HK1019851B - Improved containers for parenteral fluids - Google Patents

Description

Improved container for storing parenteral fluids

The present invention relates to flexible polymeric containers having improved long term storage capabilities for sensitive pharmaceutical fluids intended for parenteral use. These containers can withstand several final sterilization actions after filling with the medicament fluid and sealing without substantially losing their barrier capacity or other important characteristics. It comprises a sealed airtight outer envelope and an inner container containing one or more pharmaceutical agents, which inner container is also highly compatible with the stored lipophilic agent.

Traditionally, fluids intended for parenteral use into the bloodstream of a patient are packaged in glass containers. However, industry has expended considerable effort in finding alternative polymeric materials that are less resource consuming, less expensive and more convenient to use than glass.

As discussed in international patent application WO94/19186 (in the name of Pharmacia AB and wipak vihury Oy), a considerable number of technical problems have to be solved before a polymeric material for storing parenteral injection fluids with satisfactory properties is obtained. Such materials and containers made therefrom should be able to withstand different sterilization techniques without losing important properties such as forming an oxygen barrier and a moisture barrier to the environment. They should be compatible with the stored fluid, even after long-term storage and even fluids containing lipophilic components which may lead to migration and dissolution of unwanted compounds in the polymer matrix. In addition, such materials must be weldable together, printable, flexible and other mechanical properties can be maintained after the sterilization process, and an aesthetically pleasing appearance (i.e., transparent). It is also an important requirement that the sterilization of the container after filling and assembly should be a final step, providing the most reliable safety for the patient. It has been found that even the complex multilayer film of the above-mentioned WO94/19186, does not fully meet the stringent requirements for maintaining an oxygen barrier when sensitive fluids such as lipid emulsions containing polyunsaturated fatty acids are stored for long periods of time, e.g. several months, at room temperature after autoclaving in a simple package.

However, it has heretofore been thought impossible to achieve all of the appropriate combinations of properties in a single material, achieving an inexpensive, convenient structure that is environmentally friendly and can be recycled by the manufacturer. For example, in U.S. patent 5,176,634 to McGaw inc, a three-compartment flexible container separated by a frangible seal is disclosed wherein the diluent and drug are stored separately until the seal is broken to mix the contents together for delivery to a patient. This patent suggests the introduction of an aluminum foil as a supplement to the multilayer polymeric material of the container if it is desired to form a protective barrier to ambient oxygen for the stored product. Such a mixture of metal and polymer in the same package is however not suitable from an environmental point of view, since the collection and recycling of such material would be difficult. Furthermore, U.S. patent 5,176,634 does not specifically teach that the containers can be steam sterilized after they are assembled and filled, which is a prerequisite for container systems intended to replace glass bottles for long-term storage of parenteral nutrients. The container disclosed in U.S. patent No. 5,176,634 would obviously not be suitable for separately storing two or more steam sterilized parenterally-used nutrients.

Us patent 4,997,083 in the name of Vifor s.a. discloses a flexible three compartment pouch for separate storage of lipids, amino acids and sugars to be mixed in the pouch and used parenterally. To mix the components, the user opens the transfer channel between the chambers from the outside. This type of container has the disadvantage that mixing is rather slow and complicated, especially if all chambers are filled to capacity, and the liquid has to be squeezed back and forth through the channels to complete the mixing process. If the low mixing chamber is made large enough to contain the volumes of all three components in the mixing, the low chamber must fill a large front space, which is disadvantageous during sterilization and storage of the product and results in a low utilization of the polymer packaging material. It is also suggested in U.S.4,997,083 that the polymeric material from which the flexible pouch is constructed will not be sufficient to avoid oxidative degradation of the nutrients after prolonged storage.

International patent application WO 95/26177 in the name of Fresennius AG discloses a more simple multi-compartment bag wherein the barrier between the compartments is made by a weak weld which can be broken immediately to obtain a larger cross-blend area without the risk of tearing the frangible tool portion. Even if such a bag is made of a multilayer film of a particular design and having sealing layers that can form different types of welds at different temperatures, it does not form a satisfactory barrier to oxygen after autoclaving to protect highly sensitive contents during long periods of storage. The construction of the filling ducts in the permanently bonded layer between the closed chambers constitutes a risk of infiltration and may cause problems if it is desired to have an additional hermetically sealed outer envelope. Thus, as a three-compartment container, such a container does not appear to be well suited for separate storage of the lipid emulsion, the carbohydrate solution, and the amino acid solution. Furthermore, the addition of liquid paraffin to the multilayer material will be hardly compatible with the stored lipid emulsion when considering the migration risk.

British patent specification GB 2134067 in the name of c.r.bard inc. discloses a flexible three-compartment packaging bag having a rupturable seal between the compartments so as to enable mixing prior to dispensing the contents. However, such a package would not be suitable for parenteral medical products, such as infusion nutrients, for material reasons.

US patent 4872553 in the name of Material Technology Engineering teaches a single compartment container made of a polymer suitable for storing an amino acid solution for parenteral nutrition, and US patent 4998400 assigned to the same company discloses a method of making such a container. It discloses how to fill and seal the inner primary container in an inert atmosphere, after which it is wrapped in an outer envelope together with an oxygen scavenger and then autoclaved. The inner container consists of a linear low density polyethylene and the outer envelope consists of a three layer laminate film: an outer nylon layer, an intermediate ethylene vinyl alcohol copolymer layer, and an inner polypropylene layer. However, such a material cannot be steam sterilized at 121 ℃ while maintaining quality, as specified in the european pharmacopoeia. Even such containers have not been entirely successful in providing a barrier to atmospheric oxygen, such as lipid emulsions having relatively high concentrations of triglycerides in polyunsaturated fatty acids and certain amino acids, after autoclaving to more sensitive fluids and during storage for periods of 12 months or more. The teaching of US 4998400 shows that the sterilization of the outer envelope with steam risks losing important features. In one embodiment it is suggested that only the inner container should be sterilized by high pressure steam. The inner container is then cooled in an inert atmosphere and finally wrapped with an oxygen impermeable envelope. Such a procedure is entirely unsatisfactory, since it is appropriate, from a reasonable point of view, to sterilize the final filled and assembled containers. In another embodiment it is suggested to autoclave the finally assembled and sealed container. However, in order to maintain the oxygen barrier after autoclaving, a special drying process must be introduced to remove the moisture absorbed from the outer envelope.

Another flexible multi-chamber bag for storing oxygen sensitive reagents was recently disclosed in european patent application EP 0639364 by Otsuka pharm. The bag is preferably used for compartmentalized storage of a medicament consisting of a degradable powder and its diluent. An oxygen-barrier envelope surrounds the chamber filled with the oxygen-sensitive powder, the envelope being sealed by welding to the bag under a controlled atmosphere. One disadvantage of the containers exemplified in the application is that they may not withstand autoclaving after final assembly.

Clearly, the construction of flexible multicompartment containers intended to replace glass bottles for the storage of parenteral nutrients, such as lipid emulsions, is a highly complex development process. The ability of the material to be autoclaved and to retain its properties, the ability to provide a barrier to ambient oxygen and water vapour must be carefully considered, while it must be easy to process into functional multi-compartment containers, for example with the usual welding techniques, and follow the requirement that it can be recycled and recycled in a single and simple process. For the part of the container that comes into contact with the depot, often a lipophilic substance, it is required that the potentially harmful substance must not be allowed to migrate into the parenteral product. Polymers commonly used in pharmaceutical packaging, like polyvinyl chloride (PVC) and other polymers containing migrating plasticizers, therefore cannot be considered. However, these polymers have a higher oxygen permeability than glass bottles, which makes them unsuitable for the long-term storage of particularly sensitive fluids. Moreover, such materials must have a transparent, aesthetically appealing appearance, and not be destroyed after sterilization and storage. Furthermore, such materials must be printable with instructions and loading levels without printed ink migration. It is also important that the material retains all mechanical properties, such as flexibility and strength, after sterilization if sterilized with steam or radiation alone. In addition to these important material properties, when considering the manufacture of the container and the use by the user in the patient's home or hospital, the container must be convenient to use when mixing the preserved products and must provide a high degree of safety for the patient.

It is an object of the present invention to provide a flexible container consisting essentially of a polymeric material and having improved barrier to ambient oxygen and moisture, which is also capable of withstanding sterilization by high pressure steam and radiation methods, and which does not substantially lose any barrier and other important properties, including flexibility and clarity, so that even highly oxygen sensitive stored reagents can be stored for long periods of time and maintain their integrity.

It is also an object of the present invention to provide a container for long term separate storage of agents which are easily spoiled when stored together in their final parenteral form of use and to provide such a container with a means for sterile mixing of the agents in the container into an injectable fluid.

It is a particular object of the present invention to provide such a container for separately storing parenteral nutrients, i.e., a lipid emulsion, a carbohydrate solution and an amino acid solution, and then mixing the nutrients into a homogeneous fluid nutrient mixture just prior to parenteral use.

Another particular object of the invention is to prolong as far as possible the storage time of sensitive fluids intended for total parenteral nutrition in cold and room temperature to overcome the problem of short shelf life of these products.

It is a further object of the present invention to provide a container having the capability of separately storing several components filled in a manufactured inner container with a minimum number of potential leak sites

It is another object of the present invention to provide such containers which are safe and convenient to use, minimizing the risk of misuse and contamination during all steps of parenteral use of the fluid which are required to obtain a predetermined performance.

Another object of the present invention is to provide such containers which are inexpensive and environmentally friendly, and which are mostly made of polymeric materials that can be recycled and recycled together without the need for cumbersome disassembly of the different parts of the container.

It is a further object of the present invention to provide a method of preparing such filled containers which are sterilized as a final step after assembly and filling, wherein the filling is performed in a manner which avoids permanent potential leakage through the filling holes.

These objects of the invention, as well as other obvious advantages shown herein, are also achieved by the appended claims.

The container of the present invention is a parenterally applicable agent intended to improve the sensitivity of storage of oxygen and generally comprises an inner main container enclosed in a substantially oxygen-impermeable outer envelope together with an oxygen absorber capable of consuming substantially all the residual oxygen after sealing of the outer envelope and the oxygen permeating through the envelope for a sufficient period of time. The inner container and the wrapped outer envelope are both made of a flexible and transparent polymeric material. The inner container is composed of a flexible polymeric material containing polypropylene which is compatible with lipophilic agents and capable of forming a permanent and peelable seal, and the outer envelope is composed of a substantially water impermeable flexible multilayer polymeric material comprising a first substantially water impermeable outer polymeric sheet having oxygen barrier capability in combination with a second inner polymeric sheet having supplemental oxygen barrier capability. An important feature of such assembled containers is that the oxygen and moisture barrier and the transparency and flexibility characteristics are substantially maintained after being subjected to steam or radiation sterilization.

The inner container may be a single or multi-compartment container containing one or more reagents for parenteral use. In a particularly important embodiment of the invention, the inner main container is divided into two or more compartments by one or more leak-free sealing layers, which can be broken by hand from outside the container when the contents of the compartments are to be mixed into a homogeneous fluid and administered to a patient by infusion or injection. For this reason, the inner container is provided at the bottom with a fluid-communicating channel through which the mixed product is made available, through which other additional reagents can be supplemented into the mixed product or into the reagents stored in the lower compartment. The channel may be connected to conventional injection devices and other devices for parenteral use, and preferably has separate channels for the introduction and collection of fluid agents. Both the inner container and the sealing envelope are made of a particular selection of polymeric materials, which will be described in more detail below. As will also be explained in more detail below, the envelope is ultimately sealed in a protective atmosphere, placing an oxygen scavenger in the space between the envelope and the inner container.

The reagents stored in the containers of the present invention are preferably oxygen sensitive fluids or powders that would otherwise lose activity or suffer degradation during long term storage. Examples of such agents are parenteral nutrients such as lipid emulsions containing oxygen sensitive polyunsaturated fatty acids, amino acids containing sensitive amino acids like cysteine, and many pharmaceutical agents which are inactive when stored in dissolved or diluted form and therefore have to be stored as solid powders (freeze-dried) or as concentrates separate from diluents. Another example of agents that may benefit from being stored in the containers of the present invention are those that must be stored separately during heat sterilization, such as carbohydrate solutions and amino acid solutions, which may form a discolored complex when brought together.

The multi-compartment container of the present invention is prepared according to a conventional method in which a pouch-shaped sealed inner container is formed of a flexible polymer material by fusing together a polypropylene-containing sealant layer. At least two sealed chambers are formed by welding at least one sealing joint layer which is peelable and can be broken by hand outside the container. One side of the container is provided with a temporary opening to fill the parenteral fluid chamber, and the temporary opening is then closed again by a welded permanent bonding layer. The filled and sealed inner container is enclosed with an oxygen absorber in an oxygen barrier envelope which is sealed by welding in a controlled atmosphere. The finally assembled container is sterilized with steam or with radiation.

The following detailed description is intended to describe preferred embodiments and specific examples of containers and methods of manufacture in accordance with the invention, while indicating suitable alternatives. These examples are not intended to limit the scope of the invention, which is outlined by the appended claims.

Figure 1 diagrammatically shows a plan view of a container according to one embodiment of the invention.

FIGS. 2a and 2b schematically show examples of two peelable sealing bonds according to the present invention.

As discussed above, there are several important requirements for a material suitable for the inner container. It must be a polymer material that is autoclavable or radiation sterilizable and compatible with the stored product. The material must be capable of being permanently welded to the bag and to other polymer details, such as the saddle channel system referred to, while also forming a rupturable peel seal bond from improved welding conditions as compared to forming a permanent bond layer. Furthermore, such materials should be environmentally friendly and recyclable in a simple manner. The material should be substantially impermeable to water vapor during steam sterilization, but need not be impermeable to air when an outer sealing envelope is used in conjunction with an oxygen remover. It would be an advantage if the material allowed for mass transfer of oxygen such that the oxygen remover could consume most of all of the residual oxygen dissolved in the stored fluid. If the containers are sterilized by irradiation according to international patent application PCT/SE95/00684, residual oxygen dissolved in the polymer network of the material of the inner container must also be removed. The material must have a suitable aesthetic appearance and be clear and transparent and not prone to discoloration or opacity after sterilization. Finally, the material must retain its flexibility and not become brittle or brittle after sterilization and storage.

The polymer for the inner container having all the above-mentioned properties is preferably a flexible film having a region with a higher melting point as an outer layer and a region with a lower melting point as an inner sealing layer, which can be welded together with usual welding means to a permanent or peelable sealing seam. It will be appreciated that the inner layer is reagent-storing facing and can form a permanent bond and a distinct peelable sealing bond when subjected to different welding conditions and operations.

Preferably the film is composed of at least two different polymer layers, wherein at least one of the inner sealant layers is based on a polyolefin, such as polyethylene or polypropylene which is chemically inert to the stored fluid, autoclavable, weldable and recyclable. "polyethylene" and "polypropylene" are meant to include homopolymers and copolymers having the above characteristics, unless otherwise indicated. Preferably the sealing layer is polypropylene based, including propylene and ethylene copolymers and/or blends of polypropylene and polyethylene.

However, since the usual polyolefins, in particular polypropylene, are often not sufficiently flexible and are somewhat brittle, it is advisable to blend them with polymers having elastic properties. In one embodiment of the invention it is therefore preferred to blend the polypropylene with an additional elastomer to increase its flexibility and elasticity. The elastomer may constitute a contiguous layer of film or be mixed with polypropylene in a sealing layer. It is preferred for the multilayer material to have an inner sealing layer consisting of a high content of polypropylene to facilitate inertness to the stored fluid and to facilitate the manufacture of the container by means of different welding techniques. It is particularly preferred that the layer is capable of forming an air-tight, but controlled rupture, peelable, sealed joint and a permanent, highly consistent sealed joint at a predetermined temperature when welded together under different conditions, such as different welding temperatures or welding pressures. It is also desirable to introduce a flexible polymeric material having a high melting point that provides the material with greater stability at high temperatures local to the welding process. If such a material constitutes a multilayer film, it should be placed on the outer layer of the release layer and, in addition, be easy to print without migration of the printing ink. Suitable materials can be found in certain polyesters and their copolymers (copolyesters) and especially cycloaliphatic polyesters.

One preferred material for the inner primary container is composed of a multilayer film comprising a) an outer layer comprising copolyester, b) a sealing inner layer comprising polypropylene, a propylene ethylene copolymer or a mixture of polyethylene or polypropylene, c) an inner layer comprising a thermoplastic elastomer. In such a film, the sealing layer may also comprise a thermoplastic elastomer, which may be a styrene-ethylene/butadiene-styrene block copolymer (SEBS) or other suitable elastomer having the properties described above in place. One material that has proven particularly suitable for this type of inner container is Excel , manufactured by MaGaw inc, which is a multi-layer structured polymeric material about 200 microns thick, as described in european patent EP 0228819. Excel  has a multilayer structure, consisting essentially of: a) a sealed inner layer consisting of polyethylene/polypropylene copolymer (FINA Dypro Z9450) and Kraton  G1652 (a copolymer of styrene/ethylene/butadiene/styrene (SEBS)) from Shell towards the medical fluid; b) a pure intermediate tie layer of Kraton  G1652; and c) Ecdel  9965 (or 9566 or 9967) by Eastman Chemical Co. the external release layer is a cycloaliphatic thermoplastic copolyester (a copolyester ether, the trans isomer of 1, 4-dimethyl-cyclohexanedicarboxylate, the condensation product of cyclohexanedimethanol and hydroxy-terminated polytetramethylene glycol).

The inner sealant layer comprises a blend of 80% polyethylene and polypropylene copolymer and 20% elastomeric SEBS copolymer with minor amounts of additives of antioxidants and deacidification agents. The copolymer of polyethylene and polypropylene forms an interpenetrating network with the SEBS copolymer which provides a strong seal. The mixture itself seals over a wide temperature range and is capable of forming peelable sealing joints of varying strengths when welded at a temperature selected from between about 85 ℃ and 120 ℃. Welding at about 110-120 ℃ has been shown to form peelable sealing joints that are easily broken by hand. It also provides a suitable vapor barrier and withstands both chemical and physical testing satisfactorily, as shown in the examples section below. The middle layer contained only the highly flexible copolymer Kraton  and a small amount of antioxidant. It imparts elasticity and impact strength to the film. The outer layer of Ecdel  is flexible and printable, with a higher melting point of 200 ℃, which gives the assembled film better welding ability. When using Excel  as the material for the bag-like inner container, it is preferred that the saddle channel system attached to the sealing layer also comprises polypropylene, preferably a mixture of polypropylene and Kraton  which is weldable to the inner layer of Excel  film. A suitable blend is about 60% polypropylene and 40% Kraton . Preferably, a saddle-shaped channel system is used as disclosed in Swedish patent application 9601540-9 in the name of Pharmacia AB.

The inner container made of the preferred Excel  film has excellent performance in being autoclaved with commonly used parenteral nutrients. In addition, surprisingly Excel^The film and the lipophilic fluid are compatible. Even if the inner layer consists of a physical blend of polypropylene and SEBS polymer, it involves placing it in pure soybean oil (commercial lipid emulsion Intralipid @^Major lipid component) has not had any reason to suspect migration of potentially toxic agents. However, it has a relatively high oxygen permeability of about 1000 to 1600 cc/sq.atm.day, and it must incorporate an outer surrounding sealed envelope and an oxygen absorber in order to meet the requirements for long-term storage of lipid emulsions and primary amino acid solutions when measured at a specific temperature of 25 ℃ and a relative humidity of 60%. Even though the inner container made of Excel  constitutes a suitable embodiment of the invention, others are based within the scope of the inventionFilms of polyolefins must also be considered as an option for conceivable use if they meet the above-described requirements. It is therefore an important alternative to provide an inner container having a flexible transparent film highly compatible with lipophilic fluids, the film consisting of one or several layers substantially comprising only or completely comprising one or more polymers selected from the group consisting of polypropylene, copolymers of propylene and ethylene, blends of polypropylene and polyethylene. For example, a multilayer construction film material comprising an inner seal layer such as a propylene ethylene copolymer and an elastomer, such as SEBS polymer, is an alternative material for attachment to a corona discharge treated printable outer layer of virgin polypropylene. Films consisting of an inner layer of ethylene-containing polypropylene bonded to a pure corona discharge treated polypropylene layer with a regularity modified polypropylene (e.g., Rexflex  from Rexene or Dow) are another possible option, films incorporating both pure polypropylene with improved elasticity and printability due to modification in their molecular configuration or due to physical processing. For example, with metallocene-based catalysts, a high degree of control of the stereoregularity of the polypropylene chains can be obtained, as described in Macromolecules, Vol.28, 1995, pp.3771-3778: w J Gauthier et al. This can have a large impact on the physical properties of the material and result in highly flexible or highly elastic polypropylene, which can be included as a future replacement for Excel . All these polypropylene-based materials should be considered as alternative embodiments for the inner container material if they meet the requirements set out above.

As discussed for the choice of material for the inner container, the material of the peripheral envelope must meet a number of requirements to replace the glass bottle. Most importantly, it must provide a high barrier to ambient oxygen. The allowable oxygen ingress, when tested at a specific temperature of 25 ℃ and a relative humidity of 60%, is preferably less than 30cc/m²Atmospheric pressure day more preferably less than 15cc/m²Day at atmospheric pressure, most preferably less than 515cc/m²Atmospheric pressure day when tested under the same conditions. It must be autoclavable for at least 30 minutes at 121 ℃ and also have the ability to withstand radiation sterilization for use in existing aseptic packaging techniquesThe operation base is improved. Conventional aluminum foil can meet these requirements, but it has the disadvantage of being opaque so that the integrity of the storage material and, for example, oxygen indicators, cannot be visually observed. Furthermore, the envelope material must be strong and flexible, have a low environmental impact and contain only additives that are not susceptible to contamination by migration or to affecting the stored substance. Polyvinylidene chloride also meets oxygen barrier standards, but it is not steam sterilizable nor environmentally benign. As discussed previously in international patent application WO94/19186, it was attempted to construct multilayer structured films for packaging and autoclaving of parenterally applied agents. The film is intended to maintain the oxygen barrier capability of a polyethylene-vinyl alcohol (EVOH) layer by adding a water-resistant and moisture-absorbing outer layer structure during steam sterilization to protect the EVOH layer. Unfortunately, even such multilayer-structured films do not maintain a satisfactory oxygen barrier for a long time after autoclaving. It is therefore highly desirable to improve the film by incorporating into the EVOH layer a protective structure that is not only vapor impermeable but also advantageously oxygen barrier.

According to the present invention, it has surprisingly been found that if a first outer polymeric film having oxygen barrier properties, which is substantially water impermeable, is combined with a second inner polymeric film having a relatively higher oxygen barrier properties at a temperature of 25 ℃ and a relative humidity of 60%, a multilayer structure material suitable for forming an outer sealing envelope for a container according to the invention can be obtained, which is capable of maintaining, for example, less than 5ml oxygen/m at normal relative humidity²Atmospheric pressure. The daily high barrier to oxygen, even after autoclaving, still meets the requirements set above.

Preferably the outer film comprises a metal oxide coated polymer layer attached to a second inner film comprised of a polymer layer that forms a barrier to oxygen. The outer film preferably comprises a metal oxide, such as silicon oxide and/or aluminum oxide and/or titanium oxide and at least one polymeric material, while the inner film preferably comprises an EVOH layer. The outer film preferably comprises a layer of metal oxide coated polyethylene terephthalate and the inner film comprises at least one layer of polypropylene. The outer film may include a second layer of polyethylene terephthalate. In this case, the first outer polyethylene terephthalate layer is coated on one side with a metal oxide which is bonded to the second layer of polyethylene terephthalate PET. According to another case, both sides of the PET layer are coated with metal oxide. The outer film may suitably comprise a polyethylene terephthalate layer coated with a metal oxide of about 10 to 30 μm, preferably about 25 μm thickness, bonded together with an inner film of about 50 to 200 μm, preferably 100 μm thickness, in a conventional manner to obtain a multilayer material of PET-metal oxide/glue/polypropylene/tie layer/EVOH/tie layer/polypropylene main structure, the inner film preferably comprising an EVOH layer bonded together with a surrounding polypropylene-based layer (consisting of polypropylene, different propylene and ethylene copolymers or mixtures thereof). Such a material would provide an oxygen barrier EVOH layer with an effective protective barrier against moisture permeation through polypropylene during steam sterilization and storage that would otherwise destroy the subsequent barrier capability. At the same time, the glassy outer layer film is beneficial to oxygen barrier. Inorganic glassy metal oxides comprise a thin layer of metal oxide of thickness of about 200 to 1200A and are deposited on smooth polymer surfaces by conventional techniques, as described in european patent specification EP 0460796(e.i. du Pont De Nemours & Co.), wherein suitable PET-glass films are disclosed. The metal oxide can also be deposited on both sides of the film or another layer of PET is added, thus obtaining a film of glass-PET-glass-glue/polypropylene/EVOH/polypropylene or PET-glass/glue/PET/polypropylene/EVOH/polypropylene structure.

The glue used to bond the two films together is of a type that has a suitably low tendency to migrate, which is commonly used in adhesive bonding of multilayer polymeric structures. One particularly suitable film is composed of PET-alumina/glue/PET/glue/polypropylene/tie/EVOH/tie/polypropylene. In the examples section that follows, it is shown to have excellent performance in forming a protective outer envelope for the container to safely store parenteral nutrients.

The oxygen absorber of the present invention is preferably iron which contains water and is water dependent when consuming oxygen, as in the international patent application PET/SE95/00684(Pharmacia AB). The oxygen absorber, preferably iron, can also consume a certain amount of hydrogen sulfide degraded from sulfur-containing amino acids, such as cysteine containing essential amino acids in the storage solution, as discussed in german patent DE 4233817. The oxygen absorber should be able to withstand without damage either the steam sterilization or the radiation sterilization process. The oxygen absorber can be present in the container as a pouch or mixed together as part of the multilayer structured film. When closed under a controlled atmosphere with a surrounding closed envelope, it is preferred to use an oxygen absorber containing a ferrite removing component in the form of one or several sachets or trough-like carriers placed in the vicinity of the saddle-shaped channel system of the inner filling vessel. For the preferred type of oxygen absorber, it is therefore important that a source of water be present, either in the oxygen scavenger component or in the space where the oxygen absorber should function. Certain oxygen absorbers require an atmosphere of at least 80% relative humidity (25 ℃) for maximum activity, and therefore require high humidity in the space sealed between the inner container and the envelope to ensure proper function (typically greater than 60% in the present container). Such humidity dependent types of oxygen absorbers are preferred according to the present invention. When designing the container of the present invention, the skilled person will have no difficulty in obtaining the appropriate amount of the appropriate oxygen absorber. When values are given such as the volume of the container storing the substance and the barrier capacity to oxygen surrounding the envelope, an estimation of the necessary properties and contents can be easily made on the basis of its pre-determined oxygen consumption capacity. For example, if the total capacity of the oxygen absorber is at least 100 ml of pure oxygen, if the envelope is made of a material having an oxygen permeability of no more than 5ml oxygen/m at normal relative humidity²Atmospheric pressure day of material composition, this value must be higher than the amount of oxygen expected to permeate a given area of the envelope over a certain period of time. An example of a suitable oxygen absorber according to the invention is Ageless  FX 200 PA from Mitsubishi.

In the particular example embodiment shown in fig. 1, the container has an outer sealed envelope 10 and an inner three-compartment container 30 filled with three different parenteral fluids. In the space between the envelope and the inner container an oxygen absorber 20 is placed. Optionally, an oxygen indicator that would indicate inadvertent permeation of oxygen from the fracture, an indicator that indicates proper sterilization and other conditions, may also be placed in the space. Of course, these indicators can withstand steam or radiation sterilization processes and must not cause migration of toxic or potentially harmful substances into the stored product.

The inner container shown in fig. 1 is bag-shaped and is provided with three parallel chambers 31, 32, 33, which may have the same or different volumes, depending on the intended amount of product to be stored. The inner container is shown with a handle portion 34 at the upper portion to facilitate conventional hanging use. At the bottom a channel system 35 is provided, which may be a saddle-shaped channel of conventional shape, which is welded to the container material during the manufacturing process. The preferred channel system is designed to be more easily sterilized and is described in a similar, but as yet unpublished, swedish patent application.

The channel system has an outlet channel 36 through which fluid can be delivered to a patient in need of fluid treatment using conventional infusion devices, but a more detailed discussion of conventional infusion devices is not intended. Additional reagents may be added to the container fluid at any desired time via channel system inlet 37. These agents are typically additional drugs or nutrients or micronutrients that can be stored with the container fluid.

In this embodiment, the three chambers 31, 32, 33 are filled with three different parenteral nutrients in fluid form, which should be mixed together uniformly to form a Total Parenteral Nutrient (TPN) solution just prior to their use in a patient. To allow for free mixing, the chambers are separated by a junction layer that is easily ruptured by the user outside the container. The two joined layers 50, 50' of the compartment are generally formed by peelable seal fusion in the container, which is highly hermetic but can be broken by the deliberate action of the user. Peelable seals or weak welds are well known in the art of prior polymer processing and are described in more detail in US patent 5128414 or european patent specifications EP 0444900 and EP 0345774 (which are incorporated herein by reference) with respect to the conditions and characteristics of formation. One particularly preferred container configuration for a peelable heat seal tie layer suitable for the present invention is discussed in more detail below.

In the embodiment of the container according to FIG. 1, one compartment is a carbohydrate solution containing glucose, one compartment is a lipid emulsion typically containing 10-30% by weight of lipids, such as Intralipid  manufactured by Pharmacia AB, and one compartment is an amino acid solution (including the necessary amino acids, if appropriate), such as Vamin  manufactured by Pharmacia AB. These parenteral nutrients and suitable additives for obtaining total parenteral nutrients and/or supplemental medication are described in more detail in other documents, such as european patent application 0510687 to Green Cross corp, which is incorporated by reference in its entirety. When clinically appropriate, any of the three nutrients may contain other ingredients such as trace elements, electrolytes, vitamins, energy substrates, supplemental therapeutic agents and agents to maintain the metabolism of the above nutrients. However, each component must be carefully analyzed and stored in the chamber to maintain integrity and to minimize the impact on the selected nutrients.

The designation of chambers 31, 32, 33 for the nutrients mentioned above is made after careful consideration of convenience and safety. For this reason, it is preferable that the amino acid solution or the lipid emulsion is stored in the lower chamber 33 because if the user fails to properly perform the mixing process for some reason, the input of pure amino acid solution or lipid emulsion has little influence on the patient, and the input of pure glucose solution may cause unexpected side effects, for example, if the patient suffers from complications of diabetes. Therefore, it is preferred that the upper chamber 31 be filled with a carbohydrate solution, which is also advantageous in view of the relatively large volume of carbohydrate that is able to exert sufficient pressure to rupture the upper peelable sealing tie layer 50 when mixing the nutrients.

According to one embodiment, the middle chamber 32 contains a lipid emulsion because it can act as a visually observable indicator of cracks if cracks occur in the sealing interface between the chambers during storage, while the lower chamber 33, facing the channel system, is designated to store the amino acid solution. As another embodiment, the lower chamber 33 may store a minimum volume of lipid emulsion, which will allow the filling chamber to have the same shape of volume extension and heat penetration during the steam sterilization period to achieve the same temperature in the three chambers.

However, in certain applications, the ease of fluid mass transfer by rupturing a peelable sealing bond to open the chamber is a priority. For example, it may be desirable to have the largest fluid volume component designated in the upper chamber to facilitate its mass to rupture the peelable sealing interface layer regardless of the contents of the chamber. It is understood within the scope of the invention that other chamber configurations are possible instead of the parallel chambers shown in fig. 1.

In addition to parenteral nutrients, a wide variety of other parenterally useful products may be stored in the container of the invention, and when suitable for stability, the products in solid powdered or freeze-dried form may be stored with diluents and other parenteral fluids.

The container of the invention is preferably made by the method of the invention wherein a flexible polymeric multilayer structure material is added at the bag forming station where the bag-like closed inner container is formed by welding together sealing layers of material comprising polypropylene, optionally at least two compartments are formed by welding at least one peelable seal joint at a relatively low temperature. During the bag forming process, one side of the inner container is provided with at least one temporary hole, and then the inner container is filled with at least one parenteral fluid through the temporary hole. The temporary hole in one side of the inner container may then be sealed by a welded permanent joint. The filled and sealed inner container is enclosed in an oxygen barrier envelope together with an oxygen absorber, and finally the sealed container is sterilized.

Preferably the polymeric material of the inner container is formed from a flexible sheet of predetermined, appropriate size when introduced into the process of making the bag. The foil is first combined with a sealed channel system for fluid transport, preferably of the saddle type described above, and the channel system is then fused to the foil. When the channel system is combined, the foil may first be pierced with a suitable tool, whereby one or several apertures corresponding to the channels of the channel system are formed in the foil. Preferably two such apertures are prepared to correspond to one outlet and one inlet channel.

The pouch-sealed inner container, which has two identical sides, a bottom, a top and two sides, is formed at the bottom with the associated channel system by welding together sealing layers of material containing polypropylene with conventional tools, thereby forming two side joints and a top joint.

Although the bag forming process described above is preferred according to the invention, it is possible (and considered part of the invention) in some applications to prepare it additionally starting from a brown-coloured tube parison of polymer material, at the top and bottom of which a permanent sealing joint is formed by welding, in which joint a system of channels is provided. The filling channels of the chambers must therefore be connected during the welding process described above. This type of manufacturing process is suitable for the preparation of inner containers having one or two compartments, but less suitable if three or more compartments are preferred. Alternatively, the manufacturing process may start with two sheets and four bonds around to weld the two sheets together to form a bag-like inner container with a sealed channel system for fluid exchange welded in the bottom bond. Such an inner container may be provided with a peelable sealing joint layer and additional temporary filling channels between the storage compartments, as disclosed below.

If two or more chambers are desired for separate storage of two or more reagents, at least one layer of a hermetically peelable sealing joint is formed as a barrier layer between the chambers of the inner container, which can be ruptured by hand in a predetermined manner. Such a peelable seal bonding layer may be made by welding at a lower temperature than the permanent welds previously described. As will be discussed in more detail below, the peelable sealing tie layer may be prepared with a specifically designated area to obtain an initial rupture point for easy manual opening when it is desired to mix stored substances in the container.

In order to be able to fill the inner container, at least one temporary filling channel is provided on the side of the bag-like inner container, which is subsequently sealed with a permanent weld seal after the filling has been completed. The filling process is preferably carried out under a controlled atmosphere and blown with an inert gas (e.g., nitrogen or helium) to remove air from the inner vessel.

According to a first embodiment of the manufacturing method, one or several special temporary filling tubes destined for one or several fluid agents are attached in the joining layer of the inner container during the welding process. The chamber may then be filled with one or more parenteral fluids via a temporary fill tube, and the junction of the fill nozzle of a conventional filling apparatus is then closed. After filling, the side of the filling tube provided with the connection in the joint is cut off and subsequently reclosed with a permanent welded seal.

According to a second embodiment of the manufacturing method, one side of the multi-chambered inner container is sealed with a weak weld, which can be broken with a filling device in order to form at least one temporary hole in the side joint. The weak side joins are preferably welded, and two sleeves are formed from the edges of the sheet outside the weak joins so as to enable the filling device to open the joins by peeling. For example, the filling device may be provided with one or several twistable rods connected to one or several filling nozzles introduced from the side of the inner container, which open the seal by a peeling action, preferably in a controlled atmosphere in combination with blowing in an inert gas, as mentioned above. After filling, the filling nozzle is removed and the sides of the inner container are resealed with a permanent weld seal. Another method may be used to open the peelable bond to form a temporary tunnel for filling. For example, the filling nozzle may provide the stripping tool in the form of a protruding member that may perform a twisting, stripping action. After filling and removal of the filling nozzle, the inner container sides are welded and sealed with a permanent joint.

According to a third embodiment, at least one filling channel is formed in the container side junction, the shape corresponding to the filling nozzle of the filling device, so as to provide a sealed connection between the channel and the nozzle during filling. Such a filling channel may be formed by the flexible material being directly formed into a channel corresponding to the shape of the nozzle or by attaching a separate channel to the side of the inner container when forming the side joint.

The degree of filling or headspace in each chamber must be carefully controlled. It is desirable that the filling degree of each chamber is, if not the same, at least comparable, which is advantageous for obtaining the same heat penetration of the filled product during the heat sterilisation period. When considering the filling level, it must be taken into account that the large space in the front due to the low filling level will lead to partial disintegration of the sensitive lipid emulsion if the container is inadvertently shaken during use; the small space in the front part caused by a high filling level will lead to difficulties in reading the correct amount of fluid in the container.

The fully assembled and filled inner container is enclosed in an envelope forming a barrier to oxygen together with an oxygen absorber and optionally one or more visual observation indicators. The final assembled container can now be sealed by permanently welding the envelopes together in a controlled, inert (if desired) atmosphere handling tool. The containers are now sterilized with steam (high pressure steam) at about 120 c or by gamma-ray. The described manufacturing method of the invention is advantageous in the industrial preparation of parenteral products, minimizing the use of a controlled atmosphere and the use of inert gases to be reduced to one step in filling the inner container, which greatly saves resources and ensures a simplified production process. Furthermore, the use of temporary holes in the sides of the container for filling minimizes the risk of leakage that has traditionally been experienced when incorporating permanently affixed filling channels. Such filling also benefits smaller closed envelopes and shorter autoclaving processes.

The peelable sealing engagement described above, as a sealing barrier between the compartments during storage of the container, must be easily manually openable by the user from outside the container in a simple predetermined manner, preferably without the need to remove the sealing envelope. According to the invention, the peelable sealing joint is preferably a straight joint with a rupture zone.

According to the embodiment shown in fig. 2a and 2b, the rupture zone of such peelable sealing engagement comprises two points where straight engagements meet at an angle. A small or acute angle will easily break when used, but at the same time it creates a risk of unintentional opening when the container is used. Such joining would enable the breaking or peeling process to proceed surprisingly easily by concentrating the opening force at a single point at a joint angle, and then enabling easy peeling. In contrast, a very large angle makes the joint difficult to open. It is desirable to have an optimum angle that gives the initial resistance to opening engagement but provides a decreasing resistance as fluid enters between the sheets and separates them as opening progresses towards the sides of the container. When there is a sufficiently large angle, the opening force and the foil will become almost perpendicular to the engagement, which facilitates the opening process. A too small angle may also result in holes appearing in the joint, but the joint cannot open further, because the lines of force at the opening point are in a tangential direction, not contributing to opening of other partial joints. For the embodiment of fig. 2a and 2b and the same shape of the joint, the angle of the joint (or in the projection of the joint when the joint is curved) is at least 90 °. Preferably, the angle is less than about 170 deg., and more preferably, from about 110 deg. to about 160 deg.. According to particularly preferred embodiments, the angle is between about 120 ° and about 140 °, and according to a preferred embodiment of two experimental runs the angle is about 120 ° or about 140 °. The two rupture zones shown in figures 2a and 2b are provided for locally reducing the force opening the aperture, which greatly facilitates the manual opening of the peelable joint. As also shown in fig. 2a, the rupture zone may include a curved portion of the junction. This may also be advantageous to round one or several sharp portions of the joint in order to control the hand force required for the rupture process. The engagement according to fig. 2a provides an easy peel off hole in a container, 450 mm long comprising a handle portion and 300 mm wide, as shown in fig. 1. This engagement can be easily opened by different techniques of use, which are intended as part of the description of the container. The engagement can be opened properly while still having an outer closing envelope protecting the inner container, which is advantageous for a prolonged protection.

Preferably the rupture zone is in the middle of the seam and thus can be opened continuously from the middle to the sides, since the user can perform a highly repeatable opening process from the outside of the bag. Typically the rupture zone extends less than half of the full engagement, preferably less than or equal to about 40% of the engagement, more preferably less than one third of the engagement length. Typically the width of the weak sealing joint is less than 10 mm, preferably about 3-8 mm, for example about 6 mm in the joints shown in fig. 2a and 2 b. The fig. 2a and 2b examples and the alternative designs of the rupture zones discussed above are conceivable to the skilled person, as long as they are able to comply with the sealing requirements during storage and transport and can be easily opened manually according to simple instructions. For example, the peelable bond may be made completely straight and by different methods and different shaped fusion tools such as fusion pressure and/or temperature variation.

The suitable peelable seal bonding temperature of the Excel  material in the inner container is in the range of 106-121 ℃, the application pressure is about 315 +/-20N, and the thickness is about 0.3 mm within 2-10 seconds. Such a joint shows a proper seal after conventional mechanical packaging tests and is indeed easy to open, also after the container has been steam sterilized at 121 c for about 20 minutes.

A first preferred opening procedure is to gently roll up the container (the other side of the bonded channel system) from the upper side thereby taking advantage of the maximum chamber volume, suitably containing a glucose solution, to exert sufficient pressure to rupture the weakest point of the sealed joint, which peels away towards the container side. Another method of opening the seal is to pull the front and rear walls of the inner container apart from each other by a careful pulling action, thus creating a rupture at the weakest point at which the peel joint can be easily broken.

When preparing the container of the present invention for use, its peelable sealing bond may be ruptured in a predetermined manner as discussed above. The stored parenteral agents can thus be mixed in a mixing chamber that contains the entire volume of the inner container. If necessary, the container can be gently agitated into a homogeneous fluid that can be used immediately. For alternative methods of mixing separately stored lipid emulsions, amino acid solutions and carbohydrates, a TPN solution can be readily mixed in a convenient form. The closed envelope can be removed and additional reagents can be added to mix into the container through the channel system, if desired. The inner container is now completely ready for use and can, if desired, be hung on a rack with the container's hooks or other off-the-shelf means before connection to the patient, for example by using a conventional infusion device after piercing the outlet channel of the channel system. The container according to the invention is intended to be suitable for use with a large number of conventional infusion devices, and the details thereof will not be discussed in detail here since they are not part of the present invention.

Example 1

This example shows the stability of Intralipid  20% stored in a 500 ml Excel  polymer inner container enclosed in a closed envelope made of layers of PET-alumina/glue/PP/EVOH/PP (trade name Oxmil, Pharmacia & Upjohn AB) together with an oxygen absorber (Ageless Fx100, manufactured by Mitsubishi gas Co.). Intralipid  20% stored in a 500 ml glass bottle was used as a reference.

Intralipid  20% stored in the container of the present invention was compared to Intralipid  20% stored in a glass vial at 25 ℃ and 60% relative humidity for 18 months. The PH and the content of Free Fatty Acids (FFA) and Lysolecithin (LPC) were tested after 18 months of storage. According to the conventional intravenous injection of fats in the pharmaceutical industryThe average droplet size was measured by the method used by the emulsion manufacturer.

	Number of months of storage	Peroxide (mEq/L)	PH	LPC(mg/ml)	FFA(mmol/L)	Average droplet size (nm)
							Emulsion stored in glass bottle	1218	0.00.1	7.27.1	0.690.84	2.32.7	387348
Emulsions stored in polymeric containers	1218	0.00.1	7.57.3	0.740.83	2.22.7	334335

(average of 5 groups)

The initial pH was about 8.0-8.4 and the value decreased as expected after storage because of the increased FFA and LPC due to the hydration of triglycerides and phospholipids. A slight weight loss was measured in the polymer container: weight loss was 0.6% in 12 months and 0.8% in 18 months.

This test shows that the container of the invention exhibits a storage capacity that is fully comparable to glass containers in terms of preventing degradation and physical changes that affect the quality of the emulsion. The emulsion stored in the container of the present invention will therefore have a shelf life of at least 18 months when stored under normal storage conditions.

Example 2

The ability of the envelope material selected as an inner filled container to form a barrier to oxygen was tested. The wrapper material comprises a multi-layer polymeric structure: PET-metal oxide/gum/PP/EVOH/PP as disclosed in example 1 above.

To determine the effect of PET-metal oxides, such films (film 1) were compared with conventional PP/EVOH/PP (PP is polypropylene and EVOH is polyethylene vinyl alcohol) films (film 2) with respect to oxygen permeability. Oxygen permeability is measured in milliliters of oxygen per square meter per day that permeates oxygen at two different temperatures and a humidity of 75%. The permeability test was performed using a standard Macon permeability test method.

	Film 1 (ml/day, m)2)	Film 2 (ml/day, m)2)
			25℃	1.1	4
40℃	2.9	23

It is evident that the film containing PET-metal oxide (film 1) corresponds to an oxygen permeability of less than 5 ml/day, m²The requirements of (1). The PET-metal oxide films were also tested for chemical and mechanical properties after steam sterilization according to the european pharmacopoeia and a supranormal test at 121 ℃ for 60 minutes. When considering the migration of components from the film and the excellent values in terms of absorption, pH, oxidizable substances and appearance of the storage solution, it was found that the material also meets the requirements of the European pharmacopoeia.

Example 3

This example is intended to investigate the mixing performance of a batch of lipid emulsion stored at 5 ℃ and 25 ℃ for 12 months in a container according to the invention into a safe-to-use TPN solution.

Intralipid  20% filled in a 500 ml inner container made of Excel  was stored together with an oxygen absorber in a closed envelope consisting of layers of PET-metal oxide/glue/PP/EVOH/PP, as disclosed in examples 1 and 2.

The lipid emulsion thus stored was brought together with 1000 ml of an amino acid solution (Vamin  14gN/l) and 1000 ml of a glucose solution (glucose 20%). Adding 10 ml Addiphos  to glucose solution, adding Soluvit  reconstituted in Vitalipid  to lipid emulsion, and adding common electrolytes (Addamel , Addex  NaCl, Addex  KCl and CaCl) to amino acid solution₂1M). After gentle agitation, the mixture was transferred to a 3 liter IV bag with air vented, which was thoroughly agitated to ensure proper mixing. Portions of the bags were dispersed in glass vials for day 0 and day 6 analysis.

The IV bag with the remainder is leveledStored in a standing place, stored at a cold temperature of about 5 ℃ for 6 days, and then vertically hung for 1 day at room temperature of about 25 ℃. The vials were stored at room temperature for 7 days and 24 hours, respectively. In view of physical stability, the mixture must be carefully checked after being stored at room temperature for 24 hours and cold temperature for 6 days, and then stored at room temperature for 1 day.

Mean droplet size (. mu.m) (D (4, 3), Malvern calibration Scale	Day 0	6+1 day
			+5℃	0.37	0.39
+20℃	0.37	0.38

The appearance of the emulsion was checked by conventional visual inspection methods, which were performed by experienced emulsion makers as standard methods. In all mixtures, a 1-3.5 mm emulsion layer was present, but was easily redispersed by gentle agitation. There was no significant change in both the average droplet size and droplet size distribution after 6+1 days of storage.

The proportion of droplets of less than 5.29 μm was 100% in all samples and there were no droplets larger than 8 μm in any sample when measured with a Malver calibration scale, as observed with a contrast microscope.

The mixtures tested had satisfactory physical stability according to the appearance of the emulsion.

Example 4

The mixing performance of Intralipid  20% (20% soybean oil and fat emulsion manufactured by Pharmacia AB) filled in a three-compartment inner container made of Excel  and steam sterilized was compared with that of Intralipid  20% stored in a glass bottle with heat sterilization. Immediately prior to filling, each three-compartment container was flushed twice with filtered nitrogen, 500 ml of sterile Intralipid  was transferred from the glass bottle to the middle compartment, and the other compartments were filled with 614 ml and 1193 ml of water for injection, respectively. The filled and sealed container was placed in an envelope made of layers of PET-metal oxide/glue/PP/EVOH/PP (as mentioned in the previous examples) together with the oxygen absorber between the outlet and inlet channels of the saddle-shaped channel system.

Before sealing the envelope, the envelope is evacuated in a Multivac and filled with nitrogen again to form a gas volume suitable for sterilization, and then closed. And (3) sterilizing the container for 17-20 minutes by high-pressure steam at 121 ℃. The reference glass bottles were autoclaved at 121.1 ℃ for 12 minutes according to the usual preparation process. If mixing is to be carried out in a three-compartment container, mixing is carried out in the same order in a sterile environment. A17.2% glucose solution was transferred to a mixing vessel under nitrogen, followed by addition of the lipid emulsion treated as above (Intralipid  20%), gentle shaking followed by mixing with an amino acid solution (electrolyte-containing Vamin  18), and stirring. The mixture is poured into a sterile infusion bottle under the protection of nitrogen. After sealing the bottles, they were stored at room temperature (about 25 ℃) for 2 days or at about 5 ℃ for 6 days, followed by storage at about 25 ℃ for 2 days.

The mixtures were tested for creaming (visual observation of the emulsion layer), emulsion appearance (visual observation of the droplets on the surface and glass wall), mean droplet size and droplet size distribution (calibration of the scale with Malvern).

No significant differences in creamed or emulsion appearance were found between the different mixtures.

The following are the average micron size of the mixture with lipid emulsion in glass bottles andthe average micrometer size of the droplets of the mixture of three different lipid emulsions stored in the polymer container.

Storage time/temperature	Glass bottle	Polymer container
			48 hours, about 25 deg.C	0.40	0.43
6 days, 5 ℃ and 48 hours, 25 DEG C	0.42	0.44

The results show that the high pressure steam sterilized lipid emulsions maintained their mixing performance in the three-compartment polymer container without physical disruption, when compared to the high pressure steam sterilized emulsions in glass bottles. Due to the high integrity of the stored ingredients, the particular chamber configuration in the multi-chamber embodiment, and the convenient mixing configuration, the container greatly enhances safety and convenience for patients relying on long-term use when compared to conventional mixing systems consisting of special glass bottles and comparable flexible containers having shorter shelf lives. Even the amino acids most sensitive to oxygen can now be contained for long term storage within the container of the invention. The container of the present invention is also highly suitable for industrial mass production by the process of forming, filling, closing of the inner container, thereby assembling the final container prior to final sterilization and storage, and being sealed in an outer envelope, with minimum requirement to remove the oxygen atmosphere.

Claims (36)

1. A flexible transparent container for storing an oxygen sensitive parenteral agent comprising an inner main container (30) enclosed in an oxygen impermeable outer envelope (10) with an oxygen absorber (20), wherein the inner container (30) is made of a flexible polymeric material comprising polypropylene, the flexible polymeric material being compatible with lipophilic agents and capable of forming a permanent and peelable seal; characterized in that the envelope (10) is made of a water-impermeable flexible multilayer polymer material comprising: a first outer water impermeable film comprising a metal oxide coating-polymer layer in combination with a second inner film comprising a polymer layer forming a barrier to oxygen.

2. A container according to claim 1, characterized in that the inner main container (30) is divided into two or more compartments (32, 33) by one or more sealing peelable seals (50') which can be ruptured by hand from the outside.

3. A container according to claim 1, characterized in that the inner primary container is composed of a flexible film, wherein a first region of the inner primary container (30) as an outer layer has a higher melting point than a second region of the inner primary container (30) as an inner sealing layer.

4. A container according to claim 3, characterized in that said inner region of low melting point is capable of forming a permanent seal and a peelable seal (50') when subjected to different welding conditions.

5. A container according to claim 3, characterized in that the inner main container is made of a film having an at least two-layer structure, wherein at least the inner sealing layer comprises polypropylene and is capable of forming a permanent seal and a peelable seal (50') when welded at higher or lower temperatures, respectively.

6. Container according to claim 5, characterized in that the polypropylene is a copolymer with ethylene or is mixed with polyethylene.

7. The container of claim 5 wherein the film has a layer comprising a thermoplastic elastomer.

8. A container according to claim 4, characterized in that the film has an outer layer with a higher melting point than the inner sealing layer.

9. The container of claim 8, wherein the outer layer is printable.

10. Container according to claim 9, characterized in that the outer layer comprises a polyester or copolyester.

11. The container according to claim 5, characterized in that the inner main container (30) is made of a multilayer structure film comprising:

a) an outer layer comprising a copolyester of a type selected from the group consisting of,

b) an inner sealant layer comprising polypropylene, a propylene ethylene copolymer or a mixture of polypropylene and polyethylene, and

c) an intermediate layer comprising a thermoplastic elastomer.

12. The container of claim 11 wherein the sealing layer further comprises a thermoplastic elastomer.

13. Container according to claim 11, characterized in that the thermoplastic elastomer is a styrene-ethylene/butadiene-styrene block copolymer.

14. A container according to claim 3, characterized in that the flexible film comprises one or more materials selected from the group consisting of polypropylene, propylene-ethylene copolymers and mixtures of polypropylene and polyethylene.

15. A container as claimed in claim 1, characterised in that the sealing envelope (10) is made of a flexible multilayer transparent material which provides an oxygen permeability of less than 30cm after steam sterilisation at 121 ℃³/m²Atmospheric pressure day oxygen barrier capacity when measured at a specific temperature of 25 ℃ and a relative humidity of 60%.

16. The container of claim 1 wherein the outer film comprises a polyethylene terephthalate layer coated with a metal oxide.

17. The container of claim 1 wherein the outer and inner films are joined by adhesive bonding.

18. The container of claim 1 wherein the second inner film layer forming a barrier to oxygen comprises polyethylene vinyl alcohol.

19. The container of claim 1 wherein the second layer inner film comprises at least one layer of polypropylene.

20. The container of claim 1 wherein the first outer film comprises a second polyethylene terephthalate layer.

21. The container of claim 20 wherein the first outer film has a first outer side of a layer of polyethylene terephthalate coated with a metal oxide in combination with a layer of second polyethylene terephthalate.

22. The container of claim 21 wherein the first outer polyethylene terephthalate layer is coated on both sides with a metal oxide.

23. Container according to claim 21, characterized in that the material forming the envelope (10) comprises a film having a polyethylene terephthalate/metal oxide/glue/polyethylene terephthalate structure, which is adhesively bonded to a film consisting of a polypropylene/tie layer/polyethylene-vinyl alcohol/tie layer/polypropylene structure.

24. The container according to claim 1, wherein the metal oxide is selected from the group consisting of silicon oxide, aluminum oxide, and titanium oxide.

25. A container according to claim 2, characterized in that it has at least three chambers (31, 32, 33), including an upper chamber (31), at least one intermediate chamber (32), and a lower chamber (33) provided with a system of channels for the output of a mixed fluid product made of stored reagents and for the addition of additional reagents.

26. Container according to claim 25, characterized in that the upper chamber (31) is destined to be filled with the reagent having the largest volume.

27. Container according to claim 26, characterized in that the inner container (30) has three compartments (31, 32, 33), each assigned to a parenteral fluid nutrient, wherein the lower compartment (33) contains a lipid emulsion or an amino acid solution.

28. Container according to claim 25, characterized in that the inner container (30) has three parallel chambers (31, 32, 33), wherein the upper chamber (31) is filled with an aqueous solution of a carbohydrate, the middle chamber (32) is filled with a lipid emulsion and the lower chamber (33) is filled with an aqueous solution of an amino acid.

29. A container according to claim 25, characterized in that the inner container (30) has three parallel chambers (31, 32, 33), wherein the upper chamber (31) is filled with an aqueous solution of a carbohydrate, the middle chamber (32) is filled with an aqueous solution of an amino acid and the lower chamber (33) is filled with a lipid emulsion.

30. The container of claim 27, wherein the carbohydrate solution comprises glucose and the amino acid solution comprises the essential amino acids.

31. A container according to claim 2, characterized in that the peelable seal (50, 50') of the compartment (31, 32, 33) is provided with a rupture zone in engagement.

32. The container of claim 31 wherein the rupture zone comprises a point at which two linear junctions intersect at an angle of 110 ° and 160 °.

33. The container of claim 31, wherein the rupture zone comprises at least one portion that engages the bend.

34. The container of claim 31 wherein the weak bond is straight at the rupture zone.

35. Container according to claim 31, characterized in that it comprises at least two parallel peelable sealing joints (50, 50').

36. A method of making a container according to any one of claims 1 to 35, the steps of making comprising:

a) introducing a flexible polymeric multilayer material to form a pouch-like sealed inner container (30) by welding together polypropylene-containing sealant layers and to selectively form at least two chambers (32, 33) by forming at least one barrier peelable sealing joint (50');

b) providing the side of the inner container (30) with at least one temporary hole;

c) filling the inner container (30) with at least one parenteral fluid through the temporary hole;

d) closing the temporary holes of the side of the inner container (30) by welding permanent joints;

it is characterized by comprising the following steps:

e) enclosing a filled and sealed inner container (30) together with an oxygen absorber (20) in an envelope (10) forming a barrier to oxygen, wherein said envelope (10) is made of a water-impermeable flexible multilayer polymer material comprising: a first outer water-impermeable film comprising a metal oxide coating-polymer layer in combination with a second inner film comprising a polymer layer which forms a barrier to oxygen;

f) welding the sealing envelope (10) and finally sterilizing the container.