Containers for parenteral fluids

Surgery – Container for blood or body treating material – or means used... – Bag type

Reexamination Certificate

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C604S416000, C604S408000, C206S219000

Reexamination Certificate

active

06398771

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to flexible polymeric containers with an improved long term storage capacity of such sensitive medical fluids that are intended to be administered parenterally. The containers have ability to withstand several types of final sterilization after being filled with medical fluids and seals, substantially without losing its barrier capacity or any other important characteristics. It comprises an outer sealed airtight envelope and an inner container filled with one or several medical agents which has high compatibility also to stored lipophilic agents.
BACKGROUND OF THE INVENTION
Traditionally, fluids aimed for parenteral administration to the blood stream of patients have been packaged in glass containers. There has, however, been much industrial efforts devoted to find alternative polymeric materials which are less resource consuming, cheaper and more convenient to handle than glass.
As discussed in, for example the International patent application WO 94/19 186 (in the name of Pharmacia AB and Wipak Vihury Oy), it is considerable amount of technical problems that must be solved before a polymeric material with satisfying properties for storing parenterally injectible fluids is obtained. The material and container made thereof should be capable of withstanding different sterilization techniques without losing important characteristics, such as forming both an oxygen barrier and moisture barrier against the environment. They shall be compatible with fluids to be stored, even after a long term storage and even if the fluids contain lipophiic constituents that might lead to migration and dissolution of unwanted compounds from the polymeric matrix. In addition, the materials must be possible to weld together and be printable and maintain their flexibility and other mechanical properties, as well as their aesthetic appearance (i.e. transparency) after the sterilization procedure. It is also an important requirement that such a container shall be sterilized as a final step, after being filled and assembled, to provide the highest possible safety for the patients. It has been found that not even the highly sophisticated multilayer films according to the mentioned WO 94/19 186 will be completely capable of meeting the highly rigorous requirements of keeping an oxygen barrier, when it is desired to store such sensitive fluids as lipid emulsions containing polyunsaturated fatty acids, for such a long time as several months in room temperature after autoclavation in a single package.
However, so far it has not been regarded as possible to obtain all the desirable properties combined in a single material and arrive with a cheap, convenient construction which also is environment friendly and possible to recycle by its manufacturer. For example, in the U.S. Pat. No. 5,176,634 to McGaw Inc., it is disclosed a flexible container having three chambers separated by frangible seals, in which diluents and medicaments are separately stored until the seals are ruptured to mix the contents together for delivery to a patient. if it is necessary to form a sheltering barrier against environmental oxygen for a stored product, this patent suggests the introduction of an aluminum foil as a complement to the multilayered polymeric material of the container. Such a mixture of metal and polymers in the same package, would however not, be desirable from an environmental viewpoint, since a recollection and recycling of the material would be difficult. Furthermore, the U.S. Pat. No. 5,176,634 does not particularly teach containers that can be steam sterilized after their assembly and filling which is a precondition for container systems for long term storage of parenteral nutrients intended to substitute glass bottles. The container disclosed in U.S. Pat. No. 5,176,634 obviously will be less suitable for separate storage of two or more steam sterilized parenteral nutrients.
The U.S. Pat. No. 4,997,083 in the name of Vifor S. A. discloses a flexible three-chamber bag for separate storage of lipids, amino acid and sugar to be mixed within the bag and used parenterally. For the mixing of the ingredients, transfer passages between the chambers are opened from the outside by the user. It is a drawback with this type of containers that the mixing will be relatively slow and complicated, especially if all the chambers are filled to a high degree and liquid must be pushed back and forth through the passages in order to complete the mixing procedure. If the lower mixing chamber is made large enough to comprise the volume of all three constituents during the mixing, the lower chamber must be filled with a large head space which gives disadvantages during the sterilization and storage of the products and leads to a poor utilization of the polymeric packaging material. Furthermore, the polymerized materials suggested to constitute the flexible bag in the U.S. Pat. No. 4,997,083 will not be sufficient to keep the nutrients from oxidative degradation after long term storage.
The International patent application WO 95/26117 in the name of Fresenius A G discloses a more convenient type of multi-chamber bag wherein the partition between the chambers are made by a weak welding possible to rupture to immediately obtain a large mixing cross-sectional area without the risk of tearing away parts of the breakable means. Even if this bag is made of a specifically designed multilayer foil having a sealant layer capable of forming different type of weldings at different temperatures, it will not be able to form a satisfactory oxygen barrier to protect highly sensitive contents during long time storage after autoclavation. Also its construction having filling tubes in the permanent seams sealing the chambers constitutes a risk of leakages and may cause problems if it is desired to have an additional airtight enclosure. This container therefore seems less suitable as a three-chamber container for joint separate storage of lipid emulsion, carbohydrates and amino acid solutions. Moreover, the exemplified incorporation of a paraffin oil in the multilayered material, would hardly be compatible with the storage of lipid emulsion when considering the risk for migration.
Also the British patent specification GB 2 134 067, in the name C. R. Bard Inc., discloses a flexible three compartment package having rupturable seals between the chambers to enable mixing before dispensing of its contents. This package will, however not, for material reasons be suitable for parenteral medical products, such as infusible nutrients.
The U.S. Pat. No. 4,872,553 in the name of Material Technology Engineering teaches a single chamber container made of polymers, suitable for storing an amino acid solution aimed for parenteral nutrition, while the U.S. Pat. No. 4,998,400, assigned to the same company, discloses a method of making such a container. It is disclosed how to fill and seal an inner primary container in an inert atmosphere, whereupon it is enclosed in an outer envelope together with a deoxidizer and autoclaved. The inner container consists of a linear low density polyethylene while the outer envelope consists of a three-layered laminated film formed of an outer nylon layer, a middle layer of an ethylene-vinyl alcohol copolymer and an inner polypropylene layer. Such a material will, however, not be possible to steam sterilize with maintained quality at 121° C., as required by the European Phannacopoeia. However, not even such a container is likely to be entirely successful to provide a barrier for atmospheric oxygen after autoclavation and during long-term storage, up to 12 months or more, of more sensitive fluids, like lipid emulsions based on triglyceridic oils rich in polyunsaturated fatty acids and certain amino acids. The teachings of U.S. Pat. No 4,998,400 indicates that the outer envelope risks to lose important characteristics by the steam sterilization. In one embodiment it is suggested that only the inner container shall be autoclaved. The inner container is thereafter cooled in an inert atmosphere

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