DE7910395U1 - MEDICAL DEVICES FOR PARENTERAL LIQUIDS - Google Patents

Description

HOECHST AKTIENGESELLSCHAFT HOE 79 / F 089 G Dr.ZR / cr

Medical parenteral fluid devices

It is known that vessels made of plasticized polyvinyl chloride for the collection, storage and: administration of parenteral fluids, e.g. of Blood, blood plasma, blood substitutes, infusion solutions, and other physiological fluids will. It is also known that the plasticizer contained in such mixtures increases the risk of migration or extraction. This is referred to e.g. in DE-AS 25 03 182. It is also known that plasticized polyvinyl chloride, as well as the also very often used silicone material and conventionally processed polyolefins damage the blood or blood components that come into contact with them, by activating or adsorbing various cellular and plasmatic factors of the coagulation system. The medical devices made from them are therefore only usable to a limited extent. This conditional usability also applies to medical devices, especially polyurethane blood bags due to their fairly high permeability for water vapor and air. Also, some are medical Devices can only be produced in a complex manner because of the relatively difficult processibility of polyurethane.

The object of the present invention was therefore to provide a medical device made of a plastic material, which does not have the known disadvantages and in particular an increased compatibility with Owns blood.

This object is achieved according to the invention in that a plastic material consisting of chloropolyolefin or this is used for the medical device and which contains glycerol esters of aliphatic fatty acids as an additive.

The invention therefore relates to a medical device for parenteral fluids, characterized in that at least those surfaces which come into contact with these fluids are made of chlorinated polyolefin or of a plastic material with a chlorinated polyolefin content of at least 50 parts by weight per 100 parts by weight of total polymer - except a plastic material of 50 to 95.5 parts by weight of chlorinated polyolefin with an average molecular weight of 30,000 to 300,000 and 0.5 to 50 parts by weight of polymers of acrylic and / or methacrylic acid esters, the chlorine content of the chlorinated polyolefin being 15 to 45 percent by weight and its average Molecular weight M _w 20,000 to 2,000,000 (weight average, calculated from the chlorine content and the molecular weight of the starting polyethylene, determined by gel chromatography, (calibrated with polyethylene standards of the National Bureau of Standards, Washington DC) and the polymer pro Contains 100 parts by weight of 0.01 to 10 parts by weight of glycerol esters of aliphatic fatty acids.

As chlorinated polyolefins that are preferred according to the invention are used for medical devices, the well-known chlorination products of Polyolefins, especially of polyethylene, polypropylene and copolymers of ethylene and propylene, before all low-pressure polyethylene and copolymers of ethylene with small proportions of e.g. 1-5 mol% Propene, butene (1) or hexene (1). The average molecular weight M of these chlorinated polyolefins is preferably 70,000 to 400,000 and the chlorine content 25 to 40% by weight. Since the water vapor permeability of the Masses influenced by the crystallinity of the chloro-polyolefins chlorinated polyolefins with a residual crystal content of 0-20, particularly preferred 0 - 15%, determined by means of differential thermal analysis, used. Mixtures of different Chloropolyolefins can be used.

The polyolefins used for the chlorination advantageously have a reduced specific viscosity (RSV), determined on a 0.1% solution in decahydronaphthalene at 135 ⁰ C according to ISO / R 1191, from 0.5 to 35, preferably from 1.2 to 5 dl / g. If polyolefins with a higher RSV value and thus a higher molecular weight are used for the chlorination, thermoplastic compositions are obtained which are difficult to process, while polyolefins with a lower RSV value result in compositions with poorer mechanical properties. Basically, however, the effect of the combination of chloropolyolefin or the plastic material containing it is with. Glycerol esters of aliphatic fatty acids are also given for lower and higher molecular weights, although, for high molecular weight materials, for example, thermoplastic processing has to be changed to other processing methods such as sintering. The average molecular weight M is generally between 15,000 and 1,500,000, preferably 50,000 to 300,000, and the distribution range M (weight

mean / numerical mean) between 2 and 20, preferably 4 and 15.

The chlorination of the polyolefins takes place according to the processes known for this purpose; preferably it is aqueous Suspension e.g. according to the method of DE-AS 14 20 415 or in dilute hydrochloric acid in the presence of agglomeration inhibitors, as described in DE-OS 2.260.525,

30 carried out.

The plastic material to be used according to the invention In addition to the required at least 50 parts by weight of chlorinated polyolefin, other polymers can also be used or copolymers, the molecular weight of which is advantageously in the above for chloropolyolefin specified ranges.

These can be the known, miscible with chloropolyolefins Polymers - with the exception of polyacrylic or polymethacrylic acid esters - or copolymers, provided that the latter not predominantly made from acrylic and / or methacrylic acid esters exist and contain no vinyl chloride as a comonomer. Examples of such polymers are Polyvinyl chloride, polyolefins such as polyethylene or polypropylene, polyvinyl acetate, polyacrylonitrile.

The copolymers preferably contain vinyl chloride, olefins, in particular ethylene or propylene, diolefins such as butadiene, isoprene or ethylidene norbornene vinyl ester like vinyl acetate or acrylonitrile as monomer building blocks. Examples of copolymers are: vinyl chloride copolymers such as vinyl chloride / ethylene or vinyl chloride / Vinyl acetate copolymers, ethylene / vinyl acetate copolymers, Ethylene / propylene copolymers (APK), ethylene / propylene / diolefin terpolymers (APTK), acrylonitrile / butadiene copolymers (NBR rubber), acrylonitrile / butadiene / styrene ter-

20 polymers (ABS rubber).

In the case of the use of a plastic material Chloropolyolefin and another polymer can manufacture by mixing the polymers in question, preferably by the melt blending process. One Better homogenization and thus generally also better transparency are obtained through the polymerization of the respective monomers or monomer mixture in the presence of the chlorinated polyolefin among the known Polymerization conditions, as a result of which to a certain extent also a grafting of the monomer or monomers on the chlorinated polyolefin takes place.

The use of different contents and compositions of the plastic materials mentioned is based on known Way depending on the field of application of the medical

- D -

Devices to the properties to be optimized in each case, such as mechanical durability, flexibility, Transparency, gas permeation or sterilizability.

Within the scope of these variable usage properties, the compatibility of the material, especially the dem Blood or the blood components facing surface according to the invention through the use of glycerol esters Aliphatic fatty acids achieved as additives, preferably in amounts of 0.5 to 5 parts by weight per 100 parts by weight of polymer can be used.

These glycerol esters can be saturated as acid components or contain and represent unsaturated fatty acids with 5 to 30 carbon atoms, preferably naturally occurring Fats or oils, such as soybean oil or epoxidation products of such fats and oils with up to 10 wt .-%, preferably 2 to 7 wt .-% epoxy oxygen content, such as epoxidized soybean oil.

These glycerol esters are available in pure form or in the form of mixtures, preferably in the naturally occurring form Mixture, mixed or mixed into the plastic material as part of a melt mixing process prior to processing also only after the processing step on the side of the respective fluid facing the parenteral fluid Applied device.

In the latter case, even small amounts such as 0.01 parts by weight of the glycerol ester can be sufficient, while with Incorporation after a melt mixing process, in particular when granulating the plastic material, in general 0.1-10 parts by weight, preferably 0.5 to 5 parts by weight, of these glycerol esters of aliphatic fatty acids required are.

It is therefore essential that at least the surfaces '' of the medical device that is connected to the parenteral

alen liquid come into contact, from the invention material used, i.e. the special polymer that contains the special additive, exist.

"Surface" is here preferably the area up to a depth of up to approx. 5 μm, preferably 1 μm, understood, although for the present application in general already the invention

TO athrombogenic equipment to a surface depth of a few angstroms is enough.

In addition to the above additive according to the invention, which also acts as a lubricant and stabilizer, additional, preferably physiological harmless stabilizers such as fatty acid salts of calcium, magnesium, aluminum and zinc, for example Calcium zinc stearate or calcium aluminum stearate, organic. Phosphites and phenolic antioxidants be contained in the polymer material. In addition, the usual light stabilizers, lubricants, Pigments and fillers, e.g. barium sulfate as a contrast medium for radiographic purposes. These additives can be used during the manufacture of the thermoplastic Mass or can be added afterwards.

Medical devices are to be understood here primarily as those devices or device parts with parenteral Liquids come into direct or indirect contact,

3Q such as blood bags, flexible containers for infusion solutions, infusion tubes, suction tubes, blood filters, Cannulas, parts of the artificial kidney or the heart-lung machine. Parenteral fluids are included in both Blood, blood serum and blood components, as well as all other injectable solutions for medical purposes like blood substitute solutions. The term "medical devices" is also intended to include implantation devices such as, arterio-venous shunt, arterial prostheses,

Cardiac bypass pumps, Herζ valves, cardiac pacemakers, Include catheters or artificial hearts.

These devices are manufactured using the usual methods such as pressing, injection molding, extrusion

or blow molding and on the usual processing machines, such as extruders or calenders.

The good mechanical strength of these devices is usually sufficient for the purposes at hand. In some cases, however, it can be useful to increase the mechanical strength by incorporating support fabrics of inorganic or organic material, such as glass fibers or plastic fibers, for example from Polyester or polyamide. In addition, it is also possible to use composite films for this purpose, in which the inner film, which comes into contact with the parenteral fluids, is made from the inventive The molding compound used consists (so to a certain extent acts as a lining) and the outer film is mechanically special strong and possibly also as transparent or gas-tight material as possible.

For the medical devices mentioned above, plasticized polyvinyl chloride, Silicones or polyethylene are used, their compatibility with blood and important blood components through the inventive application of the materials described is exceeded. As blood compatibility (athrombogenicity) is the property of a material to oppose the coagulation systems contained in the blood to behave neutrally, i.e. not to cause clots (thrombi). Foreign material affects everyone Usually both the cellular and the plasmatic blood components; of particular importance here is the Action on coagulation factors II, IX, Xi and XIi.

The coagulation factors are usually determined analogously to the method of Hardisty and Macpherson (cf. Thromb. Diath. Haemorrh., Volume 1_ (1962), page 215).

The blood compatibility of the one used according to the invention Plastic material and the medical devices according to the invention produced therefrom are made with the aid a series of examinations determined, the results of which, taken together, provide a statement about the blood tolerance enable. The plastic material to be tested is used as a flexible hose (rotating hose test) used. This test uses human whole blood that is 10% by volume of a 3.8% by weight aqueous sodium citrate solution was added.

The plastic material is used in the form of a tube with a length of 75 cm and an internal diameter of 4 mm. The tube is filled with 10 ml of blood, and then the ends of the tube are sealed together. The hose is bent into a circular shape and attached to a turntable that is inclined at 75 degrees. The turntable is rotated at an ambient temperature of 37 ⁰ C for two hours with a speed of 15 rpm. After completion of this rotating tube test, the number of platelets contained in the test blood is determined with a commercially available particle counter (manufacturer: Coulter Electronics Ltd.) and compared with the number of platelets in the starting material. This gives the value of the platelet retention (PR) in Table 1. The cellular components of the blood are then removed by centrifugation (3,000 g, 20 min), and the following parameters are determined on the resulting blood plasma:

a) Platelet factor 3 (PF 3) (after Hardisty and Hutton, Brit. J. Haemat., Volume 11 (1965), page 258).

b) Platelet factor 4 (PF 4) (after Harada and Zucker, Thromb. Diath. Haemorrh., Volume 25 (1971), page 41).

c) recalcification time (RCZ): 0.2 ml of the plasma are, at a temperature of 37 ⁰ C with 0.2 ml of an aqueous calcium chloride solution (0.025 molar) was added and the time to clot is determined using a commercially available automatic coagulometer .

d) Partial thromboplastin time (ΡΊΤ): Behringwerke AG) were pipetted and incubated for 2 min: To 0.1 at a temperature of 37 ⁰ C 0.1 ml of a thromboplastin reagent (manufacturer ml of the plasma. 0.1 ml of an aqueous calcium chloride solution (0.025 molar), which has been preheated to 37 ° C., is then added, and the time until coagulation is determined using a commercially available automatic coagulometer.

e) Coagulation factors II, IX, XI and XII.

According to Table 1, all measured values are set to standard value 1 of the respective initial values of the untreated blood or plasma converted. The relative deviations from the initial values are added, in this case the platelet retention (PR) and the partial thromboplastin time (PTT) are double weighted and by the number of measurement parameters divided. The value obtained from this (= measure) is, in Expressed in percent, a measure of the influence of the plastic material on the blood, the smaller the value, the smaller the influence. One recognises in Table 1 that according to Example 1 by the inventive Combination of chlorinated polyethylene with epoxidized soybean oil with the hoses made in this way

a blood tolerance index of 7.7% over the The sum of the determined parameters are better tolerated by blood than the unmodified chlorinated polyethylene (comparative example A) (measure 24.1%), commercially available medical-grade polyvinyl chloride tubing with plasticizer and epoxidized soybean oil (comparative example H) (measure 18.3%), medical-grade silicone hose customary on the market for blood transfusions (comparative example G) (measure 25.9%) or a polyethylene (comparative example B) (Measure 27.7%) or ethylene / propylene / xthylidene norbornene terpolymer tubing (Comparative Example F) (measure 24.3%).

The attached figure gives a view of a container for a parenteral solution with the features of the invention again; (1) means the container, (2) suspension devices, (3) the infusion tube and (4) / (5) Filling or emptying nozzle.

example 1

100 parts by weight of a fine-grain chlorinated polyethylene with a chlorine content of 34 wt .-%, which consists of a

Polyethylene of molecular weights: weight average

(Molecular weight determinations on the output ■ was prepared 160,000 and number average 31 000 by chlorination of polyethylene by gel permeation chromatography at 135 ⁰ C
in 1,2,4-trichlorobenzene, calibrated with polyethylene standards

of the National Bureau of Standards, Washington DC) are in
a mixer stirrer with 2 parts by weight of a stabilizer system of calcium stearate and zinc stearate, with 0.15
Parts by weight of a polyethylene wax as a lubricant
and 5 parts by weight of epoxidized soybean oil with 6% epoxy

Oxygen mixed and the mixture gently over 20 hours
The mixture is stirred in an extruder with a
140 - 170 ° C temperature program from the intake to the nozzle
melted and mixed, the cooling extrusion strand chopped up into granules. This granulate is used on

a single screw extruder with a 30 mm screw
same temperature program (i 40-170 ⁰ C ^ a hose des
Internal diameter 4 mm and wall thickness 0.8 mm extruded ί and the tube in pieces of 75 cm without any further f

Measure of the blood compatibility test I "rotating hose system" described above. The Blutverträglich- ϊ keitsmaßzahl is shown in Table 1 at 10 versions i this example 1 with a total of 25 blood coagulation testing | 7.71 + _ 2.17% standard deviation or 0.43% mean |

error of this mean. I.

· &

Example 2

Under otherwise constant conditions as in Example 1
instead of 5 parts by weight of epoxidized soybean oil 2.5 weight

parts used. The measure of blood tolerance
was 9.7%, the repeat value is 10.5%.

Example 3

Under otherwise constant conditions as in Example 1, instead of 5 parts by weight of epoxidized soybean oil, 1.25 Parts by weight used. Blood tolerance index: 5.2%; Repetition value: 8.7%.

Example 4

Under otherwise the same conditions as Example 1, 100 parts by weight of a chlorinated polyethylene with a chlorine content of 39 wt .-% are used, which was obtained from a polyethylene with an M _w value of 57,000 and an M value of 13,000 by chlorination. Blood tolerance index: 4.0%; Repetition value: 8.3%.

15 Example 5

Under otherwise the same conditions as in Example 1, instead of the polyethylene used as the starting material there an M / M ratio of 220,000 / 30,000 in the chlorination to a chlorine content of 34% by weight based on. Blood tolerance index: 8.3%; Repetition value: 11.5%.

Example 6

Under otherwise the same conditions as Example 1, 60 parts by weight of a chlorinated polyethylene with a chlorine content of 34% by weight (M _W / M of the polyethylene = 160,000 / 31,000) and 40 parts by weight of a chlorinated polyethylene with a chlorine content of 39% by weight .-% (M _w / M _{n of} the polyethylene = 57,000 / 13,000) and combined with 1 part by weight of epoxidized soybean oil. Blood tolerance index: 7.4%; Repetition values: 7.9% and 6.0%.

Comparative example A.

Under otherwise the same conditions as Example 1, 5 parts by weight are used instead of 5 parts by weight of epoxidized soybean oil an epoxidized polyethylene wax with an average of 3 * 0 carbon atoms and 2.6% by weight of epoxy oxygen

I t *

used (melting point 80 ⁰ C).

The measure of blood tolerance as the mean value of 4 different tube extrusions and 16 individual blood tolerance measurements (see Table 1) was 24.1%, with a standard deviation of + _ 9.4% or a mean error of 2.35% of this mean.

Example 7

The tube obtained without epoxidized soybean oil according to Comparative Example A is filled with epoxidized soybean oil, stored for 24 hours at rest, the epoxidized soybean oil is allowed to run off and dried under a stream of nitrogen. Soybean oil content: about 0.1% by weight based on the total hose. Measure of blood tolerance from 3 measurements: 12.1 + _ 2.1%.

Example 8

The hose obtained without epoxidized soybean oil according to Comparative Example A is made with natural (non-epoxidized) Treated soybean oil according to Example 7. Measure of the

20 Blood tolerance: ⁸ ' ^7%

Comparative example B

Under otherwise the same conditions as Example 1, 100 parts by weight of a chlorinated polyethylene with a chlorine content of up to 39% by weight (M _w / M of the polyethylene = 57,000: 13,000) with 1.75% by weight of the stabilizer system Ca stearate + Zn -stearate, 1.75 wt .-% of the epoxidized polyethylene wax, 0.25 wt .-% of a non-epoxidized polyethylene wax and 0.15 wt .-% oxy-stearic acid mixed, granulated with the help of a melt mixing process and extruded to form a tube. Measure of blood tolerance from 6 measurements: 27.9 + 4.2.

Example 9

The without epoxidized soybean oil according to Comparative Example B tube obtained is filled with epoxidized soybean oil, stored for 24 h, the epoxidized soybean oil is allowed to drain, washed with hexane, under a stream of nitrogen and then dried in a vacuum drying cabinet. Blood tolerance index: 10.4% / 13.5%.

Comparative Example C

Under otherwise the same conditions as in Example 1, 100 parts by weight of a polyethylene chlorinated to 34% by weight of chlorine (^ / M _n of polyethylene = 160 31,000) with 0.5% by weight of calcium stearate and 1.5% by weight of barium -Cadmium laurate and 0.5 wt .-% trisnonyl phosphite mixed, granulated and extruded to form a tube. Blood tolerance index: 46.3 + 4.7% (from 4 measurements).

Comparative Example D ""'

The hose produced according to the invention according to Example 1 with the blood tolerance index 7.71 + _ 0.43% from 25 Individual measurements are made on the inside of the hose with a • mixture of 25% toluene and 75% ifethanol (as a solvent for the epoxidized soybean oil contained in the hose) extracted, the toluene with Washed out methanol and dried the hose. From the weight s decrease, it is found that about half of the epoxidized soybean oil was extracted in 24 hours.

Measure of blood tolerance after superficial extraction of the epoxidized soybean oil: 20.4 J ₁ 7.2%. 30th

Comparative example E.

A tube of the same dimensions as in Example 1 is extruded from high-pressure polyethylene (M ₁ / M = 72,000: 18,000); Blood tolerance index: 27.7 + _ 3.4% (from 6 measurements).

Ill · * tt ······ j

Ή '* · »* J 15" - "

Comparative example F

A hose of the same dimensions as in Example 1 is extruded from ethylene / propylene / ethylidene norbornene rubber with the composition 71% by weight of ethylene, 24% by weight of propylene and 5% by weight of ethylidene norbornene. Measure for the blood tolerance according to Table 1 from 17 individual measurements: 24.3 * _ 1.7 %.

Comparative example G

A tube of the same internal diameter of 4 mm as in Example 1, but with a wall thickness of 1 mm, made of medical-grade silicone for biomedical applications, such as blood transfusion tubing on the market, is comparatively measured:

Blood tolerance index according to Table 1 from 44, individual measurements: 25.9 + 1.1%.

Comparative Example H.

A tube with an inner diameter of 4 mm and a wall thickness of 1 mm, made of medical-grade PVC with 39% by weight of dioctyl phthalate as a plasticizer and 5% by weight epoxidized soybean oil for biomedical purposes, e.g. as a blood transfusion tube is offered on the market is being tested. The measure of blood tolerance is 45

25 individual measurements: 18.3% + 1.2%.

- 16 TABLE 1

AVERAGE FACTOR CHANGES IN THE DETERMINATION OF THE CONTRACTUALITY FIGURES ACCORDING TO THE IN-VTTRO "ROTATING" HOSE SYSTEM "

example + 1 V E A. RGL EIC HSBE I. GAMES G + + ] 0.022 H + + 0.048 Factors 25 * + 16 * E. F. 44 * + 0.018 45 * + 0.027, 0.946 + 0.011 0.684 + _ 9 * ί 17 * 0.634 + 0.103 0.849 + 0.115 (PR) X 2 1.060 + 0.016 1.129 + _ 0.036 0.519 + 0.049 1.163 + 0.013 1.252 + 0.012 PF 3 1.125 + 0.035 2,156 + _ 0.017 1,100 + 0.182 2.133 + 0.013 1.729 + 0.024 PF 4 1.025 0.016 1,074 jf 0.191 2.206 + 0.256 0.947 + 0.016 0.959 + 0.016 '
! F XII 1.012 + 0, u! 7 1,061 + _ 0.028 1.017 + 0.038 0.958 + 0.002 0.954 + 0.015; F XI 0.991 + 0.015 1.068 _ + 0.030 1.060 + _ 0.028 0.908 + 0.020 0.940 + 0.031 F IX 0.905 + 0.012 0.926 * _ 0.051 1.013 + 0.022 0.857 0.008 0.853 + 0.056 F II 0.957 - ü 0.024 0.911 + _ 0.024 0.848 + 0.031 0.87I 1.1 0.822 1.2 RCZ 1.066 0.004 1.074 _ + 0.037 0.824 + 0.042 1,112 1.031 (PTT) X 2 7.71 η , 43 24.1 + 0.008 1.084 + 0.007 2b, y 18.3 Measure (%) 2.35 21, ι + 3.4 0.622 + 0.032 1.159 + _ 0.035 1.903 + 0.176 1.042 + _ 0.023 0.957 + _ 0.042 i, 025 + _ 0.035 0.888 + _ 0.026 0.855 + 0.037 1.060 J ₁ 0.037 24.3 + 1.7

* Number of the respective tests

Claims (5)

. ■ ■ '' '' "''" 'L 1' - "'HOE 79 / F 089 G j SCHÜTZ CLAIMS": 1. Medical device for parenteral fluids, characterized in that at least those surfaces that come into contact with these fluids. come from chlorinated polyolefin or from a. '' Plastic material with a chlorinated polyolefin content of at least 50 parts by weight per 100 parts by weight of total polymer - with the exception of a plastic material made of 50 to 99.5 parts by weight of chlorinated polyolefin with an average molecular weight of 30,000 to 300 0OC and 0.5 to 50 parts by weight of polymers of acrylic and / or methacrylic acid esters - exist, the chlorine content of the chlorinated polyolefin 15 to 45 percent by weight and its average molecular weight M _w (weight _{average) s} 15 20,000 to 2,000,000 and the polymer per Contains parts by weight of 0.01 to 10 parts by weight of glycerol esters of aliphatic fatty acids. 2. Medical device according to claim 1, characterized in that that the glycerol ester of aliphatic fatty acids naturally occurring fat or oil or their Is epoxidation products. 3. Medical device according to claim 1 and 2, characterized characterized in that the glycerol ester of aliphatic fatty acids is epoxidized soybean oil. 4. Medical device according to claim 1 to 3, characterized in that the polymer is a chlorinated polyethylene with a residual crystallinity of 0 to 15%. 5. Medical device according to claim 1 to 4, characterized in that it is in the form of a bag or "Hose owns.