CA2017951C - Thermoplastic elastomer hydrophilic polyetherurethane expandable catheter - Google Patents

Abstract

A melt extruded catheter of thermoplastic elastomeric hydrophilic polyurethane synthesized from a diisocyanate, polyethyleneoxide glycol of high molecular weight and a chain extender expands to a larger lumen size when contacted with an aqueous liquid. The catheter may include an antithrombogenic agent, antiinfective agent and radiopaque agent. The hydrophilic polyurethane may be synthesized by one-shot bulk polymerization, and may be melt extruded into the catheter tubing.

Description

2~1795~
-- I
THERMOPLASTIC ELASTOMER HYDROPHILIC
POLYETHERURETHANE EXPANDABLE CATHETER

BACKGROUND OF THE INVENTION

1. Field of -the Invention. This invention relates to catheterizatio~ of a patient, and more particularly relates to a catheter which expands to a larger gauge size whe~ it comes into contact with an aqueous liquid.

2. Backqround of the Invention. Catheteri-zation procedures conventionally include puncture of a patient's skin and insertion of a catheter into a body cavity, such as the blood stream, using some type of catheter insertion device. For patient comfort, it is highly desirable that the catheter, and perforce any insertion equipment, be of the smallest possible cross-sectional area during insertion. It is nevertheless evident that the catheter lumen must be large enough to achieve the required rate of administration of a medicament solution through the catheter.

Catheters of the prior art have generally been made of rigid polymeric materials which do not substantially change in cross-section when contacted with a body fluid. Exemplary of such conventional catheters is the Insyte~ line of catheters available from the Deseret division of Becton, Dickinson and Company, Sandy, Utah.

Recently, hydrophilic polymers which absorb water and expand, often termed hydrogels, have been *

disclosed. Gould et al., in U.S. Patent No. 4,454,309 discloses hydrophilic polyurethane diacrylate thermoset compositions which swell on insertion in water and may be molded and cured to form shaped products.

U.S. Patent Nos. 4,728,322 and 4,781,703 to Walker et al. disclose catheters fabricated of a composition which includes a nonhydrophilic first component and a hydrophilic polyurethane diacrylate second component. When contacted with a liquid, the composition swells and softens due to absorption of the Iiquid, causing the catheter to increase in cross-sectional area.

In similar fashion, U.S. Patent No. 4,668,221 to Luther discloses a catheter made of hydrophilic polymer which fits over a stylet for insertion. The catheter, on contact with blood, swells and softens so that the stylet can be removed.

While the above disclosures have advanced the art ~f catheter design, further improvements are needed. The present invention addresses this need.

SUMMARY OF THE INVENTION

A catheter comprises a thermoplastic elastomeric hydrophilic polyetherurethane (HPEU) or an HPEU
blend. The HPEU is the reaction product of at least a diisocyanate, polyethylene oxide glycol (PEG) and a chain extender. The HPEU blend consists of 50% or more of HPEU with a high soft segment content and 50%
or less of a stiff HPEU, polyetherurethane (PEU) or other polymer. Polyether glycols other than PEG may be included in the HPEU composition. The tubing is formed by melt processing methods such as extrusion and does not require any curing or crosslinking. When the tubing is brought into contact with an aqueous liquid, it absorbs the liquid and expands whereby the lumen increases in cross-sectional area.

Preferred catheters of the invention have as the main component a high soft segment content HPEU which is the reaction product of high molecular weight PEG, 4,4'-diphenylmethane diisocyanate (MDI) and a low molecular weight diol chain extender, and expand by absorbing 50 to 200% of their weight of water so that the lumen increases about 5 to 50%. The most preferred main HPEU component is the reaction product of MDI, PEG of about 8,000 molecular weight and 1,4-butanediol (BDO) as the extender. The PEG 8000 based HPEU can be blended with a stiff HPEU, PEU or other polymer for stiff catheter applications. The stiff HPEU and PEU have a hard segment content of 55 to 90% by weight and are based on relatively low molecular weight, 200 to 2,000 polyether glycols.

In other embodiments of the catheter of the invention, the HPEU may have an antithrombogenic agent such as heparin affixed to the surface, an antiinfective agent either affixed to the surface or distributed substantially evenly throughout the HPEU
(hereinafter referred to as bulk distributed) or a radiopaque agent bulk distributed or associated with the HPEU in the form of one or more stripes or layers coextruded with the HPEU.

2(:)17951 -Thus, the invention provides an expandable catheter having significant advantages over prior art catheters for central venous, and particularly for vascular catheter applications. For use in peripheral intravenous applications, a smaller gauge catheter of the invention than needed for the intended medicament administration may be introduced for patient comfort and the catheter allowed to swell to the required size by contact with the patient's body fluid. In contrast to prior art expandable catheters, the catheter of the invention is made of a thermoplastic elastomeric HPEU
and does not contain any catalyst, crosslinks or crosslinker by-products. The HPEU or the HPEU blend of the invention is linear, melt processable, and easily formed into catheter tubing by normal heat extrusion, in contrast to the hydrogels used to fabricate most prior art expandable catheters which are not melt extrudable and require curing.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates the swelling rate of the catheter of the invention compared to the swelling rate of a prior art catheter; and Fig. 2 compares the change in the inside diameter of the catheter of the invention and a prior art catheter as a function of time.

DETAILED DESCRIPTION

While this invention is satisfied by embodiments in many different forms, there will herein be described in detail preferred embodiments of the Z~7951 -- S -invention, with the understanding that the present disclosure is to be considered as exemplary of the principles of the invention and is not intended to limit the invention to the embodiments described and illustrated. The scope of the invention will be measured by the appended claims and their equivalents.

In accordance with the present invention, there is provided an expandable catheter made of an HPEU or an HPEU blend. When the catheter comes into contact with a body fluid, such as blood, it absorbs water and expands to a larger gauge size.

The HPEU includes three essential ingredients, a diisocyanate, PEG and a chain extender. Other components may be included as described below.

lS Suitable diisocyanates are aromatic diisocyanates such as MDI, 3,3'-diphenylmethane-diisocyanate, alicyclic diisocyanates such as isophorone diisocyanate and 4,4'-dicyclohexylmethane-diisocyanate, and aliphatic diisocyanates, as, for example, hexamethylene diisocyanate. The most preferred diisocyanate is MDI. Other diisocyanates which may be used include fluorine substituted isocyanates and silicones containing isocyanate groups.

The polyether glycol component may be PEG, alone or mixed with from 0 to 50% by weight of another polyglycol. Suitable polyglycols which may be mixed with the PEG include polypropyleneoxide glycol, polytetramethyleneoxide (PTMO) glycol and a silicone glycol. Silicone glycols and PTMO glycol are substantially hydrophobic, and by mixing a suitable 2~17951 -quantity of those glycols with the PEG, the degree of hydrophilicity of the HP~U blend may be tailored according to the desired extent of expansion.
Silicone glycols are well-known, and representative examples are described in U.S. Patent No. 4,647,643 to Zdrahala et al. A particularly useful silicone glycol is commercially available from Dow Corning Corp. under the designation 4-3667 fluid (formerly Q4-3667).

The PEG of the high soft segment content HPEU
may have a molecular weight of about 650-16,000, preferably about 3,350-12,000. The most preferred PEG
has a molecular weight of about 8,000. In accordance with the present invention, it has been found that the catheter made from a high soft segment content HPEU
containing high molecular weight PEG, (PEG 8000) is stiffer when it is dry and expands significantly more upon hydration than a catheter made from an HPEU based on a low molecular weight PEG.

The chain extender may be water and/or a low molecular weight branched or unbranched diol, diamine or aminoalcohol of up to 10 carbon atoms or mixtures thereof. Representative nonlimiting examples of chain extenders are BDO; ethylene glycol; diethylene glycol;
triethylene glycol; 1,2-propanediol; 1,3-propanediol;
1,6-hexanediol; 1,4-bis-hydroxymethyl cyclohexane, hydroquinone dihydroxyethyl ether, ethanolamine, ethylenediamine and hexamethylenediamine. Preferred chain extenders are 1,6-hexanediol, ethylenediamine, hexamethylenediamine and water, most preferably, BDO.

The percentages of the components may be such that the hard segment of the HPEU may be from about 25 Z~17951 -to 50%, preferably from about 30 to 45% of the total weight of the formulation. From the predetermined percentage of hard segment, the proportions of the components may readily be calculated.

The HPEU of the invention has excellent wet and dry physical properties, having tensile properties in the range of 2,000-10,000 pounds per square inch (psi). It may absorb about 10-200, preferably about 50 to 150% of its weight in water wherein water absorption increases with increasing soft segment content and increasing PEG molecular weight. Upon absorption of water, a tubing extruded therefrom may increase from 5-75%, preferably about 25% in inside diameter.

The HPEU of the invention may be prepared by a one-shot or bulk synthesis method wherein all the ingredients are combined at one time. This procedure as known in the art is generally carried out with a catalyst. However, a feature of the method of the invention is that the HPEU is prepared from the components by bulk polymerization without adding a polymerization catalyst. Conventional catalysts in the art, for example, organometallic compounds such as dibutyl tin dilaurate, are leachable and may cause deleterious effects in blood-contacting elements. By avoiding use of a catalyst, the HPEU of the invention is potentially purer and less toxic than those of the prior art.

The HPEU as described above may be melt extruded into tubing of any suitable size for use as catheter tubing. The catheter tubing may have a range of gauge 2~179Sl sizes from 28 gauge to 14 gauge French.

The catheter of the invention may have an antiinfective agent, a radiopaque agent or an antithrombogenic agent associated with the HPEU.
Suitable antithrombogenic agents are prostaglandins, urokinase, streptokinase, tissue plasminogen activator and heparinoids. Preferred antithrombogenic agents are sulfonated heparinoids, such as dextran sulfonate, most preferably heparin. The antithrombogenic agent may be about 1 to 10, preferably about 5% by weight of the HPEU.

The antithrombogenic agent may be coated onto the surface of the expandable catheter by conventional methods. For example, a complex of heparin with a quaternary salt may be used. Such complexes are well-known in the art and are described by McGary et al. in U.S. Patent No. 4,678,660. Suitable complexes may be formed with cetylpyridinium chloride or benzalkonium chloride. Preferred complexes are those in which the heparin is complexed with dodecylmethyl ammonium chloride or, most preferably, with tridodecylmethyl ammonium chloride (conventionally referred to as TDMAC). Application of the HPEU-heparin coating may be accomplished by dipping the rod into a solution containing about 1 to 10, preferably about 5% by weight of the HPEU and about 0.5 to 20, preferably about 2-8% by weight of the heparin complex in a suitable solvent or solvent combination. Exemplary of useful solvents are DMAC, DMF, N-methylpyrrolidone, toluene, methyl ethyl ketone, petroleum ether, isopropanol and propylene glycol methyl ether acetate (PGMEA). A preferred solvent is a 1:1 by volume mixture of DMAC and PGMEA.

20179Sl -_ g _ Any conventional radiopaque agent as known in the art may be included in the HPEU of the invention, as for example, an inorganic radiopaque such as barium sulfate, bismuth trioxide or tungsten powder, or an iodinated or brominated polyurethane. The radiopaque agent may be about 2 to 35% by weight of the catheter. The radiopaque agent may be included in the expandable catheter of the invention as one or more stripes or layers formed by conventional extrusion or coextrusion techniques.

Antiinfective agents as known in the art which may be used include chlorhexidine, silver sulfadiazine, or antibiotics such as penicillin.
These materials may be included in the HPEU over a range of 1 to 10% by weight, and may be surface coated onto the expandable catheter, or, preferably may be bulk distributed. A preferred method for fabrication of the catheter having the antiinfective agent bulk distributed in the HPEU is by melt extrusion. The antiinfective agent and HPEU may be blended in particulate form by any suitable mixing technique, such as stirring or tumbling the polymer pellets and antiinfective agent together, or preferably by conventional twin screw extruding. In the latter process, the ingredients may be simultaneously uniformly blended, melted and extruded into catheter tubing using a commercial twin screw extruder such as the Werner and Pfleiderer Model ZDSK-28 unit.

The expandable catheter of the invention is of constant diameter until it comes into contact with an aqueous liquid. In use, a catheter of smaller gauge size may be introduced into a patient's blood stream 201795~.
-whereupon it absorbs water, expands, and any insertion equipment may easily be removed because of the increased size of the lumen. The larger lumen provides enhanced flow of a solution being administered to the patient.

Comparison of the expandability of the catheter of the invention and the prior art catheter of U.S.
Patent No. 4,781,703 is illustrated in the Figures.
Fig. 1 shows that, where brought into contact with water, a 20 gauge catheter of the invention having a 45% hard segment increases in inside diameter at a rate of 1.1% per minute whereas a 20 gauge, 45% hard segment expandable catheter of the prior art increases at a rate of only 0.1% per minute. Fig. 2 shows that the catheter of the invention is substantially fully expanded after only five minutes whereas expansion of the prior art catheter proceeds slowly over 30 minutes and is not complete until about 60 minutes after contact with water. It is immediately evident that this rapid rate of expansion will render the catheter of this invention highly advantageous in a hospital setting. For example, a nurse monitoring a patient's intravenous medication will know that, after only five minutes, the catheter has fully expanded and the rate of administration will thereafter remain constant.
With the prior art catheter, however, the rate of administration will change over 60 or more minutes, requiring constant vigilance during this time to prevent the rate of administration from exceeding the desired rate.

The following Examples are provided to further describe the invention but are not to be considered as limitative of the invention.

2~17951 -EXAMPLE I

HPEU Synthesis Materials PEG of various molecular weights were obtained from Union Carbide Corp. and used as received.
Determination of the hydroxyl number by the phthalic anhydride-pyridine method and the water content by Karl Fisher titration were performed to verify and adjust formulation stoichiometry. 1,4-Butanediol (BDO) was used as chain extender, as received, from DuPont. MDI was received from Mobay and filtered before use.

Polymer Synthesis Hydrophilic polyetherurethanes (HPEU) were synthesized using a one-shot bulk polymerization. PEG
was dried at 60 to 70C under vacuum for approximately 24 hours. MDI was filtered and vacuum stripped.
Stoichiometric amounts of PEG and -BDO were placed in the polymerization vessel and degassed at 60C for 30 minutes. Then, the stoichiometric amount of MDI (1.02 Index) was added and stirred vigorously until the polymerization temperature reached about 85C. The polymer was discharged and postcured at 125C for 30 minutes. Representative HPEU formulations of the invention are given in Table I.

Z~1795~
-TABLE I

HPEU FORMULATIONS

No. PEG MW HS% MDI% BDO% PEG%
1 600 35 33.1 1.9 65 2 600 45 39.4 5.6 55 3 600 55 45.6 9.4 45 4 600 65 51.9 13.1 35 1450 35 28.9 6.1 65 6 1450 45 35.8 9.2 55 7 1450 55 42.8 12.2 45 8 1450 65 49.7 15.3 35 9 3350 35 27.2 7.8 65 3350 45 34.4 10.6 55 11 3350 55 41.6 13.4 45 12 3350 65 48.7 16.3 35 13 8000 35 26.3 8.7 65 14 8000 45 33.6 11.4 55 8000 55 41.0 14.0 45 16 8000 65 48.3 16.7 35 EXAMPLE II

Extrusion of HPEU

The HPEU slabs of Example I were chipped and extruded into medical tubing and 8 to 12 mil thick ribbons using a conventional 3/4 inch or 1 inch single screw extruder. The extrusion temperature profile range was: Feeding Zone, 150 to 175C; Melting Zone, 190 to 220C; Metering Zone, 190 to 220C and Die, 190 to 220C depending on the hard segment content.

Z~7951 -EXAMPLE III

Tensile Properties of HPEU

Tensile property tests of dry (23C and 50%
relative humidity) and hydrated (in 0.9% saline solution at 23C) HPEU samples were performed on die cut samples from extruded ribbons according to standard ASTM procedures and are given in Table II.
The dry thickness of the test samples was used in calculation of the hydrated tensile parameters, therefore, the hydrated tensile values are not absolute and are for comparative purposes only.

TABLE II

HPEU* 35% HS 45% HS 55% HS 65% HS

dry hyd** dry hyd** dry hyd** dry hyd**

tensile (psi) 890 750 2020 12303090 2740 2890 2910 25% modulus (psi) 530 250 1080 510 810 890 1000 1100 100% modulus (psi) 590 520 1190 880 1070 1430 1350 1660 Elongation (%) 500 200 490 180 530 360 360 350 T.S. Die-C (pli)*** 290 60 490 160 220 220 300 270 * MDI, PEG-8000, BD0 ** hydrated *** Tear Strength in pounds/linear inch 20179Sl Water Absorption and Deqree of Swellinq The water absorption and the degree of swelling were determined using O.s inch x 1 inch injection molded samples. These samples were kept in distilled water at room temperature (23C) for 24 hours, for establishing equilibrium water absorption. The samples were removed and the surface water was carefully blotted with filter paper without applying pressure. Each swollen sample was carefully weighed, vacuum dried at approximately 60C for 48 hours and then reweighed. The water absorption and the degree of swelling were calculated from weight difference data using the following equations:

WA = (Ws - Wp) / Wp x 100 tl]

DS = [(Wp / dp) + (Ws - Wp) / dw] / (Wp / dp) [2]

where WA is percent water absorption, Ws is weight of swollen sample, Wp is weight of dry sample, DS is degree of swelling, dp is the density of dry sample (1.15 g/cm3) and dw is the density of water (1.0 g/cm3). An average polyurethane density of 1.15 g/cm3 was used for all HPEU formulations.

Inside diameter was measured on samples removed from the distilled water bath at selected times.

Thus, the invention provides a catheter which, on contact with a patient's blood, expands to a larger lumen size to allow greater flow rate and concurrently Z~179Sl -stiffens to allow adjustment of the catheter position 2 without kinking.

Claims (11)

1. A melt extruded catheter comprising a substantially hydrophilic thermoplastic elastomeric polyurethane tubing, said polyurethane having a hard segment of 25 to 50% and a high soft segment of at least 50%, and comprising the reaction product of a diisocyanate, polyethyleneoxide glycol and a chain extender, said tubing, when brought into contact with an aqueous liquid, absorbing about 10 to 200%
of its weight of said liquid and expanding whereby its inside diameter increases about 5 to 75%.

2. The catheter of Claim 1 wherein said diisocyanate is selected from the group consisting of 4,4'-diphenylmethane diisocyanate, 3,3'-diphenylmethane diisocyanate, isophorone diisocyanate and hexamethylene diisocyanate.

3. The catheter of Claim 1 wherein said chain extender is selected from the group consisting of 1-4-butanediol, ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,6-hexanediol, 1,4-bis-hydroxymethyl cyclohexane, hydroquinone dihydroxyethyl ether, ethanolamine, ethylenediamine and hexamethylenediamine.

4. The catheter of Claim 1 wherein said polyethyleneoxide glycol has a molecular weight of about 650 to 16,000.

5. The catheter of Claim 1 wherein said thermoplastic elastomeric hydrophilic polyurethane further comprises the reaction product of a polyglycol selected from the group consisting of polypropyleneoxide glycol, polytetramethyleneoxide glycol and a silicone glycol.

6. The catheter of Claim 1 further comprising an agent selected from the group consisting of an antiinfective agent, a radiopaque agent and an antithrombogenic agent.

7. The catheter of Claim 6 wherein said antithrombogenic agent is selected from the group consisting of a prostaglandin, urokinase, streptokinase, tissue plasminogen activator and a heparinoid.

8. The catheter of Claim 6 wherein said antiinfective agent is selected from the group consisting of chlorhexidine, silver sulfadiazine and an antibiotic.

9. The catheter of Claim 6 wherein said radiopague agent is selected from the group consisting of an inorganic radiopaque, an iodinated organic radiopaque and a halogenated polymer.

10. A melt extruded catheter comprising a substantially hydrophilic thermoplastic elastomeric polyurethane tubing, said polyurethane comprising the reaction product of a diisocyanate, polyethyleneoxide glycol and a chain extender, said polyurethane tubing comprising a blend with at least 50 % soft segment and 50 % or less stiff segment, said tubing expanding when brouqht into contact with an aqueous liquid.

11. A melt extruded catheter comprising a substantially hydrophilic thermoplastic elastomeric polyurethane tubing, said polyurethane having a hard segment of 30 to 45% and a high soft segment of at least 50 %, and comprising the reaction product of 4,4'-diphenylmethane diisocyanate, 1-4-butanediol and polyethyleneoxide having a molecular weight of 6,000 to 12,000, said tubing when brought into contact with an aqueous liquid absorbing about 50 to 150 %
of its weight of said liquid and expanding whereby its inside diameter increases about 5 to 50%.