DE7733140U1 - MEDICAL DEVICE FOR LIQUIDS TO BE USED PARENTERAL - Google Patents

Description

known, vessels made of plasticized polyvinyl chloride for collecting, processing and administering parenteral To use fluids, e.g. blood, blood substitutes, infusion solutions and other physiological fluids. For this application, high strength with good flexibility, sterilization resistance and good weldability are required, and in order to be able to observe possible agglutination of the blood, a high degree of transparency is desired. Disadvantageous is that the plasticizer contained in such mixtures carries the risk of migration or extraction. On it will e.g. pointed out in DT-AS 2 503 182. It is critical when it contains plasticizers Polyvinyl chloride continues to have the relatively high water vapor permeability that occurs with prolonged storage of aqueous Liquids in such containers lead to evaporation losses. The plastic containers must therefore also be enclosed in metal containers.

Migration and extractability are in the case of polyvinyl chloride mixtures, which contain so-called polymer plasticizers are much lower. In the case of steam sterilization in the autoclave 120 ° C, however, due to a certain hydrolyzability of the polymer plasticizers, a pH shift occurs and, as a result of extraction oxidizable substances, an increase in the permanganate numbers in the aqueous extract. For this reason it is mentioned in the DT-AS 2 503 182 proposed the use of a certain polyurethane of high purity as a plasticizer for PVC.

However, this requirement for maximum purity makes the mixtures according to this DT-AS 2 503 182 expensive and the water vapor permeability is also higher than desired for these mixtures.

The object of the present invention was therefore to provide a thermoplastic To provide mass for the production of medical devices, which does not have the known disadvantages, i.e. especially with low water vapor permeability, high transparency, strength and good weldability none

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Contains extractable or hydrolyzable components.

This object is achieved in that · for the production of medical devices, which with parenteral fluids such as blood,

Blu & substitutes, infusion solutions and other (physiological) Liquids come into contact, a thermoplastic mass is used, which consists of 50-95, preferably 70-90 parts by weight chlorinated polyolefin with a chlorine content of 15-45, preferably 25-40 wt .-% and an average molecular weight of 30,000 - 300,000, preferably 40,000 - 100,000 (calculated from the chlorine content and the molecular weight determined by gel chromatography of the starting polyethylene? See Weßlau, Makromolekulare Chemie, 2 £, (1958) pages 96-101) and from 5-50, preferably 10-30 parts by weight of polymers of acrylic and / or methacrylic acid esters consists.

Suitable chlorinated polyolefins are chlorination products of polyolefins, in particular of polyethylene, polypropylene and Copolymers of ethylene and propylene, especially low-pressure polyethylene and copolymers of ethylene, with low Contents of e.g. 1-5 mol% propene, butene (1) or hexene (I).

The polyolefins used for the chlorination expediently have a reduced specific viscosity (RSV), determined on a 0.1% solution in decahydronaphthalene 135 ° C according to ISO / R 1191, between 1 and 10, preferably between 1.2 and 5 dl / g. Are used for chlorination polyolefins with higher RSV value (higher molecular weight) is used, one obtains thermoplastic masses that are difficult to process, while polyolefins with a lower RSV result in compositions with poorer mechanical properties.

Because the water vapor permeability of the masses on the crystallinity the chloro-polyolefins are influenced are preferred chlorinated polyolefins with a residual crystal content of 1-20, preferably 5 - 35%, determined according to the difference

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The chlorination of the polyolefin is preferably such in aqueous suspension, B, by the process of DT-AS ί 420,415 performed.

The thermoplastic composition to be used according to the invention can be produced by mixing the two polymers, wherein this is preferably done by the melt blending process. The transparency of such mixtures is improved, if a polymer of acrylic and / or methacrylic acid ester is used, its refractive index is that of the chloropolyolefin is largely matched, for example by using a mixed polymer of two appropriately selected Acrylates or methacrylates.

A better homogenization and thus a better transparency is obtained by polymerizing the acrylic and / or methacrylic acid esters in the presence of the chlorinated polyolefin. The use of a thermoplastic produced by this process Mass is therefore preferred.

This polymerization of the acrylic and / or methacrylic acid esters in the presence of the chlorinated polyolefins is preferably carried out in aqueous suspension. This can be done, for example, in such a way that the chloropolyolefin is suspended in water in the presence of the usual suspending agents, such as partially saponified polyvinyl acetate, alkyl celluloses such as methyl cellulose, hydroxyalkyl celluloses such as hydroxypropyl cellulose, alkoxyalkyl celluloses such as methyl-oxy-ethyl cellulose or gelatin ) Monomer (s) is then added (v / ground) and thereupon the entire system for swelling of the Chlorpclyolefxns in the monomers or monomer mixture is stirred at room temperature or slightly elevated temperature. The free radical forming initiator and optionally a molecular weight regulator, then v / ill be added and on the polymerization temperature, generally 30 to 120 ° C, preferably 40 to i is 100 ° C heated. Alternatively, §

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it is also possible to swell and / or dissolve the chloropolyolefin first in the monomers or monomer mixture, this dispersion Ji> zw. To disperse the solution with the addition of the suspending agent in water and then proceed as above.

The usual starters, e.g. peroxides such as benzoyl peroxide, lauroyl - Peroxide, perester such as tert. Butyl peroxibenzoate or tert. Butyl perpivalate, Percarbonates such as Isopropylperoxidi carbonate, azo compounds such as Azobisisobytyronitril and the like. as well as corresponding Mixtures in question. The amount of initiator is generally about 0.1 to 3% by weight, based on monomers. It naturally hangs on the effectiveness of the initiator, the polymerization temperature etc. from.

I The following can be used as molecular weight regulators:

longer-chain mercaptans such as dodecyl mercaptan, dimerized α-methylstyrene, halogenated hydrocarbons

\ Aldehydes, ketones etc. · ·

In principle, it is also possible to use the above polymerization, which to a certain extent also results in grafting of the or the monomers on the chlorinated polyolefin, so that thus chloropolyolefin, polymer of acrylic and / or methy! acrylic acid ester and graft polymers of these esters on the chloropolyolefin are present next to one another, even after the solution or Perform mass technology, although this usually offers no advantages in the present case.

Depending on the intended use, the properties of the invention thermoplastic mass by varying the content of polymeric acrylic · and / or methacrylic acid esters, within of the area used. The elarticity increases with an increase in the chloropolyolefin content, while rigidity (hardness) and transparency increase with the content of polyacrylic and / or methacrylic acid ester.

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Acrylic or! ^^ acrylic acid esters are especially those whose alcohol components contain 1 to 6 carbon atoms, since their polymers are well compatible with the chloropolyolefins and do not lead to cloudiness. The alcohol component can be substituted by hydroxyl groups or the furan group. Single esters or mixtures of several esters can be polymerized. Examples of esters that can be polymerized alone or together in the presence of chloropolyolefins are:

Methyl methacrylate, hydroxyethyl methacrylate, hydroxypropyl methacrylate, Furfuryl methacrylate, ethyl acrylate, isopropyl acrylate and butyl acrylate.

Optionally, the acrylic used according to the invention can and / or methacrylic acid esters also contain other monomers in small amounts, provided that they are intended according to the invention Properties, especially the low water vapor permeability and the high level of transparency is not significantly impaired. Examples of such monomers are: Acrylonitrile, methacrylonitrile, methacrylamide, vinyl ester, in particular Saturated carboxylic acids containing from 2 to 12 carbon atoms, especially vinyl acetate and vinyl propionate, continue N-vinyl lactams such as N-vinyl pyrrolidone, also copolymerizable ones unsaturated hydrocarbons such as ethylene, propylene or styrene and the like. Among small amounts there are mostly such to understand from about to 10 wt .-%, preferably up to 5 wt .-%, although in the case of some monomers larger amounts may also be present without any significant impairment of the above properties can, which can easily be determined by simple experiments.

The term "acrylic and / or methacrylic acid ester" should therefore be understood here in such a way that it also includes mixtures such monomers included in small amounts.

The thermoplastic compositions according to the invention can be used for the production of the most varied medical devices or device parts that come with

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parenteral fluids directly or indirectly in contact e.g. blood bags, flexible containers for infusion solutions, infusion tubes, suction tubes and catheters will. Parenteral fluids include blood and blood serum as well as any other injectable solution for medical purposes such as blood substitute solutions etc. Roger that.

For good storage stability, medical containers are it is necessary that little or no gas exchange between the closed container and the environment, e.g. evaporation the fluid or oxygen uptake present in the vessel takes place from outside. In addition, no microorganisms that break down the parenteral fluid must penetrate. With the thermoplastic cash registers according to the invention, the above requirements are met; also is the water vapor permeability significantly lower than with plasticized polyvinyl chloride. However, it is big enough to prevent that during sterilization with steam a cloudiness occurs, which otherwise only very slowly, sometimes only after Days to go back again. The water vapor permeability can also be easily optimized through the choice of the monomeric ester will; for example, it increases due to partial replacement of methyl methacrylate by hydroxypropyl methacrylate.

The thermoplastic composition according to the invention can be based on conventional Processing machines such as extruders or calenders are shaped into the desired devices using conventional methods. In order to avoid degradation during processing, stabilizers must be added. This should only be physiological perfect stabilizers, such as fatty acid salts of calcium, magnesium, aluminum and zinc, organic phosphites, aliphatic epoxies, polyhydric alcohols and phenolic antioxidants can be used. Particularly proven has a stabilizer combination of 1-3% by weight calcium-aluminum'-stearate, 0.5-1 wt. ~% Of a secondary or tert. organic phosphite, 1-3% by weight of an aliphatic

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Epoxy and 0.05-10% by weight of a phenolic antioxidant, based on the thermoplastic mass. In addition, the usual light stabilizers. Lubricants, pigments and fillers e.g. barium sulfate can be added as a contrast medium for radiographic purposes. The accessories can be used during the production of the thermoplastic mass or afterwards.

In most cases, the good mechanical strength is that of those according to the invention Moldings produced molding compounds for the present application purposes are sufficient. In some cases it can however, it can be useful to increase the mechanical strength by incorporating supporting fabrics made of inorganic or organic materials Increase material such as glass fibers or plastic fibers, for example from polyester or polyamide. Besides, it is about this Purposes also possible to use composite films in which the inner film, which is in contact with the parenteral fluids comes, consists of the molding compositions according to the invention (that is to say acts as a lining) and the outer film mechanically particularly strong, and also as transparent as possible material is constructed. The water vapor permeability In contrast, this outer support film can be relatively high, since the inner film is of course only slightly permeable.

The attached figure shows a container for

again a parenteral solution having the features of the invention;

e (1) means the container, (2) the inlet or outlet

opening and (3) a hanger.

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example 1

81 parts by weight of a fine-grain chlorinated polyethylene with a chlorine content of 40% by weight and a residual crystallinity of 4% (determined by differential thermal analysis), which was obtained by chlorinating a low-pressure polyethylene with an RSV value of 2.3 dl / g (measured in 0, 1% solution in decahydronaphthalene at 135 ° C.) are mixed with 160 parts of water and 0.2 parts of a partially saponified polyvinyl acetate (viscosity = 2 cP in 2% aqueous solution, acetyl content = 42%) in a stainless steel kettle suspended with 40 l content with an anchor stirrer, 19 parts by weight of methyl methacrylate are injected with exclusion of oxygen and the chlorinated polyethylene is swollen in the monomer with stirring at room temperature. Then 0.06 parts by weight of tert-butyl perpivalate are added and the polymerization is started by heating the contents of the kettle to 90.degree. After 2 hours, the mixture is cooled and the fine-grained product is drained off, washed and dried. The yield, based on the monomer used, is 99.9%.

The product is made with 1% by weight Ca / Al stearate, 0.5% by weight trisnonylphenyl phosphite, 3% by weight epoxidized soybean oil and · _. 0.1% by weight of tetrakis [methylene-3 - (. 3 ^I , 5'-di-tert-butyl-4'-hydroxyphenyD-propionate] methane (Irganox ^v '1010) stabilized ..

A rolled sheet is prepared from this polymer at 175 ° C. on a mixing roller and foils 400 μm thick are pressed from it. the The clarity of the film produced in this way (scatter 21%) is significantly better than that of a corresponding film made from the Starting chloropolyethylene (variance 55%).

The films were sterilized in an autoclave at 120 ° C. and the aqueous extract was tested in accordance with DIN 58 361/4 (blood bag test). The result, in comparison to a state-of-the-art film made of soft PVC (70% PVC + 30% dioctyl

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phthalate) is shown in Table 1.

As can be seen from Table 1, the values to be observed are well below the values to be observed in all tests and are in some cases better than with soft PVC.

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Table 1

Blood loot, olives
according to DIN 58 361Λ Highest permissible values example 1
81 % CPE ¹ V 19 % MMA ^{2 5} comparison
70 % PVC / "50 % DOP ^ Auasohön dor test solution clear, colorless clear, colorless clear, colorless
I. Shift dos pH values «,
Consumption during tatration / 250 ml
-. J * i = 10 ml of 0.01 n-HCl
£ 10 ml of 0.01 N NaOH 0.0 ml
0.0 ml 3 - 5 ml c, o
CAE steam freshener cotand / 250 ml
*** S 12.5 mg 1.7 mg 3 - 10 mg '". CD
hJJV absorption in the range of
r »230 - 360 nm
e » = 0.2 at 230 nm
0.090 .
at 230 nm -
0.1 - 0.25; .... Chlorine ions / 250 ml ^ 1.0 mg Cl ' Track· Track '■ ··. ■ Sulfate ions / 250 ml S 2.5 mg SOz ₁ . ¹ ' undetectable undetectable Ammonium ionon / 2'jO ml = 0.5 mg Nny track track Foaming undetectable undetectable undetectable Oxidizing substances
Consumption
0.01 n-KMnO ^ -LHg. / 25O ml S 25.0 ml • 3.8 ml ' 10-20 ml

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Examples 2 to 16 show further properties of the invention thermoplastic compositions for their use in medical devices that come into contact with parenteral fluids come, are essential.

Examples 2 and 3

Example 1 is using a chlorinated polyethylene with a chlorine content of 34 wt .-% and a residual crystallinity of 10%, which was produced by chlorinating a low-pressure polyethylene with an RSV value of 1.5 dl / g, repeated with varying amounts of methyl methacrylate (MMA). Calender foils with a thickness of 400 μm are used to test the tensile strength and elongation at break from the polymers obtained 3 mm press plates produced to determine the ball indentation hardness. As can be seen from Table 2, the hardness depends on the thermoplastic mass from the content of methyl methacrylate.

Table 2

example 85 % CPE / 15 \ Ball pressure
- hardness
N / nm? Elongation at break
% Tear resistance
• N / itm 2: 80 % CPE / 20! 16 742 10.9 3: 32 534 12.7 i MMA h MNA

Examples 4 and 5

Examples 2 and 3 are repeated, using instead of methyl methacrylate Hydroxypropyl methacrylate (HPMA) is used. Table 3 shows the water vapor permeability of 400 μm thick films of the various samples compared to a soft PVC film. By incorporating hydroxyl groups into the polymer the water vapor permeability increases and can therefore can be adjusted to a desired level.

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Table 3
example

2: 80% CPE / 20% MMA 4: 85% CPE / 15% HPMA 5: 80% CPE / 20% HPMA comparison 70% PVC / 30% DOP

Water vapor permeability g / m ² · 24h

0.33 1.42 2.03 2.52

Examples 6-8

According to Example 1, different amounts of methyl methacrylate are used (MMA) in the presence of a chlorinated polyethylene (CPE) with a chlorine content of 38 wt .-%, which by chlorination of a low-pressure polyethylene with an RSV value of 1.5 dl / g was produced, polymerized. The products obtained in this way and the starting chloropolyethylene were converted into calender foils with a thickness of 400 pounds and compared the transparency and scattering with that of soft PVC films. The result is shown in Table 4. The The clarity of the film improves with an increasing proportion of methyl methacrylate and, at 15% MMA, almost reaches the value of the soft PVC film.

Table 4

example

Transparency scattering

6 Comparison: CPE

7; 90% CPE / 10% MMA

8th; 85% CPE / 15% MMA

Comparison; 70% PVC / 30% DOP

89 51 90 23 90 16 92 10

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Example 9

Example 2 is repeated, but after cooling the aqueous liquor to 50-60 ° C., 1% by weight of the stabilizers

Ca / Al stearate, 0.5% by weight distearyl pentaerythritol diphosphite,

0.25% by weight of tetrakis [methylene ~ 3- (3 ', 5'-di-tert-butyl-4' - 'hydroxyphenyl) propionate] methane and 3% by weight of a solid epoxidized α-oil with 26-28 carbon atoms below 1 / 2-1 added stirring for hours. After the usual work-up, the polymer has the same thermal stability and rheological stability Properties as with subsequent stabilization of the powder.

Examples 10-11

Example 5 is repeated, but instead of pure hydroxypropyl methacrylate (HPMA) a mixture of hydroxypropyl methacrylate and methyl methacrylate (MMA) in the presence of the chlorinated Polyethylene is polymerized. Table 5 shows the water vapor permeability of the products produced in this way in comparison to Examples 2 and 5. By varying the monomer ratio, the water vapor permeability for the respective Application can be optimized.

Table 5

Example permeable to water vapor

ability of a 400 μm thick film

g / m ² x 24 h

2: 80% CPE / 20% MMA 0.33

10: 80% CPE / 18% MMA / 2% HPMA 0.51

11: 80% CPE / 10% MMA / 10% HPMA 1.14

5: 80% CPE / 20% HPMA 2.03

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Examples 12-14

Example 5 is repeated, using a mixture of stylacrylate (fiAl and methyl methacrylate in the presence of chlorinated polyethylene is polymerized »The yield, based on the monomer mixture and the light scattering is shown in Table 6:

Table 6

Example yield scattering

12: 8G% CPE / 18% MMA / 2% & A 13: 80% CPE / 16% MMA / 4% ÄÄ 14: 80% CPE / 14% MMA / 6%

99 19th 97 21 96 22nd

Examples 15-16

80 parts of a chlorinated polyethylene with a chlorine content of 34%, and a refractive index η of 1.522, produced by chlorinating a low-pressure polyethylene with an RSV value of 1.5 dl / g, v / earth on a mixing roller at 175 ° C with 20 parts Polymethyl methacrylate (n _D = 1.492, weight average molecular weight; 100,000) mixed and pressed to 400 μm thick films. A milky, cloudy film is obtained, the mechanical and physiological properties of which correspond to the graft polymer of the same composition. This mixture can be used according to the invention when transparency is not required. If the polymethyl methacrylate is replaced by a mixed polymer whose index of refraction is matched to that of the chlorinated polyethylene, transparent films are obtained of the homopolymer; 1.5381) mixed with the same chlorinated polyethylene on the mixing roller. The result of these tests is shown in Table 7;

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Table 7

Example Mixture Scatter

15: 80% CPE / 20% PMMA 100

16s 80% CPE / 20% Mipo from 70% MMA 28 and 30% FMA

Claims (3)

Medical devices for liquids to be used parenterally Protection claims: 1. / Medical device that handles parenteral fluids in Comes into contact, characterized in that it consists of a thermoplastic mass of 50-95 parts by weight chlorinated Polyolefin with a chlorine content of 15-45% by weight and • an average molecular weight of 30,000-300,000 and off 5-50 weight re, i3 en polymers of acrylic and / or methacrylic acid esters consists. 2. Medical device according to claim 1, characterized in that it has the shape of a bag or tube. 3. Medical device according to claim 1 and 2, characterized in that that the thermoplastic mass of chlorinated polyolefin, polymers of acrylic and / or methacrylic acid ester and graft polymers of these esters to the chlorinated polyolefin. 7733140 09/21/78