JPH0528633B2 - - Google Patents

Description

[Detailed description of the invention]

FIELD OF THE INVENTION This invention relates to catheter insertion into a patient. More particularly, the present invention relates to catheters that expand to larger inner diameter dimensions upon contact with aqueous liquids. Catheterization traditionally consists of puncturing a patient's skin and inserting a catheter into a body cavity (eg, the bloodstream) using some type of catheterization device. In order to reduce patient discomfort, it is desirable that the catheter (and therefore its insertion instrument) have as small a cross-sectional area as possible during insertion. However, the lumen of the catheter must be large enough to provide the necessary rate of administration of the drug solution through the catheter. Prior art catheters are generally made from rigid polymeric materials whose cross-sectional area does not substantially change upon contact with body fluids. Examples of such conventional catheters include the Insyte ^R series, available from the Deseret division ^of Becton Dickinson and Campany, Sanday, Utah. ) There is a catheter. Recently, hydrophilic polymers (often called hydrogels) that absorb water and swell have been disclosed. US license number by Gould et al.
No. 4,454,309 discloses hydrophilic polyurethane diacrylate thermoset compositions that swell when placed in water and can be molded and cured into articles of desired shapes. U.S. Patent by Aniuk et al.
No. 4,883,699 discloses a tube having a non-hydrophilic polyurethane component and a hydrophilic polyvinyl alcohol component. The tube is
It is described as absorbing water and swelling while retaining its tensile strength. U.S. Patent by Walker et al.
No. 4,728,322 and No. 4,781,703 disclose catheters made from compositions that include a non-hydrophilic first component and a hydrophilic polyurethane diacrylate second component. When the composition comes into contact with a liquid, it swells and softens due to absorption of the liquid, resulting in an increase in the cross-sectional area of the catheter. U.S. Patent No. 4,668,221 by Luther
The '999 patent discloses a catheter made from a hydrophilic polymer that fits over a stylet used during insertion. The catheter swells and softens upon contact with blood, allowing the stylet to be removed. Although catheter structural design techniques have advanced through the disclosures of the above-mentioned patent documents, further improvements are required. The present invention answers this need. The catheter tube is made of hydrophilic polyether urethane (HPEU), a thermoplastic elastomer.
Or it comprises a mixture of HPEU and a stiffening polyurethane. HPEU has a hard segment (HS) content of 25-50%, diisocyanate,
It is a reaction product obtained from a polyglycol component containing at least 50% polyethylene oxide glycol (PEG) and a chain extender. In the present disclosure, all percentages are expressed in % by weight. The stiffening polyurethane has a HS content of 50-90% and/or a water absorption of about 10% or less. This mixture contains approximately 50-99%
Contains a homogeneous blend of HPEU and 1-50% stiffening polyurethane. In another embodiment of the invention, a stripe of stiffening polyurethane is encapsulated by HPEU. The tubes are made by melt processing methods such as extrusion and do not require treatments such as curing or crosslinking. When the tube comes into contact with an aqueous liquid, it absorbs the aqueous liquid and expands, thereby increasing the cross-sectional area of the lumen. The HPEU of the preferred catheter of the present invention is a reaction product obtained from a chain extender of high molecular weight PEG, 4,4'-diphenylmethane diisocyanate (MDI), and a low molecular weight diol, which absorbs 50% of its own weight of water. Inflated by ~200% absorption,
This increases the diameter of the lumen by about 5-50%.
The most preferred HPEU is MDI, molecular weight approximately 8000
PEG and 1,4-butanediol (BDO) as a chain extender. In other embodiments of the catheters of the invention, the HPEU is an antithrombotic agent such as heparin that is immobilized on the surface, or
The anti-infective agent is substantially evenly distributed throughout the HPEU (hereinafter referred to as bulk distributed), or the HPEU in the form of one or more stripes or layers that are bulk distributed or coextruded with the HPEU. a radiopaque agent combined with a radiopaque agent. Accordingly, the present invention provides an inflatable catheter with significant advantages over prior art central venous catheters, particularly vascular catheters. When used for peripheral veins, in order to alleviate patient pain, the catheter of the present invention is inserted into the patient's body and has an inner diameter smaller than that required for the intended drug administration, and the patient's body fluids are The catheter can be expanded to the required size by contact with the catheter. Unlike prior art inflatable catheters, the catheters of the present invention are made from HPEU, a thermoplastic elastomer, and do not contain any catalysts, crosslinkers, or by-products from crosslinkers. The HPEU or HPEU blends of the present invention are melt processable, unlike the hydrogels used to make most prior art inflatable catheters (which cannot be melt extruded and require curing). In contrast, it can be easily formed into a catheter tube by conventional hot extrusion. Although there are many different forms of suitable embodiments of the invention, preferred embodiments of the invention will now be described in detail. It goes without saying that the present disclosure should be considered as a representative example of the principles of the invention, and the invention is not limited to the embodiments described below. The scope of the invention is defined by the claims and their equivalents. According to the present invention, an expandable catheter made of HPEU or a mixture of HPEU and a stiffening polyurethane is provided. When the catheter comes into contact with bodily fluids (eg, blood), the catheter absorbs moisture and expands to a larger internal diameter dimension. Referring to the drawings, FIG. 1 shows a conventional catheter insertion instrument (hollow needle 11 for puncturing the patient's skin and placing the catheter into the patient's bloodstream).
Figure 1 depicts a catheter tube 10 secured to a catheter tube (shown as 1). The catheter insertion instrument is of conventional type and does not form part of the present invention. The tube 10 has a gradual taper 13 leading to a point 14 in contact with the body 12 and the needle 11. FIG. 2 shows the striped encapsulation catheter of the present invention, with tube 10 defining a lumen 15 and having a lumen wall 16 and an outer wall 18. One or more stripes 20 of stiffening polymer are longitudinally disposed along at least a portion of the tube length and are encapsulated within the base polymer 22. Although stripes 20 are shown in FIG. 2 in an annular shape, they may have any other suitable shape. HPEU contains three essential components: diisocyanate, PEG, and chain extender. Other ingredients may also be included as described below. Suitable diisocyanates include MDI, 3,
These include aromatic diisocyanates such as 3'-diphenylmethane diisocyanate; cycloaliphatic diisocyanates such as isophorone diisocyanate and 4,4'-dicyclohexylmethane diisocyanate; and aliphatic diisocyanates such as hexamethylene diisocyanate. The most preferred diisocyanate is MDI. Other diisocyanates that can be used include fluorine-substituted diisocyanates and silicones containing diisocyanate groups. The polyether glycol component of HPEU is
PEG may be alone or mixed with 0-50% by weight of other polyglycols.
Suitable polyglycols that can be mixed with PEG include polypropylene oxide glycol, polytetramethylene oxide glycol (PTMEG), and silicone glycols. Silicone glycols and PTMEG are essentially hydrophobic, and appropriate amounts of these glycols
By mixing with PEG, the degree of hydrophilicity of the HPEU blend can be adjusted depending on the desired degree of swelling. Silicone glycol is a well-known one, Zdrahara
A typical example is described in US Pat. No. 4,647,643 by et al. A particularly useful silicone glycol is 4-
It is a glycol sold under the trade name 3667 Fluid (formerly Q4-3667). PEG, a component of HPEU, has a molecular weight of about 650-16000 (preferably about 3350-12000). The most preferred PEG is a PEG with a molecular weight of about 8000
It is. According to the invention, high molecular weight PEG
A catheter made from HPEU containing (PEG8000) has a low molecular weight
It was found to be more rigid than catheters made from PEG-based HPEU. Suitable chain extenders are water and/or low molecular weight branched or linear diols, diamines or amino alcohols having up to 10 carbon atoms, or mixtures thereof. Typical examples of chain extenders include BDO; ethylene glycol; diethylene glycol; triethylene glycol; 1,2-propanediol;
-propanediol; 1,6-hexanediol, 1,4-bis-hydroxymethylcyclohexane; hydroquinone dihydroxyethyl ether; ethanolamine; ethylenediamine; and hexamethylenediamine; and the like. Preferred chain extenders are 1,6-hexanediol, ethylene diamine, hexamethylene diamine, and water, and most preferred is BDO. The usage ratio of each component is approximately 25 to 60% based on the total weight of the HPEU hard segment.
(preferably about 30 to 50%). From a given percentage of hard segments,
The usage ratio of each component can be easily calculated. The HPEU of the present invention has excellent wet and dry physical properties, with tensile properties ranging from 2000 to 10000 pounds per square ^inch (psi). The HPEU of the present invention is about 10-200% of its own weight (preferably about
50-150%) of water, and the amount of water absorbed is:
It increases as the content of soft segments increases and as the molecular weight of PEG increases.
When an extruded tube absorbs water, its internal diameter increases by 5-75% (preferably about 25%). The HPEU of the present invention can be produced by a one-shot synthesis method, that is, a bulk synthesis method, in which each component is mixed all at once. This process, which is known in the art, is generally carried out using a catalyst. However, a feature of the process of the invention is that HPEU is made from the components by bulk polymerization without adding a polymerization catalyst. Conventional catalysts used in the industry (for example organometallic compounds such as dibutyltin dilaurate) can cause leaching and thus cause deleterious effects on blood contacting elements. By avoiding the use of catalysts, the HPEUs of the present invention are free of extra components and are less toxic than those obtained by the prior art. The polyurethane that acts as the stiffening polyurethane has a hard segment content of about 50-90%,
and/or has a water absorption of about 10% or less. The isocyanate component and chain extender component of the stiffening polyurethane may be those described above with respect to HPEU. The polyether glycol component may be one or more polyglycols selected to provide a water absorption of 10% or less. As is well known in the art, water absorption increases with higher PEG content and decreases with higher PTMEG content.
Therefore, the preferred polyglycol for the stiffening polyurethane is PTMEG, which has about 200 to
Most preferred is PTMEG with a molecular weight of 2000.
The selection and usage ratio of polyether glycol for the stiffening polyurethane can be easily determined from the desired HS content and/or water absorption. The synthesis of the stiffening polyurethane can be carried out according to the methods described above and according to the method described in the Examples for HPEU. In other embodiments of the catheter of the invention, the HPEU can be considered a base polymer encapsulating longitudinal stripes of stiffening polyurethane. This stripe prevents substantial expansion of the catheter in the longitudinal direction (any longitudinal expansion would be accompanied by lateral expansion due to water absorption of the HPEU). HPEU, either alone or blended with a stiffening polyurethane, can be melt extruded into any suitable size for use as a catheter tube. Similarly, catheters of the present invention having encapsulated stripes of stiffening polymer can also be made by extrusion or coextrusion methods. Forming striped encapsulated catheters or blended catheters by extrusion is well known in the art and does not require detailed explanation to fully understand aspects of the present invention. Catheter tubes are 28 to 14 gauge French (gauge).
French) inner diameter dimensions. The catheter of the present invention has an anti-infective, a radiopaque agent, or an anti-thrombotic agent in combination with HPEU. Suitable antithrombotic agents include prostaglandins, urokinase, streptokinase, tissue plasminogen activators, and heparinoids. Preferred antithrombotic agents are sulfonated heparinoids such as dextran sulfonate, most preferably heparin. Antithrombotic drugs are approximately 1-10% by weight of HPEU
(preferably about 5% by weight). The antithrombotic agent can be coated on the surface of the expandable catheter according to conventional methods. For example, a complex of heparin and a quaternary salt can be used. Such complexes are well known in the art and are described by McGary.
No. 4,678,660 by et al. Suitable complexes can be formed using cetylpyridinium chloride or benzalkonium chloride. Preferred complexes are the complex of pepperin and dodecylmethylammonium chloride, and most preferably the complex of heparin and tridodecylmethylammonium chloride (conventionally referred to as TDMAC). The coating operation is approximately 0.5 to ~20
% by weight (preferably about 2-6% by weight) of heparin complex and optionally about 1-10% by weight (preferably about 5% by weight) of HPEU dissolved in a suitable solvent or solvent mixture. This can be done by dipping the tube into the solution. Examples of useful solvents include dimethylacetamide (DMAC),
dimethylformamide, N-methylpyrrolidone,
Toluene, methyl ethyl ketone, petroleum ether,
Examples include isopropanol and propylene glycol methyl ether acetate (PGMEA).
A preferred solvent is a 1:1 mixture of DMAC and PGMEA.
It is a volume ratio mixture. Any conventional radiopaque agent known in the art can be incorporated into the HPEU of the present invention. Examples of these include inorganic radiopaque agents such as barium sulfate, bismuth trioxide, and tungsten powder, iodinated organic radiopaque agents, and iodinated or brominated polyurethanes. The amount of radiopaque agent used is approximately 2-35% based on the weight of the catheter.
Weight%. Radiopaque agents can be incorporated into the expandable catheters of the present invention as one or more stripes or layers formed by conventional extrusion or coextrusion techniques. Possible anti-infectives known in the art include antibiotics such as chlorhexidine, silver sulfadiazine, and penicillin. These substances are
about 1-10% by weight anti-infective and optionally about 1-10% by weight (preferably about 5% by weight)
The catheter can be surface coated by dipping the catheter in a solution containing HPEU. Suitable solvents are those mentioned above. A preferred method for making catheters is by melt extrusion. Anti-infective (if stable to extrusion temperature) and HPEU
can be blended in particulate form by suitable mixing methods, such as stirring or tumbling the polymer pellets and anti-infective agent together, or preferably by conventional twin-screw extrusion. . In the latter process, Warner and Frieder
Using a commercially available twin screw extruder, such as a Pfleiderer model ZDSK-28 unit, each component is homogeneously blended, melted, and extruded into a catheter. The expandable catheter of the present invention has a constant diameter until it comes into contact with an aqueous liquid. In use, a smaller internal diameter catheter is introduced into the patient's bloodstream. The catheter then absorbs water and expands, increasing the size of the lumen so that the insertion device can be easily removed. A larger lumen allows for an increased flow rate of solution to be administered to the patient. A comparison of the distensibility of the catheter of the present invention and a prior art catheter (described in US Pat. No. 4,781,703) is shown in the drawings. FIG. 3 shows that when in contact with water, a 20 gauge catheter of the present invention containing 45% hard segments increases its internal diameter at a rate of 1.1% per minute;
A prior art inflatable 20 gauge catheter containing 45% hard segment has been shown to expand at a rate of only 0.1% per minute. FIG. 4 shows that the catheter of the present invention has only 5
After 30 minutes, the catheter is substantially fully inflated, whereas the inflation of prior art catheters is gradual, as long as 30 minutes, and the inflation is not complete until about 60 minutes after contact with water. It is shown that. Therefore, it can be seen that the high inflation rate makes the catheter of the present invention extremely advantageous for use in hospitals. For example, a nurse monitoring a patient's intravenous drug administration knows that after only five minutes, the catheter will be fully inflated and the rate of administration will be constant thereafter. However, with prior art catheters, the rate of administration varies over a period of 60 minutes or more, requiring constant monitoring during this time to ensure that the rate of administration does not exceed the desired rate. EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto. Examples Raw materials for polyurethane synthesis Polyglycols of various molecular weights were obtained from Union Carbide and used as they were. In order to determine and adjust the blending ratio, the hydroxyl value was determined by the phthalic anhydride-pyridine method, and the moisture content was determined by Karl-Fisscher titration. As a chain extender, 1,4-butanediol (BDO) was used as received from Dupont. MDI was obtained from Mobay and filtered before use. Synthesis Polyurethane was synthesized using one-shot bulk polymerization. stoichiometric amount of polyglycol and
BDO was charged into a polymerization reactor and degassed at 60°C for 30 minutes. A stoichiometric amount of MDI (NCO index 1.02) was then added and vigorously stirred until the polymerization temperature was approximately 85°C. The obtained polymer was taken out and post-cured at 125°C. Typical HPEU formulations of the present invention are shown in Table 1.

【table】

[Table] Example Extrusion of HPEU The slab of HPEU obtained from the example was cut into strips and extruded using a conventional type 3/4 inch or 1 inch single screw extruder to form medical tubes and 8~ A 12 mil thick ribbon was made.
The temperature distribution range of extrusion temperature was as follows: feeding zone, 150-175 °C; melting zone, 190-220 °C
°C; and die, 190-220 °C (depending on hard segment content). EXAMPLE Coextrusion of Striped Encapsulated Catheters The HPEU melt flows from the main extruder and the stiffening polymer melt flows from the coextruder were kept separate until they merged in the forward and downstream sections of the extruder head. The combined flow is passed through a tube die and a stripe of polymer for stiffness is applied.
It exited the tube die as an integral tube component incorporated into the HPEU continuous phase. EXAMPLES Properties of HPEU Tensile Properties Die-cut samples from extruded ribbons were tested in dry (23°C, 50% relative humidity) and hydrated (23°C, 50% relative humidity) test methods. in 0.9% saline)
Tensile property tests of HPEU samples were conducted. The results are shown in Table 1. In calculating the tensile parameters in the wet state, the dry thickness of the test sample was applied. Therefore, the wet tensile test values are not accurate and are provided for comparison purposes only.

[Table] Water absorption and degree of swelling Water absorption and degree of swelling were measured using 0.5 inch x 1 inch injection molded samples. These samples were kept in distilled water at room temperature (23°C) for 24 hours to ensure equilibrium water uptake. The sample was taken out, and the water on the surface was carefully blotted out without pressing it with filter paper. Each swollen sample was carefully weighed, vacuum dried at approximately 60° C. for 48 hours, and weighed again. The water absorption amount and swelling degree were calculated from the weight difference data using the following formula. WA=(Ws-Wp)/Wp×100 [1] DS=[(Wp/dp)+(Ws-Wp)/dw)]/
(Wp/dp) [2] In the above formula, WA is water absorption %, Ws is the weight of the swollen sample, Wp is the weight of the dry sample, DS is the degree of swelling, and dp is is the density of the dry sample (1.15 g/cm ³ ) and dw is the density of water (1.0 g/cm ³ ). All of
An average polyurethane density of 1.15 g/cm ³ was used for the HPEU formulation. The internal diameter was measured on the sample removed from the distilled water bath at a given time. Thus, upon contact with the patient's blood, the present invention expands to a larger lumen size to allow for greater drug flow rates and simultaneously stiffens to adjust its position without kinking. Provide a good catheter.

[Brief explanation of the drawing]

FIG. 1 is a perspective view of an intravenous catheter of the present invention in combination with a catheter insertion device. Figure 2 shows the catheter in Figure 1 in line 2.
FIG. 2 is a cross-sectional view taken along line -2. FIG. 3 is a diagram comparing the swelling speed of the catheter of the present invention with that of a catheter according to the prior art. FIG. 4 is a comparison of the change in inner diameter of catheters of the present invention and prior art catheters as a function of time.

Claims (1)

Claims: 1. A tube of polyurethane which is a substantially hydrophilic thermoplastic elastomer, wherein said polyurethane has 25 to 60% hard segments and at least 50% diisocyanate. and a reaction product obtained from a chain extender, and the tube expands upon contact with an aqueous liquid by absorbing about 10 to 200% of its own weight of the aqueous liquid. , thereby increasing the inner diameter of the tube by about 5-75%.
Melt extrusion catheter. 2. The catheter of claim 1, wherein the diisocyanate is selected from the group consisting of 4,4'-diphenylmethane diisocyanate, 3,3'-diphenylmethane diisocyanate, isophorone diisocyanate, and hexamethylene diisocyanate. 3 The chain extender is 1,4-butanediol, ethylene glycol, diethylene glycol, triethylene glycol, 1,2-propanediol, 1,3-propanediol, 1,6-
The catheter of claim 1 selected from the group consisting of hexanediol, 1,4-bis-hydroxymethylcyclohexane, hydroquinone dihydroxyethyl ether, ethanolamine, ethylenediamine, and hexamethylenediamine. 4. The catheter according to claim 1, wherein the hydrophilic polyurethane, which is a thermoplastic elastomer, further comprises a polyglycol selected from the group consisting of polypropylene oxide glycol, polytetramethylene oxide glycol, and silicone glycol. 5. The catheter of claim 1, further comprising an agent selected from the group consisting of an anti-infective agent, a radiopaque agent, and an antithrombotic agent. 6 further comprising stripes of stiffening polyurethane encapsulated by said hydrophilic polyurethane, wherein said stiffening polyurethane comprises a polyurethane having a hard segment content of at least 50% and a polyurethane having a water absorption of 10% or less. 2. The catheter of claim 1, wherein the catheter is selected from the group consisting of: 7 comprising a tube of polyurethane, a substantially hydrophilic thermoplastic elastomer, wherein said polyurethane comprises a reaction product obtained from a diisocyanate, a polyethylene oxide glycol, and a chain extender, and said tube comprises: expands when in contact with aqueous liquids,
Melt extrusion catheter. 8 Comprising a tube based on polyurethane, which is a substantially hydrophilic thermoplastic elastomer, encapsulating a stripe of stiffening polyurethane, wherein said base polyurethane accounts for 30 to 45%.
has a hard segment of 4,4'-
The tube contains a reaction product obtained from diphenylmethane diisocyanate, 1,4-butanediol, and polyethylene oxide having a molecular weight of 6,000 to 12,000, and said tube, when in contact with an aqueous liquid, transfers said aqueous liquid to about 50% of its own weight. A melt-extruded catheter that absorbs and expands by ~150%, thereby increasing the inner diameter of the tube by about 5-50%. 9. The catheter of claim 8, wherein the stiffening polymer has a hard segment content of 50-90%. 10. The catheter of claim 8, wherein the stiffening polymer has a water absorption of 10% or less.