Containers for parenteral fluids

A flexible transparent container for improved storage of oxygen sensitive parenterally administerable agents comprising an inner, primary container enclosed in a substantially oxygen impermeable outer envelope with an oxygen absorber, capable of consuming essentially all residual oxygen after the outer envelope is sealed, and for sufficient period also the oxygen penetrating said envelope. The inner container is made of a polypropylene containing flexible polymeric material compatible with lipophilic agents capable of forming both permanent and peelable seals, while the envelope is made of a substantially water impermeable flexible multilayered polymeric material comprising a first outer substantially water impermeable polymeric film with oxygen barrier forming capacity, assembled with a second, inner polymeric film with a supplementary oxygen barrier forming capacity. The container essentially maintains its characteristics after being subjected to sterilization by steam or radiation.

FIELD OF 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 
94/19186 (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 lipophilic 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 94/19186 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 
AG 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.degree. C. as required by 
the European Pharmacopoeia. 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 and finally enclosed 
with the oxygen impermeable envelope. Such a process is not completely 
satisfying since it for rational reasons is desirable to make the 
sterilization step on the finally filled and assembled container. In 
another embodiment it is suggested that the finally assembled and sealed 
container is autoclaved. However, in order to retain the oxygen barrier 
after the autoclavation an extra drying process must be introduced in 
order to remove absorbed moisture from outer envelope. 
The European Patent Application EP 0 639 364 by Otsuka Pharm. Factory Inc. 
discloses another recent flexible multi-chamber bag for storage of oxygen 
sensitive agents. This bag is preferably useful for storing degradable 
powder formed drug and its diluent in separate chambers. The chamber 
filled with the oxygen sensitive powder is covered with an oxygen barrier 
forming envelope which is sealed in a controlled atmosphere by weldings to 
the bag. A drawback with the containers exemplified in this application is 
that they may not withstand autoclavation after their final assembly. 
It is obvious that the construction of a flexible multi-chamber container 
intended to substitute glass bottles for storing parenteral nutrients, 
such as lipid emulsions is a highly complex development process. A careful 
consideration must be taken to the capacity of the materials of being 
autoclavable with maintained characteristics, to their capacity of 
providing a barrier against environmental oxygen and water vapor, while at 
the same time it must be easy to process to a functional multi-chamber 
container, for example with conventional welding technology and comply 
with the demands of being possible to recollect and recycle in one single, 
simple process. For the parts of the container in contact with the stored, 
often lipophilic substances, it is a requirement that potentially 
hazardous agents must not be allowed to migrate into the parenteral 
product. Conventionally employed polymers in medical packages, like 
polyvinyl chlorides (PVC), and other polymers containing migrating 
plasticizers therefore can not be considered. Nevertheless, these 
polymeric materials have a higher permeability to oxygen than glass 
bottles which makes them unsuitable for long-term storage of especially 
sensitive fluids. Moreover, the material must have an aesthetically 
attractive appearance with a transparency that do not deteriorate after 
sterilization and storage. In addition, the material must allow printing 
of instructions and filling levels without migration of the printing ink. 
It is also important that the material maintains all the mechanical 
characteristics, such as flexibility and strength, after the sterilization 
independently, if it is performed by steam or radiation. Besides the 
important material properties, the container must be convenient to handle 
when mixing the stored products and provide a high degree of safety for 
the patient, both when considering the manufacture of the container and 
its handling by the user either in the home of a patient or at a hospital. 
It is an object of the present invention to provide a flexible container of 
substantially made of a polymeric material with an improved barrier 
against environmental oxygen and moisture which also is capable of 
withstanding sterilization by means of high pressure steam (autoclavation) 
or irradiation essentially without losing any such barrier capacity or 
other important characteristics including flexibility or transparency, so 
even stored agents of high oxygen susceptibility may be stored for long 
periods with maintained integrity. 
It is also an object of the present invention to provide a flexible 
container for separated long term storage of such agents that are easily 
perishable when stored together in their final parenterally administerable 
form and provide the container with means for mixing such agents 
aseptically within the container to an injectible fluid. 
It is a particular object of the present invention to provide such a 
container for storing parenteral nutrition components separately, i.e. a 
lipid emulsion, a carbohydrate solution and an amino acid solution, and 
subsequently, just before parenteral administration, combine them to a 
homogenous fluid nutrient mixture. 
It is another particular object of the present invention to prolong the 
possible storage period both in a cold environment and in room temperature 
for sensitive fluids aimed for total parenteral nutrition to overcome the 
problem of short shelf-life of such products. 
It is still another object of the invention to provide a container with the 
capacity of separately storing several components filled in ready-made 
inner container which has a minimized number of potential sites where 
leakages can appear. 
It is a further object of the present invention to provide such containers 
which are safe and convenient to handle and which minimize the risks for 
erroneous handling and contamination during all the steps necessary to 
obtain a parenterally administerable fluid of a predetermined quality. 
It is a still further object of the present invention to provide such 
containers that are cheap and environment friendly by being to a high 
extent made of such polymeric materials which are possible to recollect 
and recycle together without an inconvenient dismembering of different 
container parts. 
It is also an object of the present invention to provide a process for 
manufacturing such filled containers that are sterilized as a last stage 
after being assembled and filled, wherein the filling process is performed 
in a manner that avoids permanent, potentially leaking filling ports. 
These objects of the present invention, as well as other obvious advantages 
demonstrated in this text, are attained by the appended claims. 
DESCRIPTION OF THE INVENTION 
The container according to the present invention is aimed for improved 
storage of oxygen sensitive parenterally administerable agents and 
consists generally of an inner, primary container enclosed in a 
substantially oxygen impermeable outer envelope with an oxygen absorber 
which is capable of consuming essentially all residual oxygen after the 
outer envelope is sealed, and for sufficient period also the oxygen 
penetrating said envelope. Both the inner container and the enclosing 
outer envelope are made of flexible and transparent polymeric materials. 
The inner container is made of a polypropylene containing flexible 
polymeric material compatible with lipophilic agents capable of forming 
both permanent and peelable seals and the envelope is made of a 
substantially water impermeable flexible multilayered polymeric material 
comprising a first outer substantially water impermeable polymeric film 
with oxygen barrier forming capacity, assembled with a second, inner 
polymeric film with a supplementary oxygen barrier forming capacity. 
An important feature of the assembled container is that is essentially 
maintains its characteristics of forming an oxygen and moisture vapor as 
well as transparency and flexibility after being subjected to 
sterilization by steam or radiation. The inner container can be a single 
or multi-chamber container filled with one or several parenterally 
administerable agents. According to a particular important embodiment of 
the present invention, the inner primary container is divided into two or 
more chambers by one or more leaktight seals which are possible to rupture 
by hand from the outside of the container when the contents of the 
chambers are desired to be mixed to a homogenous fluid and administered to 
a patient by infusion or injection. For this reason, the inner container 
is provided with a fluid communication port in its bottom through which 
the mixed product can be received and through which additional agents can 
be supplemented to either to the mixed product or to the agent stored in 
the lower chamber. The port is attachable to conventional infusion devices 
and other devices useful for parenteral administration and will preferably 
have separate orifice for introduction and collection of fluid agents. 
Both the inner container and the sealing envelope are made of specifically 
selected polymeric materials which will be described in more detail below. 
As also will be explained in more detail below, the envelope is finally 
sealed in a protected atmosphere and in the space between said envelope 
and the inner container an oxygen scavenger is placed. 
The agents stored in the containers according to the invention are 
preferably oxygen sensitive fluids or powders which otherwise lose 
activity or suffer from degradation during extended storage. Example of 
such agents are parenteral nutrients such as lipid emulsions containing 
oxygen sensitive polyunstaurated fatty acids, amino acids containing 
sensitive amino acids like cystein and many pharmaceutical agents which 
lose activity when stored in dissolved or diluted form and consequently 
must stored as a solid powder (lyophilized) form or as a concentrate 
separated from a diluent. Another example of agents that will benefit from 
storage in the inventive containers are such that must be kept separate 
during sterilization by means of heat like solutions of carbohydrates and 
solutions of amino acids which together may form discoloring complexes. 
The inventive multi-chamber containers are manufactured according to a 
general method, wherein a bag shaped sealed inner container is formed from 
a flexible polymeric material by welding together its polypropylene 
containing sealing layers. At least two leak tight chambers are formed by 
welding at least one peelable seal seam possible to rupture by hand from 
the outside of the container. One side of the container is provided with 
temporary openings to the chambers which are filled with the parenterally 
administerable fluids, whereupon the temporary openings are sealed again 
by welding permanent seams. The filled and sealed inner container is 
enclosed in an oxygen barrier forming envelope together with an oxygen 
absorber which is sealed by welding in a controlled atmosphere. The so 
finally assembled is sterilized by means of steam or by irradiation. 
The following detailed description aims to describe preferred embodiments 
and specific examples of containers and methods of their manufacture in 
accordance with the present invention, while illustrating appropriate 
alternatives. These examples are not intended to be limiting for the scope 
of invention outlined by the appended claims.

DETAILED DESCRIPTION OF THE INVENTION 
As previously discussed there are several important requirements set on a 
material suitable for the inner container. It must be made of an 
autoclavable or radiation sterilizable polymeric material which is 
compatible with the stored products. The material must be possible to 
permanently weld to a bag and weld to other polymeric details, such as the 
mentioned saddle-formed port system, while also providing the possibility 
of forming rupturable peelable seal seams during modified welding 
conditions compared to the formation of permanent seams. Furthermore, the 
material should also be environment friendly and possible to recycle with 
a simple process. The material should be substantially impermeable for 
water vapor during steam sterilization, but need not be airtight according 
to the present invention, when an outer sealing envelope is used in 
combination with an oxygen scavenger. It would rather be an advantage if 
the material could permit an oxygen transfer so the oxygen scavenger can 
be able consume substantially all residual oxygen dissolved in the stored 
fluids. If radiation sterilization shall successfully be applied on the 
container in accordance with the International patent application 
PCT/SE95/00684, also the residual oxygen dissolved in the polymeric 
network of material of the inner container must be removed. The material 
must have a suitable aesthetic appearance and be clearly transparent and 
not tend to be discolored or opaque after sterilization. Finally, the 
material must maintain its flexibility and not become fragile or brittle 
after sterilization and storage. 
A polymeric material for the inner container having all the mentioned 
characteristics is preferably is a flexible film having a region with a 
higher melt point designated as its outside and having a region with lower 
melt point designated as its sealing inside which can be sealed together 
by means of conventional welding tools to permanent or peelable seal 
seams. It is to be understood that the inner region is intended to face 
the stored agent or agents and can form both permanent seams and different 
peelable seal seams when subjected to different welding conditions or 
operations. 
It is preferred that film is made of at least two different polymer layers 
of which at least the inner sealant layer is based on polyolefins, such as 
polyethylenes or polypropylenes of various qualities which are chemically 
inert to the stored fluids, autoclavable, weldable and possible to 
recycle. The terms "polyethylenes" and "polypropylenes" are intended to 
include both homopolymers and copolymers having such mentioned 
characteristics unless otherwise is specified. Preferably, the sealant 
layer is based on polypropylene including its copolymers with ethylene 
(propylene ethylene copolymer) and/or its mixtures with polyethylene. 
However, since many conventional polyolefins, in particular polypropylenes, 
often have an insufficient flexibility and a certain brittleness, it is 
desirable to combine them with a polymer having an elastic property. In a 
specific embodiment according to the present invention it is therefore 
preferred to combine the polypropylene with a supplementary elastomer to 
improve its flexibility and resilience. The elastomer can be comprised in 
neighboring layer of the film or compounded with the polypropylene in the 
sealant layer. For multilayered materials it is preferred to have an 
inner, sealant layer comprising a high amount of polypropylene to benefit 
from its capacity of being inert towards the stored fluids and for 
facilitating the manufacturing of a container by means of different 
welding techniques. It is especially preferred that this layer can form 
both leaktight, but controllably rupturable, peelable seal seams at a 
predetermined temperature and permanent highly consistent seams when 
welding it together with different conditions, such as different welding 
temperatures or welding pressures. It is also desirable to introduce a 
flexible polymeric material with a high melting point that provides the 
material with an improved stability at the high temperatures locally 
reached during the welding. If such a material is comprised in a 
multilayered film, it should be placed as an outer, release layer and 
additionally be easy to print without migration of the printing ink. 
Suitable materials can be found among certain polyesters and copolymers 
thereof (copolyesters) and in particular cycloaliphatic polyesters. 
A preferred material for the inner, primary container is made of a 
multilayered film comprising: a) an outer layer containing a copolyester, 
b) an inner sealant layer containing polypropylene, a propylene ethylene 
copolymer or a mixture of polypropylene or polyethylene and c) an interior 
layer containing a thermoplastic elastomer. In such a film the sealant 
layer further may comprise a thermoplastic elastomer which can be 
styrene-ethylene/butadiene-styrene block copolymer (SEBS) or suitable 
alternative elastomer having the appropriate mentioned characteristics. A 
material that has been proofed to be especially suitable for this type of 
inner containers is EXCEL brand of multilayered polymeric material from 
McGaw Inc., a multilayered polymeric material of about 200 micrometer 
thickness which is described in the European patent 0 228 819. EXCEL brand 
of multilayered polymeric material has a multilayered structure 
substantially comprising: 
a) an inner, sealant layer facing the medical fluid consisting of a mixture 
of a polyethylene/polypropylene copolymer (FINA Dypro Z 9450) and KRATON 
G1652 brand of styrene/ethylene/butadiene/styrene copolymer from Shell (a 
styrene/ethylene/butadiene/styrene (SEBS) copolymer); 
b) a middle, tie layer of pure EXCEL brand of multilayered polymeric 
material G652; and 
c) an outer, release layer of ECDEL 9965 (or 9566 or 9967) from Eastman 
Chemical Co. which is a cycloaliphatic thermoplastic copolyester (a 
copoly(ester ether), a condensation product of the trans isomer of 
1,4-dimethyl-cyclohexanedicarboxylate, of cyclohexanedimethanol and 
hydroxyterminated polytetramethylene glycol). 
The inner, sealant layer consists of a mixture of 80% copolymer of 
polyethylene and polypropylene with 20% of the elastomeric SEBS copolymer 
combined with minor additives of antioxidants and acid scavengers. The 
copolymer of polyethylene and polypropylene forms an interpenetrating 
network with the SEBS-copolymer which provides for a strong seal. This 
mixture seals itself over a broad range of temperatures and is capable of 
forming peelable seal seams of varying strengths, when welding in an 
interval of selected temperatures from about 85 to about 120.degree. C. It 
has been demonstrated that welding at about 110 to 120.degree. C. forms 
peelable seal seams which are easy to rupture by hand. It also provides 
for a suitable steam barrier and will, as shown below, in the exemplifying 
part, satisfyingly withstand both chemical and physical tests. The middle 
layer contains only the highly flexible copolymer KRATON G1652 brand of 
styrene/ethylene/butadiene/styrene copolymer with minor amounts of 
antioxidants. It contributes to the elasticity and the impact strength of 
the film. The outer layer of EXCEL brand of multilayered polymeric 
material is flexible and printable with a high melting point of 
200.degree. C. and contributes to an improvement of the welding capacity 
of the assembled film. When using EXCEL brand of multilayered polymeric 
material as the material for the inner bag formed container, it is 
preferred that the saddle formed port system which shall be attached to 
the sealant layer also contains polypropylene and preferably consists of a 
mixture of polypropylene and KRATON G1652 brand of 
styrene/ethylene/butadiene/styrene copolymer which is weldable to the 
inner layer of the EXCEL brand of multilayered polymeric material film. A 
suitable mixture is about 60% polypropylene and 40% KRATON G1652 brand of 
styrene/ethylene/butadiene/styrene copolymer. A preferred to use the 
saddle formed port system as disclosed in the Swedish patent application 
9601540-9, also in the name of Pharmacia AB. 
An inner container made of the preferred Excel.RTM. film has excellent 
characteristics for being autoclaved together with conventional parenteral 
nutrients. In addition, the EXCEL brand of multilayered polymeric material 
film is surprisingly compatible with lipophilic fluids. Even if its inner 
layer comprising a physical mixture of polypropylene and the SEBS polymer, 
tests involving its exposure to pure soybean oil (the main lipid 
constituent of the commercial lipid emulsion INTRALIPED lipid emulsion has 
not given any reasons to suspect the migration of potentially toxic 
agents. It will, however, have a relatively high oxygen permeability of 
about 1000 to 1600 cubic centimeters/m.sup.2, atm, day, when measured at a 
specific temperature of 25.degree. C. and 60% relative humidity and to 
comply with the requirements for long term storage of lipid emulsions and 
essential amino acid solutions it must be combined with an outer 
surrounding airtight envelope and an oxygen absorber. Even if inner 
containers made of EXCEL brand of multilayered polymeric material 
constitute suitable embodiments for the present invention also other 
polyolefin based films must be regarded as conceivable alternatives to use 
within the scope of the present invention, if they comply with the 
requirements mentioned above. It is therefore an important alternative to 
provide inner containers of a flexible, transparent film with a high 
degree of compatibility with lipophilic fluids from one or several layers 
consisting essentially only of or entirely of one or several polymers 
selected from a group consisting polypropylene, copolymers of propylene 
and ethylene, mixtures of polypropylene and polyethylene. For example, a 
layered film material comprising for example an inner sealant layer of 
propylene ethylene copolymer mixed with an elastomer, such as a SEBS 
polymer attached to an outer layer of pure polypropylene which is corona 
treated to be printable is a possible alternative material. Also a film 
consisting of an inner layer of ethylene containing polypropylene tied to 
a pure corona treated polypropylene layer by a polypropylene with a 
modified tacticity, such as REFLEX film from Rexene or Dow is a another 
conceivable alternative, as well as combinations of pure polypropylene 
layers having an improved elasticity and printability due to modifications 
in their molecular configurations or due to physical processing. For 
example, with metallocene type catalysts, a higher level of control of the 
stereoregularity of polypropylene chains can be obtained, as disclosed in 
Macromolecules, Vol. 28, 1995, pages 3771-8: W. J. Gauthier et al. This 
can yield profound effects on the physical properties of the material and 
impart e.g. highly flexible or elastomeric polypropylenes which can be 
included as future alternatives to EXCEL brand of multilayered polymeric 
material. All such polypropylene based materials should be regarded as 
alternative embodiments of materials selected for the inner container, if 
they comply with the requirements set above. 
As discussed in relation to the selection of material for the inner 
container, the material of the surrounding envelope must meet a number of 
demands to replace glass bottles. It must most importantly provide a high 
barrier against atmospheric oxygen. admitting an oxygen inflow preferably 
less than about 30 cubic centimeters/m.sup.2, atm, day, when measured at a 
specific temperature of 25.degree. C. and 60% relative humidity and more 
preferably less than 15 cc/m.sup.2, atm, day and most preferably less than 
5 cc/m.sup.2, atm, day, when measured at the same conditions. It must be 
steam sterilizable at 121.degree. C. for at least 30 minutes, while also 
having the capacity to withstand sterilization by irradiation to improve 
on existing aseptic overwrapping techniques. A conventional aluminum foil 
would meet such requirements, but will have the drawback of not being 
transparent to enable a visual inspection of the integrity of the stored 
material and for example an oxygen indicator. Furthermore, the envelope 
material must be strong and flexible, have a low impact on the environment 
and only contain such additives with the lowest possible tendency to spoil 
or interfere with the stored material by migration. The criterion of 
forming a barrier against oxygen can also be met by polyvinylidene 
chloride (PVDC), but it will, however, not be possible to steam sterilize 
and will not meet the demands of being environment friendly. As earlier 
discussed in the International patent application WO 94/19186, it was 
attempted to construct a multilayer film for packaging and autoclaving 
parenteral agents. This film was intended to support the oxygen barrier 
capacity of a poly(ethylene)-vinyl alcohol layer (EVOH) by introducing a 
water resistant and moisture absorbing outer structure to protect the 
EVOH-layer during the steam sterilization. Unfortunately, not even this 
multilayered film was capable to keep a satisfactory long time barrier 
against oxygen after its autoclavation. It was therefore highly desirable 
to improve such a film by adding to the EVOH-layer a protecting structure 
which not only was steam impermeable, but also could contribute to the 
oxygen barrier. 
According to the present invention, it has been surprisingly found that if 
a first outer substantially water impermeable polymeric film with oxygen 
barrier forming capacity is assembled with a second, inner polymeric film 
with a comparatively higher oxygen barrier forming capacity at 25.degree. 
C. at 60% relative humidity, a multilayered material suitable for forming 
an outer sealing envelope for the inventive container is obtained which 
can maintain such a high oxygen barrier as less than 5 ml oxygen per 
m.sup.2, atm and day at a normal relative humidity, even after 
autoclavation and yet comply with the requirements set above. 
Preferably, the outer film comprises a metal oxide coated polymeric layer 
connected to a second, inner film comprising an oxygen barrier forming 
polymeric layer. It is preferred that the outer film comprises a metal 
oxide, such as an oxide of silicon and/or aluminum and/or titanium 
together with at least one polymeric material, while the inner film 
preferably comprises an EVOH layer. Preferably, the outer film comprises a 
layer of polyethylene terephtalate coated with the metal oxide, while the 
inner film comprises at least one layer containing polypropylene. The 
outer film may comprise a second layer of polyethylene terephtalate (PET). 
In such cases, a first outer layer of polyethylene terephtalate (PET) is 
coated on one side with a metal oxide which is bound to a second layer of 
polyethylene terephtalate (PET). According to a specific alternative, both 
sides of a PET-layer is coated with metal oxide. The outer film can 
suitably contain a polyethylene terephtalate (PET) layer coated with a 
metal oxide of about 10-30 .mu.m, preferably about 25 .mu.m, thickness 
tied together to the inner film of about 50-200 .mu.m, preferably about 
100 .mu.m thickness which preferably contains an EVOH layer tied together 
to surrounding polypropylene based (PP) layers (made of polypropylene, 
various copolymers of propylep and ethylene or mixtures thereof) in a 
conventional manner to obtain a multilayered material of the principal 
structure PET-metal oxide/glue/PP/tielayer/EVOH/ tielayer/PP. This 
material will provide the oxygen barrier forming EVOH layer with an 
effectively protecting shield against moisture penetrating the 
polypropylene during steam sterilization and storage which otherwise will 
impair its subsequent barrier forming capacity. At the same time, the 
glassy, outer film will contribute to the oxygen barrier. The inorganic 
glassy metal oxide material consists of a thin metal oxide layer having a 
thickness of about 200 to 1200 .ANG. and is deposited on a smooth polymer 
surface by a conventional technology, for example described in the 
European patent specification EP 0460796 (E.I. Du Pont De Nemours & Co.), 
wherein suitable PET-glass films are disclosed. The metal oxide may also 
be deposited on both sides of the film or a further PET layer can be 
added, so films of the structure glass-PET-glass-glue/PP/EVOH/PP or 
PET-glass/glue/PET/PP/EVOH/PP are obtained. 
The glue binding the two films together is of a type conventionally used in 
adhesive bonding of multilayered polymer structures with a suitably low 
tendency to migrate. An especially suitable film is composed of 
PET-aluminum oxide/glue/PET/glue /PP/tie/EVOHI/tie/PP. In the following 
exemplifying part, it is demonstrated that it has excellent properties for 
constituting a protecting outer envelope in container for safely storing 
parenteral nutrients. 
The oxygen absorber according to the present invention preferably is iron 
containing and dependent on water for its oxygen consumption, as described 
in the International patent application PCT/SE95/00684 in the name of 
Pharmacia AB. It is preferable that the ferrous oxygen absorber also can 
consume a certain amount of hydrogen sulfide degraded from sulfur 
containing amino acids, such as cystein in a stored solution comprising 
essential amino acids, as is disclosed in the German patent DE 42 33 817. 
The oxygen absorber shall be capable to withstand a sterilization 
procedure selected from steam sterilization and sterilization by means of 
irradiation without being impaired. The oxygen absorber can either be 
present in the container as a sachet or it can be compounded as a part of 
a multilayered film. It is preferred to use an oxygen absorber having a 
ferrous oxygen scavenging composition enclosed in one or several sachets 
or tray-like carriers placed close to the saddle-formed port system of the 
inner, filled container during the enclosure with a surrounding airtight 
envelope in a controlled atmosphere. For the preferred type of oxygen 
absorber, it is therefore important that there is a source of water 
present, either in the oxygen scavenging composition or elsewhere in the 
space wherein it shall exert its activity. Certain oxygen absorbers demand 
an atmosphere of at least 80% relative humidity (at 25.degree. C.) for a 
maximum activity and would therefore require a high humidity in the closed 
space between the inner container and the envelope to ensure a correct 
function which typically is above according 60% in containers according to 
the present invention. This type of moisture dependent oxygen absorbers 
are preferred according to the present invention. The skilled person will 
have no difficulties in obtaining suitable oxygen absorbers in an 
appropriate amount when designing a container according to the present 
invention. An estimation of a necessary quality and amount can easily be 
performed from its oxygen predetermined consuming capacity when given 
values of the container, for example, of the volume of the stored material 
and the oxygen barrier capacity of the surrounding envelope. For example, 
if the total capacity of the oxygen absorber is at least 100 ml pure 
oxygen, this value must be higher than the amount expected to penetrate 
the envelope through a given area during a given time if the envelope is 
made of a material having an oxygen permeability of not exceeding 5 ml 
oxygen per m.sup.2, atm and day at a normal relative humidity. An example 
of a suitable oxygen absorber, according to the present invention, is 
AGELESS FX200PA ferrous oxygen absorber available from Mitsubishi. 
In the specific embodiment illustrated in FIG. 1, the container has an 
outer sealing envelope 10 and an inner three-chamber container 30 filled 
with three different parenteral fluids. In the space between the envelope 
and the inner container, an oxygen absorber 20 is placed. In this space, 
also an oxygen indicator showing inadvertently penetrated oxygen from 
leakages, an indicator demonstrating a correct sterilization and other 
conditions optionally can be placed. Such indicators must, of course, be 
able to withstand the sterilization step, either with steam or radiation 
and they must not cause migration of toxic or potentially hazardous 
substances to the stored products. 
The inner container shown in FIG. 1 is bag formed and provided with three 
parallel chambers 31, 32, 33 which may have the same or different volumes 
dependent on the desired amount of the stored product. The inner container 
is illustrated as being provided with a handle part 34 in its top to 
facilitate conventional administration from a hanging position. The bottom 
of the container is provided with a port system 35 which can be a 
conventionally formed saddle port welded to the container material during 
the manufacture. A preferred port system which is designed to be more 
easily sterilized is described in a parallel, as yet unpublished, Swedish 
patent application. 
The port system has an outlet port 36, through which fluid communication to 
a patient in need of fluid therapy can be established by conventional 
infusion devices which, however, not are discussed in more detail. Through 
an inlet port 37 of the port system, it is possible to introduce an 
additional agent to the fluids of the container in any desired moment. 
Such agents are typically supplementary drugs or nutrients or 
micronutrients which can not be stored together with fluids of the 
container. 
In this embodiment, the three chambers 31, 32 and 33 are filled with three 
different parenterally administerable nutrients in fluid forms which, just 
before their administration to the patient, shall be homogeneously mixed 
together to form a total parenteral nutrition (TPN) solution. To enable 
such mixing at will, the chambers are divided by such seams that can 
readily be ruptured by the user from the outside of the container. The two 
seams 50,50' separating the chambers are typically formed by peelable seal 
weldings in the container which are highly leak tight, but possible 
rupture by a predetermined motion of the user. Peelable seals or weak 
weldings belong to a well-known technique in the art processing of 
polymers and the conditions about their formation and characteristics are 
described more in detail in U.S. Pat. No. 5,128,414 or in the European 
patent specifications EP 0 444 900 and EP 0 345 774 which documents hereby 
are incorporated as references. A particularly preferable construction of 
the welded peelable seal seams, suitable for a container according to the 
present invention, will be discussed in greater detail below. 
In the specific embodiment of a container according to FIG. 1, one chamber 
contains a carbohydrate solution comprising glucose, one chamber contains 
a lipid emulsion typically comprising 10-30% (w/w) of a lipid, such as 
INTRALIPID lipid emulsion of Pharmacia AB, and one chamber contains an 
amino acid solution such as VAMIN amino acid solution from Pharmacia AB, 
if suitable comprising the essential amino acids. Such parenterally 
administerable nutrients and their appropriate additives for giving total 
parenteral nutrition and/or complementary drug therapy are described in 
more detail in other documentation, such as the European patent 
application 0 510 687 in the name of Green Cross Corp. which is 
incorporated as a reference in its entirety. When suitable for clinical 
reasons, each of these three nutrients can comprise further constituents, 
such as trace elements, electrolytes, vitamins, energy substrates, 
supplementary therapeutic agents and agents supporting the metabolization 
of said nutrients. However, it must be carefully analyzed for each 
constituent, in which chamber it shall be stored with maintained integrity 
and minimal interference with the selected nutrient. 
The designation of the chambers 31,32,33 for the three mentioned nutrients 
has been done after careful consideration of both convenience and safety 
aspects. For such a reason, it is preferred that either the amino acid 
solution or the lipid emulsion is contained in the bottom chamber 33, 
since, if the user, for some reason, would be unsuccessful in correctly 
performing the mixing procedure, the infusion of a pure amino acid 
solution or a lipid emulsion leaves the patient unaffected compared to an 
accidental infusion of pure glucose solution which could lead to unwanted 
side effects, for instance, if the patient suffers from complications 
related to diabetes. It is therefore preferred that the top chamber 31 is 
filled with the carbohydrate solution which also is of advantage when 
considering its relatively larger volume can be used to exert a sufficient 
pressure to rupture the upper peelable seal 50 when mixing the nutrients. 
According to one embodiment, the middle chamber 32 contains the lipid 
emulsion, so it may serve as a visual or optical leak detector if any 
leakages in the seals between chambers will appear during the storage, 
while the lower chamber 33, facing the port system is designated for the 
amino acid solution. As an alternative embodiment, the lower chamber 33 
may contain the lipid emulsion having the smallest volume. This is will 
give the filled chambers a similarly shaped volume extension and heat 
penetration during the steam sterilization in order to obtain a similar 
temperature gradient in all the three chambers. 
However, in certain applications the convenience of opening the chambers 
for fluid transfer by rupturing a peelable seal are given priority. For 
example, it might be desired to have the constituent with the largest 
fluid volume designated for the top chamber in order to use its mass for 
rupturing the peelable seal seams, regardless of the contents of the 
chambers. It should also be understood that other chamber configurations 
than the three parallel chambers shown in FIG. 1 is conceivable within the 
scope of invention. 
Besides parenteral nutrients it is conceivable to store a large number of 
other parenterally administerable products in a container according to the 
present invention, also such that are in solid powdered or lyophilized 
forms can be stored together with diluents and other parenteral fluids 
when appropriate for stability reasons. 
A container according to the present invention is preferably manufactured 
with an inventive method wherein a flexible polymeric multilayered 
material is introduced in bag forming station where a bag shaped sealed 
inner container is manufactured by welding together polypropylene 
containing sealing layers of the material and where optionally at least 
two chambers are formed by welding at least one partitioning peelable seal 
seam at a lower temperature. During the bag forming process a side of said 
inner container is provided with at least one temporary opening, whereupon 
the inner container is filled with at least one parenterally 
administerable fluid through said temporary opening. The temporary opening 
at the side of said inner container can then be sealed by welding 
permanent seams and the filled and sealed inner container is enclosed in 
an oxygen barrier forming envelope together with an oxygen absorber and 
the so final sealed container is sterilized. 
Preferably, the polymeric material for the inner container is in the form 
of thin flexible sheet in a suitable, predetermined size when introduced 
to the bag forming process. The sheet is first attached to a sealed port 
system for fluid communication, preferably of the saddle-formed type 
described above, whereupon the port system is welded to the sheet. When 
attaching the port system the sheet may first be penetrated by a suitable 
tool, so to form one or several orifices in the sheet corresponding to the 
number of orifices of the port system. Preferably, two such orifices are 
made to correspond with an exit and an inlet port. 
A bag shaped sealed inner container with two identical faces, a bottom, a 
top and two sides is formed around the bottom with the attached port 
system in its bottom by welding together the polypropylene containing 
sealing layers of the material by conventional welding tools, thus forming 
two side seams and a top seam. 
Although the above described forming of the bag is preferred according to 
the present invention, it would in certain applications be conceivable and 
regarded as a part of the present invention, to, as an alternative, start 
the manufacture from a blown tubular parison of polymeric material and by 
welding form permanent sealing seams in its top and bottom and provide for 
the attachment of a port system in its bottom seams. Filling ports for the 
chambers must thereby be attached during said welding procedure. This type 
of manufacturing process suitable for preparation of inner containers 
having one or two chambers, but less suitable if three or more chambers 
are preferred. The manufacturing process may as another alternative start 
from two sheets which are welded together with four seams around to form a 
bag shaped inner container having a sealed port system for fluid 
communication welded in its bottom seam. Such an inner container can be 
provided with peelable seal seams between its storage chambers and 
alternative temporary filling ports, as disclosed below. 
If two or more chambers are desired for separate storage of two or more 
agents, at least one leak tight peelable seal seam is formed as partitions 
between the chambers of the inner container which are possible to rupture 
by hand in a predetermined manner. By welding at a specific, lower 
temperature compared to the previously mentioned permanent weldings such 
peelable seals can be manufactured. As will be discussed below in greater 
detail the peelable seal seams can be made with a specifically designed 
zone to obtain an initial rupturing point to facilitate their manual 
opening when it is desired to mix the stored contents within the 
container. 
To enable filling of the inner container it is provided with at least one 
temporary filling port in the side of the bag shaped inner container which 
subsequently to completed filling is sealed with a permanently welded 
seam. The filling is preferably performed in a controlled atmosphere and 
in connection with a blast of an inert gas, such as nitrogen or helium, to 
remove air from the inner container. 
According to a first embodiment of the manufacturing method, one or several 
specific provisional filling tubings designated for one or several fluid 
agents are attached in the seam of the inner container during the welding. 
The chambers can then be filled with one several parenterally 
administerable fluids by through the provisional filling tubings by 
sealing connection to filling nozzles of a conventional filling equipment. 
After the filling is completed, the side provided with filling tubings 
attached to the seam is cut off, whereupon the side is re-sealed with a 
permanently welded seal. 
According to a second embodiment of the manufacturing method, one side of 
multi-chamber inner container is sealed by means of a weak welding which 
can be ruptured by means of the filling equipment in order to form at 
least one temporary opening in the side seam. Preferably, the weak side 
seam is welded so as two sleeves are formed from the edges of the sheet 
outside the weak seam to enable the filling equipment to open the seam by 
a peeling. For example the filling equipment can be provided with one or 
several twistable rods which opens the seam by a peeling motion in 
connection with that one or several filling nozzles are introduced in the 
inner container from its side, preferably in a controlled atmosphere in 
connection with a blast of an inert gas, as mentioned above. After the 
filling is completed the filling nozzles are removed and the side of the 
inner container is re-sealed with a permanent welding seal. It is to be 
understood that alternative means for open the peelable seal to form 
temporary opening for filling can be employed. for example the filling 
nozzles may provided peeling means in the form of protruding devices which 
may perform a twisting, peeling motion. After filling and removing the 
nozzles, the side of inner container is welded and sealed by a permanent 
seam. 
According to a third embodiment at least one filling orifice is formed in a 
side seam of the container with a shape corresponding to a filling nozzle 
of the filling equipment in order to provide a sealing connection between 
the orifice and the nozzle during the filling procedure. Such filling 
orifices can be formed by directly shaping the flexible material to an 
orifice having a form corresponding to the nozzles or by attaching a 
separate orifice to the side of the inner container when forming a side 
seam. 
The level of filling or amount of head space in each chamber must be 
carefully controlled. It is desired that the filling level of each chamber 
is, if not identical, at least comparable which is advantageous for 
obtaining the same heat penetration of the filled products during the heat 
sterilization. When desiring the level of filling it must be considered 
that a large head space volume from a low filling level might lead to that 
a sensitive lipid emulsion partially breaks up if the container is 
unintentionally shaken during its handling. A small head space volume from 
a high filling level will lead to difficulties in reading a correct fluid 
level in the container. 
The completely assembled and filled inner container is enclosed in an 
oxygen barrier forming envelope together with an oxygen absorber and 
optionally together with one or several visual indicators. The finally 
assembled container can now be sealed by permanently welding the envelope 
together in tool operating in a controlled, if desired, inert atmosphere. 
The container can now be sterilized by means of steam at about 120.degree. 
C. (autoclavation) or by sterilizing gamma radiation. The described 
inventive manufacturing method is advantageous for industrial production 
of parenteral nutrients and minimizes the utility of a controlled 
atmosphere and the use of inert gases is reduced to one step where the 
inner container is filled which is highly resource saving and guarantees a 
simplified production process. Furthermore, the filling employs 
provisional, openings at the side of the container which minimizes the 
risk for leakages conventionally experienced in connection with 
permanently attached filling ports. Such a filling also gives the benefits 
of a smaller enclosing envelope and a shorter autoclave program. 
The previously described peelable seal seams, serving as leak tight 
partitions between the chambers during storage in the inner container, 
must be easy to open manually by the user in a simple predetermined manner 
from the outside of the container, preferably without removing its 
enclosing envelope. According to the present invention, the peelable seal 
seams are preferably straight seams provided with a rupture zone. 
According to the embodiments demonstrated in FIG. 2a and FIG. 2b, the 
rupture zone of such a peelable seal seam comprises a point where two 
straight seams meet in angle. A small or sharp angle will be easy to 
rupture by the user, but it will at the same time create a risk for 
unintentional opening when handling the container. Such a seam will enable 
a surprisingly easy rupturing or peeling process by providing a 
concentration of the opening forces on a single point in the angle of the 
seam, whereupon it can be easily peeled apart. In contrast, a very large 
angle will provide a seam that is difficult to open. It is desired to 
obtain a optimized angle which gives initial opening resistance of the 
seam while providing a successively reduced resistance as the opening 
proceed towards the sides of the container, when the fluid enters between 
the foils and separates them. When having a sufficiently large angle, the 
opening force and the foils will become almost perpendicular to the seam 
which facilitates the opening process. A too small angle might also lead 
to the appearance of hole in the middle of the seam, but no further 
opening of the seam, since the lines of forces on the opening point will 
have tangential direction and not contribute to the opening of the 
remaining seam. For embodiments of FIG. 2a and 2b and similarly formed 
seams, the angle of the seam (or in the projection of the seams when 
having curves in the seam) is at least 90.degree.. Preferably, the angle 
is less than about 170.degree. and more preferably between about 
110.degree. to 160.degree.. According to specifically preferred 
embodiments, the angle is between about 120.degree. to 140.degree. and 
according to two experimentally well functioning embodiments about 
120.degree. or about 140.degree.. Both rupture zones demonstrated in FIG. 
2a and 2b will provide for local reductions in the opening force which 
considerably facilitates a manual opening of the peelable seals. As also 
demonstrated in FIG. 2a the rupture zone can comprise a curved part of the 
seam. It may also be advantageous to round one or several sharp sections 
of the seam in order to control the manual forces required for the rupture 
process. The seams according to FIG. 2 have will provide easy peelable 
openings in a container having a length of 450 mm including a handle part 
and a width of 300 mm, as illustrated in FIG. 1. Such seams can readily be 
opened by different handling techniques which are intended to be a part of 
the instructions of the container. The seams are suitably opened while 
still having the outer enclosing envelope protecting the inner container 
which gives the benefit of prolonged protection. 
The rupture zones preferably are positioned in the middle of the seam, so 
it can be successively opened from the middle towards the sides, since 
this may enable a highly reproducible opening procedure by the user from 
the outside of the bag. The rupture zone typically has an extension of 
less than half the entire seam, preferably less or equal than about 40% of 
the seam and more preferably less than about one third of the seam length. 
The width of the weak seal seams are typically less than 10 mm and 
preferably about 3 to 8 mm and exemplified as about 6 mm in the seams 
demonstrated in FIG. 2a and 2b. Alternative designs of the rupture zone to 
what have been exemplified in FIG. 2a and 2b and discussed above are 
conceivable to the skilled person if they can comply with the demands of 
being leak tight during storage and transportation and yet are readily 
opened manually according to simple instructions. For example, the 
peelable seal seam can be made entirely straight and by various means such 
as variations in the welding pressure and/or temperature and differently 
shaped welding tools. 
Suitable peelable seal welding temperatures for the above mentioned EXCEL 
brand of multilayered polymeric material material in the inner container 
are in the range of 106-121.degree. C. using a pressure of about 315.+-.20 
N of the welding tool for 2-10 second with gauge meter of about 0.3 mm. 
Such seams are demonstrated to be suitably leak tight after being 
subjected to conventional mechanical package tests and are objectively 
easy to open, also after the container has been subjected to steam 
sterilization at 121.degree. C. for about 20 minutes. 
A first preferred opening procedure is to gently roll up the container from 
the upper side (the side opposite to the attached port system) and thereby 
make use of the volume of the largest chamber, suitably containing a 
glucose solution, to exert a pressure large enough to rupture the seal in 
its weakest point and peel apart the seam towards the sides of the 
container. Another preferred way of opening the seal is to pull the front 
and the rear walls of the inner container apart from one another by a 
careful pulling motion so a rupture is formed in the weakest spot of the 
seal which thereby may be easy to peel apart. 
When making an inventive container ready for use, its peelable seal seams 
can be ruptured in a predetermined manner as discussed above. The stored 
parenteral agents can thereby be mixed in a mixing chamber constituting 
the entire volume of the inner container. If necessary the container can 
be gently agitated to a homogenous fluid suitable for immediate 
administration. For the alternative of mixing a separately stored lipid 
emulsion, an amino acid solution and carbohydrate solution, it can be 
readily mixed into a TPN-solution in a highly convenient manner. The 
enclosing envelope can be removed and if desired supplementary agents can 
be introduced through the port system to be admixed to container. The 
inner container is now completely ready to be used and, if desired hanged 
on a rack by means of the hanger or other ready made means of the 
container before connecting to a patient, for example by using a 
conventional infusion device after penetrating the outlet port of the port 
system. The inventive container is aimed to be adapted to a large number 
of conventional infusions sets and such details will not be discussed here 
in further detail, since they are not a part of the present invention. 
EXAMPLE 1 
This example shows the stability of INTRALIPID lipid emulsion 20% in a 500 
ml EXCEL brand of multilayered polymeric material polymer inner container 
wrapped in an enclosing envelope made of the layers PET-aluminum 
oxide/glue/PP/EVOH/PP given the trade name Oxnil (Pharmacia & Upjohn AB), 
together with an oxygen absorber (AGELESS FX200PA ferrous oxygen absorber 
FX100 from Mitsubishi Gas Co.) INTRALIPID lipid emulsion 20% in a 500 ml 
glass bottle is used as a reference. 
INTRALIPID lipid emulsion 20% stored in a container according to the 
present invention was compared with INTRALIPID lipid emulsion 20% stored 
in a glass bottle at 25.degree. C. and 60% relative humidity for 18 
months. After 18 months storage the pH values and the amounts of free 
fatty acids (FFA) and lysophosphatidyl choline (LPC) were tested. The mean 
droplet size was measured according to conventional routines employed by 
manufacturers of intravenous lipid emulsions in the pharmaceutical 
industry. 
______________________________________ 
LPC FFA Mean 
Months Peroxides (mg/ (mmol/ 
droplet 
storage (mEq/l) pH ml) L) size (nm) 
______________________________________ 
Emulsion stored 
12 0.0 7.2 0.69 2.3 387 
in glass 18 0.1 7.1 0.84 2.7 348 
Emulsion stored 
12 0.0 7.5 0.74 2.2 334 
in polymer 
18 0.0 7.3 0.83 2.7 335 
container 
______________________________________ 
(Mean values of five batches) 
The initial pH-values were about 8.0-8.4 and decreased after storage, as 
would be expected due to an increase in free fatty acids (FFA) and 
lysophosphatidyl choline from hydrolysis of triglycerides and 
phospholipids. A minor weight loss was measured on the polymer containers 
about 0.6% after 12 months and about 0.8% after 18 months. 
This test demonstrates that the container according to the present 
invention exhibits an entirely comparable storage capacity in relation to 
glass containers in protection against degradation and physical changes 
that deteriorates the emulsion quality. Emulsions stored in the inventive 
container will consequently have a shelf life of at least 18 months when 
stored during normal conditions. 
EXAMPLE 2 
The oxygen barrier forming capacity of the material selected as an envelope 
for the inner filled container is tested. 
The envelope material consists of a multilayered polymer structure of 
PET-metal oxide/glue/PP/EVOH/PP as disclosed, above in Example 1. 
In order to determine the benefit of the PET-metal oxide layer, such a film 
(Film 1) is compared to a conventional PP/EVOH/PP (PP=polypropylene and 
EVOH=((poly)-ethylene vinyl alcohol) film (Film 2) for oxygen permeability 
measured in ml oxygen penetrated per day and m.sup.2, at two different 
temperatures and at 75% relative humidity. The permeability tests were 
performed with standard Mocon permeability measurements. 
______________________________________ 
Film 1 (ml/day, m.sup.2) 
Film 2 (ml/day, m.sup.2) 
______________________________________ 
25.degree. C. 
1.1 4 
40.degree. C. 
2.9 23 
______________________________________ 
It is obvious that the PET-metal oxide containing film (Film 1) complies 
with the requirements of having an oxygen permeability of less than 5 
ml/day, m.sup.2 The PET-metal oxide film was also subjected to chemical 
and mechanical tests after being steam sterilized according to the 
European Pharmacopoeia and exaggerated test at 121.degree. C. for 60 
minutes. It was found the material also fulfills the demand of the 
European Pharmacopoeia when considering the migration of components from 
the film, as well as having excellent values in terms of absorbance, 
alkalinity/acidity, oxidizable substances and appearance of the stored 
solution. 
EXAMPLE 3 
This example aims to study the mixing properties into a safely 
administerable TPN-solution of one batch of lipid emulsion stored in a 
container according to the present invention for 12 months at +5.degree. 
C. and +25.degree. C. 
INTRALIPID lipid emulsion 20% filled in 500 ml inner containers made of 
EXCEL brand of multilayered polymeric material were stored with an oxygen 
absorber in an enclosing envelope made of the layers PET-metal 
oxide/glue/PP/EVOH/PP, as disclosed in Examples 1 and 2. 
The so stored lipid emulsion was brought together with a 1000 ml amino acid 
solution (VAMIN amino acid solution 14 g N/l) and 1000 ml glucose solution 
(Glucose 20%). 10 ml ADDIPHOS phosphate solution were added to the glucose 
solution. SOLUVIT vitamin preparation reconstituted in VITALIPID lipid 
preparation was added to the lipid emulsion and conventional electrolytes 
(ADDAMEL electrolyte, ADDEX electrolyte NaCl, Addex.RTM. KCI and 
CaCl.sub.2 1M) to the amino acid solution. After gentle agitation, the 
mixture was transferred to a 3 liter IV bag with its air expelled which 
was agitated thoroughly to ensure proper mixing. Part of the bag was 
dispensed into a glass bottle for analyze day 0 and day 6. 
The IV bag with its remaining content was stored flat horizontally for 6 
days at cold temperature about +5.degree. C. followed by one day in room 
temperature about +25.degree. C. when it was hung vertically. The glass 
bottles were stored at room temperature for 7 days and 24 hours, 
respectively. To be considered physically stable the admixtures must pass 
the inspection after 24 hours storage at room temperature and 6 days 
storage at cold temperature followed by one day at room temperature. 
______________________________________ 
Mean droplet size (.mu.m) 
(D(4, 3), Malvern mastersizer 
0 days 6 + 1 days 
______________________________________ 
+5.degree. C. 0.37 0.39 
+20.degree. C. 0.37 0.38 
______________________________________ 
The appearance of the emulsions was approved according to a conventional 
visual inspection performed as a standard routine by experienced emulsion 
manufacturers. A cream layer varying between 1 and 3.5 mm was present in 
all admixtures. It was, however easily redispersed by gentle agitation. 
There were no significant change in mean droplet size or drop size 
distribution after 6+1 days storage. The fraction of droplets less than 
5.29 .mu.m were 100% in all samples when measured with a Malvern 
Mastersizer and there were no droplets larger than 8 .mu.m in any of the 
samples according to an investigation with a phase contrast microscope. 
The admixtures tested were satisfactory physically stable according 
emulsion appearance. 
EXAMPLE 4 
The mixing properties of INTRALIPID lipid emulsion 20% (20% soybean oil fat 
emulsion from Pharmacia AB), filled and steam sterilized in three chamber 
inner containers made of EXCEL brand of multilayered polymeric material , 
was compared to INTRALIPID lipid emulsion 20% heat sterilized and stored 
in a glass bottle. Each three chamber container was purged with filtrated 
nitrogen two times immediately prior to the filling and 500 ml nonsterile 
INTRALIPID lipid emulsion was transferred into the middle compartment from 
glass bottles. The other compartments were filled 614 and 1193 ml water 
for injection, respectively. The filled and sealed container was placed in 
an envelope made of PET-metal oxide/glue/PP/EVOH/PP, as mentioned in 
earlier examples, with an oxygen absorber between the outlet and the inlet 
port of the saddle formed port system. Before sealing the envelope, it was 
evacuated in a Multivac before nitrogen was flushed into the envelope to a 
suitable gas volume for sterilization, whereupon it was sealed. The 
container was thereafter autoclaved corresponding to 17 to 20 minutes at 
121.1.degree. C. The reference glass bottle was autoclaved corresponding 
to 12 minutes at 121.1.degree. C., according to a regular manufacturing 
process. The mixing was carried out under aseptic conditions in the same 
order is if mixing was performed in a three chamber container. A 17.2% 
glucose solution was transferred to the mixing vessel under nitrogen 
protection, whereupon lipid emulsions (INTRALIPID lipid emulsion 20%) 
treated as above, was added and after gentle shaking amino acid solution 
(VAMIN amino acid solution 18 with electrolytes) was admixed and agitated. 
The admixtures were dispensed into sterile infusion bottles under nitrogen 
protection. After sealing the bottles, they were stored at ambient 
temperature (about 25.degree. C.) for two days or at about 5.degree. C. 
for 6 days followed by 2 days at about 25.degree. C. 
The admixtures were tested for creaming (visual inspection of the cream 
layer), emulsion appearance (visual inspections of oil droplets on surface 
and glass walls) and mean droplet size and droplet size distribution 
(Malvern Mastersizer) 
No obvious difference could be found in creaming or emulsion appearance 
between the different admixtures. 
The following mean droplet sizes in .mu.m were found for admixtures with 
lipid emulsion from glass bottle and mean values from three different 
batches stored in the polymer container, respectively, 
______________________________________ 
Storage time/temp. 
glass bottle 
polymer container 
______________________________________ 
48 h at about 25.degree. C. 
0.40 0.43 
6 days at 5.degree. C. and 48 h 
0.42 0.44 
at 25.degree. C. 
______________________________________ 
The results show that lipid emulsion autoclaved in three chamber polymer 
containers maintain their mixing properties and do not physically 
deteriorate, when compared to emulsions autoclaved in glass bottles. 
By its high integrity of the stored constituents, its specific chamber 
configuration in multi-chamber embodiment and facilitated mixing 
provisions, the container considerably improves both the safety and the 
convenience for the patients dependent on long-term administration 
regimens when compared both to conventional mixing systems consisting of 
individual glass bottles and comparable flexible container with a shorter 
shelf life. Even the most oxygen sensitive amino acids will now be 
possible to comprise in during long term storage by using the inventive 
containers. The inventive containers are also highly suitable for being 
industrially manufactured in a large scale by a forming, filling and 
sealing procedure of the inner containers which subsequently are assembled 
to the final container and sealed in an outer envelope, with a minimum of 
requirements of an oxygen deprived atmosphere, before finally being 
sterilized and stored.