eligible for T-frames. The lower stiffness of the TPU according to the current invention results in a better wearing comfort and less pain during removal of the IUS.

[0114] FIG. 7/8 and FIG. 8/8 shows the results of the bio stability testing adapted from the ISO 10993 Part 13 method. The physical properties [i.e. solution viscosity (FIG. 7/8), and mechanical properties (FIG. 8/8)] were followed as a function of time for 12 months at oxidative condition (3% H.sub.2O.sub.2-water solution) and at body temperature. This stressed condition showed that the new materials are biostable.

EXAMPLES

[0115] The following examples serve to illustrate the invention.

Abbreviations (used in the examples):

[0116] Polycarbonate Diols [0117] DE C 2201: Desmophen® C 2201; Polycarbonate diol based on 1,6-hexanediol with a hydroxyl number of 56 mg KOH/g; product of Bayer MaterialScience AG [0118] DE C XP 2613: Desmophen® C XP 2613; Polycarbonate diol based on 1,4-butanediol and 1,6-hexanediol with a hydroxyl number of 56 mg KOH/g; product of Bayer MaterialScience AG

[0119] Isocyanate [0120] HDI: 1,6 Hexamethylen diisocyanate

[0121] Chain Extender [0122] HDO: 1,6-Hexanediol [0123] DDO: 1,12-Dodecanediol

[0124] Antioxidants [0125] Pentaerythritol tetrakis(3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate) (Trade name Irganox® 1010; Antioxidant from BASF SE) [0126] 2′, 3-bis [[3-[3,5-di-tert-butyl-4-hydroxyphenyl]propionyl]]propionohydrazide (Trade name: Irganox® MD 1024; Metal deactivator and primary, phenolic antioxidant from BASF SE)

[0127] Catalysts [0128] K-KAT® 348: Bismut catalyst from King Industries Inc. [0129] TIPT: Tetraisopropyltitanate

[0130] Additive [0131] Licowax® E: Mould release agent from Clariant GmbH

[0132] Inorganic Filler [0133] BaSO.sub.4: Bariumsulfate

[0134] Chain Terminators (Optionally) [0135] 1-Hexanol, 1-Octanol or 1-Decanol

Example 1

[0136] A mixture of 1001, 79 g DE C 2201, 254.19 g HDO, 5.11 g Irganox 1010 and 1.00 g K-Kat 348 was heated to 110° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 441.86 g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated.

Example 2

[0137] A mixture of 1001, 79 g DE C 2201, 271.93 g EDO, 5.24 g Irganox 1010 and 1.00 g K-Kat 348 was heated to 110° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 466.87 g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated.

Example 3

[0138] A mixture of 1001, 79 g DE C 2201, 303.79 g DDO, 4.94 g Irganox 1010 and 0.70 g TIPT was heated to 125° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 336.00 g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated. This material was used as base material for example 8.

Example 4

[0139] A mixture of 1056, 50 g DEC XP 2613, 354.42 g DDO, 5.38 g Irganox 1010 and 0.74 g TIPT was heated to 125° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 378.0 g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated. This material was used as base material for example 9.

Example 5

[0140] A mixture of 1001, 79 g DE C 2201, 435.43 g DDO, 5.66 g Irganox 1010 and 1.00 g K-Kat 348 was heated to 125° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 442.97g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated. This material was used as base material for example 10.

Example 6

[0141] A mixture of 1001, 79 g DEC 2201, 465.81 g DDO, 5.83 g Irganox 1010 and 1.00 g K-Kat 348 was heated to 125° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 468.05 HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated.

Example 7

[0142] A mixture of 1001, 79 g DE C 2201, 658.21 g DDO, 6.88 g Irganox 1010 and 1.00 g K-Kat 348 was heated to 125° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 625.28 HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated.

Example 8

[0143] 426.40 g BaSO.sub.4, 5.81 g Licowax E and 5.81 g Irganox MD 1024 were added to 1500 g TPU granules prepared according example 3. The mixture was extruded on an extruder of type DSE 25/4Z, 360 Nm, having the following structure: [0144] 1. cold intake zone with conveyor elements [0145] 2. first heating zone (210° C.) with first kneading zone [0146] 3. second heating zone (225° C.) with conveyor elements and second kneading zone [0147] 4. third heating zone (225° C.) with kneading zone, conveyor elements and vacuum degassing [0148] 5. deflection head (220° C.) and die (220° C.), with a delivery rate of 4.8 kg/h and a speed of 30-40 rpm.

[0149] The extrudates were then processed to granules by means of an extrudate granulator and to injection-molded sheets by means of an injection-molding machine.

Example 9

[0150] 426.40 g BaSO.sub.4, 5,81 g Licowax E and 5.81 g Irganox MD 1024 were added to 1500 g TPU granules prepared according example 4. The mixture was extruded on an extruder of type DSE 25/4Z, 360 Nm, having the following structure: [0151] 1. cold intake zone with conveyor elements [0152] 2. first heating zone (210° C.) with first kneading zone [0153] 3. second heating zone (225° C.) with conveyor elements and second kneading zone [0154] 4. third heating zone (225° C.) with kneading zone, conveyor elements and vacuum degassing [0155] 5. deflection head (220° C.) and die (220° C.), with a delivery rate of 4.8 kg/h and a speed of 30-40 rpm.

[0156] The extrudates were then processed to granules by means of an extrudate granulator and to injection-molded sheets by means of an injection-molding machine.

Example 10

[0157] 426.40 g BaSO.sub.4, 5.81 g Licowax E and 5.81 g Irganox MD 1024 were added to 1500 g TPU granules prepared according example 5. The mixture was extruded on an extruder of type DSE 25/4Z, 360 Nm, having the following structure: [0158] 1. cold intake zone with conveyor elements [0159] 2. first heating zone (210° C.) with first kneading zone [0160] 3. second heating zone (225° C.) with conveyor elements and second kneading zone [0161] 4. third heating zone (225° C.) with kneading zone, conveyor elements and vacuum degassing [0162] 5. deflection head (220° C.) and die (220° C.), with a delivery rate of 4.8 kg/h and a speed of 30-40 rpm.

[0163] The extrudates were then processed to granules by means of an extrudate granulator and to injection-molded sheets by means of an injection-molding machine.

[0164] The mechanical properties of the thermoplastic polyurethane (TPU) materials of the examples 1 to 10 are presented in FIG. 1/8.

Comparison Examples as disclosed in WO2011/039418

Comparison Example 1

[0165] A mixture of 722.3 g DE C2201, 222.0 g HQEE, 174 g Cap-HDO, 4.5 g Irganox 1010 and 0.7 g K-Kat 348 was heated to 110° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 376.4 g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated. This material was used as base material for comparison example 3.

Comparison example 2

[0166] A mixture of 954.6 g DE C2201, 249.8 g DDO, 4.5 g Irganox 1010 and 1.0 g K-Kat 348 was heated to 125° C., while stirring with a blade agitator at a speed of 500 revolutions per minute (rpm). Following this, 290.1 g HDI was added. The mixture was then stirred until the maximum possible increase in viscosity was obtained, and the TPU was then poured off. The material was thermally post-treated for 30 minutes at 80° C. and then, after cooling to room temperature, granulated.

Comparison example 3

[0167] 385 g BaSO.sub.4, 5.25 g Licowax E and 5.25 g Irganox MD 1024 were added to 1355 TPU granules prepared according example 1. The mixture was extruded on an extruder of type DSE 25/4Z, 360 Nm, having the following structure: [0168] 1. cold intake zone with conveyor elements [0169] 2. first heating zone (210° C.) with first kneading zone [0170] 3. second heating zone (225° C.) with conveyor elements and second kneading zone [0171] 4. third heating zone (225° C.) with kneading zone, conveyor elements and vacuum degassing [0172] 5. deflection head (220° C.) and die (220° C.), with a delivery rate of 4.8 kg/h and a speed of 30-40 rpm.

[0173] The extrudates were then processed to granules by means of an extrudate granulator and to injection-molded sheets by means of an injection-molding machine.

[0174] The mechanical properties of the thermoplastic polyurethane (TPU) materials of the comparison examples 2 and 3 are presented in FIG. 2/8 (Table 2).