NO168119B - APPLICATION OF AN OLEPHIN POLYMER MIXTURE FOR THE PREPARATION OF A STERILIZABLE FILM FOR THE PREPARATION OF PARENTERAL SOLUTION BAGS - Google Patents

Description

The present invention relates to the use of a polymer mixture for the production of a sterilizable film for the formation of bags for parenteral solution.

Parenteral solutions broadly cover fluid replacements, electrolyte replacements and are carriers for the medication of drugs. Solutions include blood plasma, platelets, red blood cells, kidney dialysis solutions, saline solutions and nutritional products. These solutions were initially placed in glass bottles, but with the introduction of the collapsible parenteral solution bag a few years ago, airborne contamination was significantly reduced because the flexible bags can be emptied without outside air entering the system.

The general requirements for a resin used in the manufacture of the parenteral solution bags include flexibility, clarity, toughness at low temperatures, heat sealability, good workability, resistance to vapor permeability and ability to be sterilized. The industry today uses a highly softened PVC film for this purpose. Although this resin does not satisfy most of the requirements, a material that has little or no plasticizer is preferred. The PVC film is also not very resistant to vapor permeability, and consequently the continuous loss of moisture in the parenteral solutions will reduce their storage time considerably. It is therefore necessary for the bag to be sealed in an outer bag made from a film resin designed to have a lower water vapor transmission rate (WVTR). Currently, the outer bag is made from a mixture of HD polyethylene and butyl rubber and has been extruded to a film of about 0.10 - 0.13 mm thickness to provide the required WVTR. This thickness is usually more than what is needed for physical strength and makes the device more expensive. Another disadvantage of the outer bag resin is that it lacks the desired clarity, which is an important property necessary for easy and correct identification of the contents of the inner bag.

It is therefore an object of the present invention to use a resin formulation or polymer mixture for the production of sterilizable outer bag films with improved clarity and resistance to moisture vapor permeability, for direct and for indirect content of parenteral solutions.

According to the present invention, a polymer mixture comprising

(a) 10-60 wt-# of an arbitrary copolymer of 1-6 wt-56

ethylene and 94-99 wt-# propylene; (b) 40-90% by weight of a linear low density polyethylene prepared by copolymerization of ethylene with at least one C4-C8-α-olefin comonomer and having a density between 0.915 and 0.940 g/cm 5 ; and optionally (c) 2-15% by weight of a high density polyethylene homopolymer

which is at least 0.945 g/cm5 ,

for the production of a sterilizable film for the formation of bags for parenteral solution.

The arbitrary copolymer component preferably has a melt flow in the range between 1.0 and 5.0 g/10 min at 230°C. Such polymers are readily available commercially, and their production therefore need not be discussed.

The linear LD polyethylene component, hereinafter sometimes identified as LLDPE, is an interpolymer of ethylene and at least one C₁-C₂ α-olefin comonomer. The α-olefin comonomer preferably contains 4-8 carbon atoms per molecule. Examples of particularly suitable comonomers are butene-1, pentene-1, hexene-1, 4-methyl-pentene-1, heptene-1, octene-1 and mixtures thereof such as butene-1/hexene-1 and butene-1/ - octene-1, etc. These LLDPE resins can be produced by any of the recently introduced catalytic processes using steam, dissolution or slurry techniques at low to medium pressure or high pressure catalytic polymerization in autoclaves or tubular reactors . The resin preferably has a melt index of from 0.5 to 5 g/10 min at 190°C. A variety of suitable resins are commercially available in the required density and melt flow ranges.

An optional component of the resin composition is an agent which is added in an amount effective to form films of improved clarity. Examples of suitable agents are sodium benzoate, dibenzylidene sorbitol, sorbitan monooleate and others. Generally, the agents are added in amounts between 0.1 and 2 wt-# based on the weight of the total polymers.

As mentioned, 2-15 wt-56 of a HD-polyethylene, i.e. a homo-polymer of ethylene with a density of at least 0.945 g/cm<*> can also be included -in the resin as another possible component for the purpose of increasing heat seal area. This characteristic is defined as the time interval between the minimum time for formation of a good seal and the maximum time before the film burns using a standard heat sealing device.

The polymer mixture used is easily processed into blown or cast film products which, in addition to high clarity, have other desired properties such as flexibility, toughness at low temperatures, heat sealability. The films are also resistant to the permeability of moist steam and can be steam sterilized at 131°C without particularly adversely affecting its physical properties. Finally, the films contain no additives that would prevent their use in connection with food or medicine, either through indirect or direct contact.

When used for an inner container for parenteral solution, the film should have a thickness in the range of 0.076-0.254 mm, while the outer bag need not be thicker than from 0.025 to 0.152 mm. If desired, coextruded films for either the inner bag or the outer bag can be used to reduce loss of moisture or gases through the film walls. Materials such as fluorocarbon polymers, ethylene-vinyl alcohol copolymers and polyvinylidene chloride materials are examples of suitable coextrudates.

Further improvements result from a bag system for parenteral solutions comprising an inner sealed film bag containing the parenteral solution, an outer sealed film bag containing a small amount of water and surrounding the inner bag, the outer bag having a width and a length of 0.635 to 3, 81 cm. larger than the corresponding dimensions for the inner bag.

The small amount of water can be added directly to the outer bag before the sealing operation is performed to enclose the inner bag. Alternatively, the small amount of water is contained in a separate smaller bag made from two layers of film. For economic reasons, one of the films is conveniently made from the same resin as that of the outer bag, while the other layer should be made from a porous material that allows vapor to escape but is resistant to liquid permeability. Suitable materials for this purpose are commercial

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available, e.g. "Tyvek"-spun bonded polyethylenes. Moist steam is thereby allowed to escape from the small bag faster than from the outer bag and thereby provides a saturated atmosphere between the inner and outer bag, which effectively eliminates the driving force for the release of water from the inner bag and which reduces the rate at which which vapor evaporates and leaves the inner bag. The area on one side of the small bag should not exceed approx. 5096 of the corresponding inner bag area.

The appropriate amount of water used to prevent the removal of water vapor from the Inner Bag should be at least sufficient to ensure that liquid water is still present in the space between the Inner Bag and the Outer Bag at the expiration date of the parenteral solution. This amount will obviously vary from case to case and depends on the maximum permissible storage time for the parenteral solution, the size of the outer bag and the water vapor transfer rate through said bag.

It is possible to use materials other than water in the small bag. E.g. a carbon dioxide absorbent material can be sealed in the small bag and aid the removal of carbon dioxide from the inner bag or an oxygen-evolving agent can be added to help supply oxygen to the inner bag and thereby significantly increase platelet storage time. Other materials and gases could also be handled and controlled in this way to improve the system's storage capability.

The use of the small bag inserted in the space between the inner and the outer bag greatly simplifies all packaging operations. Only one film material and thickness would be required for the manufacture and listing of the inner bag for all types of solutions. Furthermore, all outer bags can consist of the same resin formulation and of a film thickness. Only different small bags, which can be identified e.g. by color coding, needs to be added.

In the event that the materials prepackaged in the inner bag are sensitive to ultraviolet light, a small amount of an ultraviolet shielding agent can be incorporated into the outer bag which would prevent U.V. light from reaching the packaged products.

The film produced by the present application of the polymer mixture is sterilizable by means of high-energy irradiation.

Furthermore, one of the bags in the bag system for the parenteral solution can be made from other polymer film mixtures provided that they are sterilizable by means of heat or irradiation and satisfy the general requirements for flexibility, toughness, heat sealability, etc., as discussed earlier.

To further illustrate the invention, the following examples are given:

Example 1

A resin blend containing 84.75 parts LLDPE (copolymer of ethylene and butene-1, density 0.918 g/cmJ , melt index 1.0 g/10 min), 15 parts random polymer of 97 .556 propylene and 2.556 ethylene (density 0.900 g/ m', melt flow 2.0 g/10 min). 0.25 parts of dibenzylidene sorbitol were used in the production of films with thicknesses of 0.064 mm and 0.114 mm. The resulting films had good clarity, toughness, were easily heat-sealable and flexible. The bags were made from these films, filled with water, heat sealed and thrown into the air to simulate a drop of 3.05 m. All bags survived at least 6 drops at ambient temperature (18.3°C). The moisture vapor transmission rate of the films was about 0.7 g/0.025 mm/645.2 cm<2>/24 hours.

Other test samples consisting of 12.7 cm x 27.9 cm inner bags were prepared from the 0.114 mm thick film. These were filled with 1000 cm<3> of water and enclosed in 15.2 cm x 30.5 cm outer bags with a film thickness of 0.064 mm. Part of the samples were supplied with 70 cm<5> of water between the inner bag and the outer bag. All samples passed the steam sterilization test carried out in an autoclave at 121°C for 60 min.

Equally good results were obtained in trials with films made from a resin mixture which was in all respects similar to the previous one except that the LLDPE/copolymer weight ratio was changed from approx. 85:15 to approx. 60:40. The minimum time to achieve a good seal and the maximum time before the film burned through was determined, and the time difference was the seal area. Table 1 summarizes data from these trials.

As can be seen from the results, the addition of small amounts of HD polyethylene greatly increases the heat sealing area.

Peel tests also showed that the seals were significantly stronger with films made from resins containing HD polyethylene as a third resin component. Other film properties were not adversely affected by the inclusion of this material.

Claims (1)

Use of a polymer blend comprising (a) 10-60 wt-5% of an arbitrary copolymer of 1-6 wt-# ethylene and 94-99 wt-# propylene; (b) 40-90% by weight of a linear low density polyethylene prepared by copolymerization of ethylene with at least one C4-C8-α-olefin comonomer and having a density between 0.915 and 0.940 g/cm 5 ; and optionally (c) 2-15% by weight of a high density polyethylene homopolymer which is at least 0.945 g/cm 5 , for the production of a sterilizable film for the formation of bags for parenteral solution.