Medical container with improved peelable seal

[0001] The present invention relates to a container for storing pharmaceutical agents which comprises a weld with a curved fracture zone, which is easy to open even with high weld strength. Furthermore, the present invention relates to a method of making this container and the use of the container for storing pharmaceutical substances, dialysis solutions, infusion solutions and / or nutrients.

[0002] Flexible containers made of polymeric film are widely used for storing pharmaceutical substances, dialysis solutions, infusion solutions and / or nutrients. For the purposes of opening filled containers or compartments of these containers, several materials and methods have been developed for producing peelable seams (peelable, heat-sealed). In contrast to permanent welded seams, tear welds can be broken by tensile stress or by pressure on an adjacent container chamber that is filled with liquid. The weld must be opened without damaging the container material or causing leakage. The strength of the peel seal should be large enough for production or transport needs, but small enough to open the bag easily.

[0003] In order to simplify the opening of tear welds, such welds should be provided with so-called rupture zones, whereby the opening force is locally reduced and manual opening of the tear welds is facilitated. This type of weld can easily be opened using various gripping techniques.

[0004] Document EP 0 700 280 relates to a multilayer polymer film intended for the production of a multi-chamber medical bag for the preparation of mixed medical solutions, which comprises at least two chambers that are separated from each other by means of a peel seal. The document EP 0 700 280 suggests V-shaped crack zones. In this case, the weld first opens at the top of the letter V, because it produces the greatest force acting on the weld. [0005] Document EP 0 893 982 / WO97037628 relates to flexible polymer containers with improved long-term storage capacity, intended for parenterally dispensed medical liquids.

[0006] This container comprises an outer hermetically sealed shell and an inner container filled with one or more medical agents. The inner container contains tear welds having rupture zones. The rupture zones of the tear welds are V-shaped and therefore contain a point where two rectilinear seams meet at an angle. A small or sharp angle will be easy to tear by the user, but at the same time creates the risk of unintentional opening when handling the container. On the contrary, a very large angle will give a seam that will be difficult to open. Therefore, EP 0 893 982 suggests an angle for seams in the fracture zone of 120 to 140 °. [0007] The first preferred opening procedure mentioned in document EP 0 893 982 is to gently roll the container from above and use the volume of the largest chamber to apply a sufficiently high pressure to break the weld at its weakest point and break the seam towards the sides of the container. This technique was designated as the rolling method. Another preferred way of opening the weld is to pull the front and rear walls of the inner chamber apart

EP 1 773 277 wykonanie1 making a careful pulling motion so as to create a crack at the weakest point of the weld that can be easily broken. This technique was designated as the pulling method.

[0008] This document further describes a rupture zone having two rectilinear seams meeting in the formed area as a curved portion. The rupture zone still contains straight sections.

[0009] The two most common complaints about containers with peelable seals are: 1) peel seals are already open after reaching the consumer, and 2) damage to the foil when opening the peel seals.

[0010] There is always a balance between the requirement that the peel seal be strong enough to withstand the manufacturing process and be easily opened by the consumer. Flexible containers with tear-resistant low-strength welds, e.g. 5-10 N / 30 mm, can be easily opened, but low-strength welds can be damaged during the manufacturing and shipping process.

[0011] For this reason, it is preferred to produce peelable welds with a strength of at least 30 N / 30 mm, and even better 40 N / 30 mm. However, the inventors have noticed that the polymer film is often broken when a V-shaped peel seal, such as disclosed in EP 0 893 982, and with a strength of at least 30 N / 30 mm, is opened by pulling, which causes leakage in the pouch. This problem can be avoided by using a rolling method that should allow for more controlled opening by applying more even pressure to the weak weld. [0012] The inventors have, however, noticed that the V-shaped crack zone according to EP 0 893 982 shows relatively high resistance to manual opening of welds by rolling when the weld strength is equal to or higher than 30 N / 30 mm.

[0013] High resistance to opening means that a higher burst pressure inside the liquid-filled pouch is required to open the weld. For the applicant, the main disadvantage in daily operation is the relatively high burst pressure required to open the burst seams. As a result, handling the bag is more difficult. As a result of applying a high burst pressure, the weld opens rapidly in one stage instead of opening first in the rupture zone and slowly tearing the container sideways in the second stage.

[0014] When a container with three chambers is used, which are filled with different solutions, sudden and quick opening of the peelable seals is undesirable, since it is not possible to control which seam will be opened first. Even though the design of the pouch is the most important for controlling the order of mixing the contents of the chambers, uncontrolled opening of the welds, as mentioned above, can also cause uncontrolled mixing of the contents of the pouch.

[0015] In order to obtain a controlled opening of the peelable seals, it is desirable that the rupture zone opens in the first stage and in the second stage the remainder of the peelable seam remains. The experiments carried out by the inventors have shown that this can hardly be obtained with conventional V-shaped welds, especially when V-shaped welds are difficult to open due to the high weld strengths of at least 40 N / 30 mm.

[0016] US 2004/134802 A1 describes a container for storing pharmaceutical agents made of a flexible polymer film. This multi-chamber container comprises an outer chamber and an inner chamber which are separated by a weak seal made by gluing together the peripheral edges of the laminated films. This weak weld is formed in the form of a rectangle having four straight sections running along the edges of the rectangular container.

EP 1 773 277 Β1

The glued rectilinear sections of the rectangular weak weld run at an angle of 90 ° and are connected through a curved fracture zone. The curved rupture zone is curved over its entire length between straight sections and contains a circular arc.

[0017] The object of the present invention is a container with a peelable seal that can be easily opened without the risk of destroying the container. In particular, the object of the present invention is a flexible container with a well-functioning peel seal in which:

- the weld should be easy to open when the weld strength is 40 N / 30 mm

- the weld should also not open with a slight pressure on the bag, which occurs during storage and transport

- the weld should not open rapidly in one stage, but it is desirable for the weld to open in two stages, first in the rupture zone and then in the rest

- the weld should be opened by rolling as long as the weld is broken. In this case, the weld should be easily opened up to a weld strength of 40 N / 30 mm.

[0018] The above objectives are achieved in a container made of a flexible polymer film comprising at least one peel seal having at least two substantially straight sections which are connected via a rupture zone, the rupture zone of the peel seal being curved along its entire length between these straight sections .

[0019] The one or more rupture zones of the peel seal connect substantially straight sections of the peel seal. The term substantially rectilinear means that the segments can be either perfectly rectilinear or minimally curved relative to the dimensions of the container. Preferably, the sections that are connected via a curved rupture zone are perfectly rectilinear.

[0020] The peelable seal according to the present invention may comprise more than one rupture zone and more than two straight sections. However, it is preferred that it contains two straight sections that are connected via one fracture zone. In the latter case, the rupture zone, in a specific preferred embodiment, is in the middle of the length of the peelable seal, resulting in two straight sections of equal length.

[0021] The rupture zone of the peelable seal is curved over its entire length between straight sections. The term curved means that there are no straight lines or any bends or angles within the fracture zone. The curved shape of the present invention means round shapes, sigmoidal and ellipsoidal shapes, and irregular curvilinear shapes, wherein the round and ellipsoidal shapes mean that the curved crack zone is formed as a circular arc or ellipse arc. It should be understood in this connection that the term "circle arc" or "ellipse arc" are equivalent to a segment of a circle or segment of an ellipse.

According to the invention, the curved weld fracture zone is formed as an arc of a circle with a radius of 5 to 75 mm, more preferably 10 to 30 mm, and even more preferably 20 to 25 mm, this radius being measured from the center of the circle to a point on the outer edge of the weld, the outer edge is the edge that is more offset from the center of the circle than the inner edge.

[0023] The curved rupture zone formed as a circular arc has a central angle of at least 60 °, more preferably 60 ° -180 ° and especially 90 ° -150 °.

EP 1 773 277 Β1 [0024] It is also preferred that the fracture zone is S-shaped, with the preferred S-shape consisting of two connected half-circles with a radius of 5 to 75 mm, more preferably of 10 to 30 mm, and most preferably of 20 to 25 mm. This radius is again measured from the center of the circle to the outer edge of the weld.

[0025] The straight sections of the peelable seam may be at an angle, or may be parallel to each other, or may be in a line. When the straight sections form an angle, the angle is from 150 ° to 180 °.

[0026] When the straight sections are parallel to each other, the distance (displacement) between the parallel straight sections is preferably from 10 to 60 mm, more preferably from 15 to 40 mm, and most preferably from 20 to 35 mm.

In a particular embodiment, the curved rupture zone is formed as a circular arc with a central angle of 90 °, and the straight sections are parallel to each other.

[0028] The width of the weld may vary between rectilinear sections and the rupture zone. In absolute terms, the weld width of straight sections is preferably from 2 to 10 mm, more preferably from 5 to 8 mm, and the width of the weld in the rupture zone is from 2 to 10 mm, preferably from 5 to 8 mm. In principle, the width of rectilinear sections may be different from the width of the crack zone. Preferably, however, the width of the straight sections and the width of the crack zone are the same.

[0029] The rupture zone is preferably located in the center of the weld, so that it can be successively opened from the center towards the sides, as this may allow a highly repeatable procedure for the user to open from the outside of the pouch. The rupture zone usually has a length less than half of the total weld, preferably less than or equal to about 40% of the weld, and even more preferably less than about 30% of the weld length. In a more preferred embodiment of the present invention, the length of the crack zone is from 3 to 10%, more preferably from 5 to 7% of the length of the peelable seal. But it can also be advantageous if the length of the rupture zone is between 7 and 13%. In absolute terms, the length of the crack zone is preferably 20 - 40 mm.

[0030] In a preferred embodiment, the container is made of a flexible polymer film having a region with a higher melting point, designated as its external and having a region with a lower melting point, designated as the interior of the weld, which can be glued together using conventional welding tools to the form of permanent or peelable welds. It should be understood that the internal area is to be directed toward the stored substance or substances and can form both permanent welds and various types of burst welds, depending on different welding conditions or operations.

[0031] Preferably, the film is made of at least two polymer layers, the inner layer being a sealant layer that has the ability to form both permanent and peelable seams, depending on different welding conditions or operations. [0032] The most preferred multilayer polymeric material for the container according to the present of the invention has been described in document EP 0 739 713 and is known under the name Biofine ™.

[0033] Another preferred multi-layer polymeric material may have the following structure:

[0034] The inner sealant layer is preferably based on polyolefins, for example polyethylenes and polypropylenes with different properties that are chemically inert to stored liquids, susceptible to autoclaving, weldable and recyclable. The terms 'polyethylenes' and 'polypropylenes'

EP 1 773 277 mają1 are intended to include both homopolymers and copolymers having such properties, unless otherwise stated. Preferably, the sealant layer is based on a polyethylene homopolymer, polyethylene copolymer, polypropylene homopolymer, polypropylene copolymer, polyethylene-polypropylene copolymer and / or a blend of polypropylene and polyethylene.

[0035] Preferably, the inner sealant layer contains a large amount of polyolefins, especially polypropylene, to utilize their inertness to stored fluids and to facilitate the manufacture of the container using various welding techniques. It is particularly preferred that this thin layer can create both peel but controlled welds at a given temperature as well as permanent welds with high coherence, depending on different welding conditions, e.g. different temperatures or welding pressures.

[0036] However, due to the fact that many conventional polyolefins, especially polypropylenes, often have insufficient flexibility and some brittleness, it is desirable to combine them with an elastic polymer. In a particular embodiment of the present invention, it is therefore preferable to combine the olefin sealant layer with the secondary elastomer to improve its elasticity and elasticity.

[0037] The thermoplastic elastomer that can be combined with the polyolefin in the sealant inner layer is preferably selected from the group consisting of a styrene-ethylene / butylene-styrene triblock polymer (SEBS), a styrene-ethylene / propylene-styrene triblock polymer (SEPS), and a triblock styrene-butadienestyrene polymer (SBS), and / or styrene-isoprene-styrene triblock polymer (SIS).

[0038] The outer layer preferably contains a flexible polymer material with a high melting point, which gives a material with better stability at high temperatures achieved locally during welding. Suitable materials can be found among some polyesters and their copolymers (copolyesters), especially cycloaliphatic polyesters.

[0039] At least one inner layer between the outer layer and the inner sealant layer containing a thermoplastic elastomer may be present.

[0040] Another material that has proved particularly useful for this type of container according to the present invention is Excel ™ from McGaw Inc., a multilayer polymer material with a thickness of about 200 microns, which is described in European Patent No. 0 228 819. Excel ™ has a multilayer structure essentially containing:

a) the inner sealant layer towards the medical fluid, consisting of a blend of polyethylene / polypropylene copolymer (FINA Dypro Z 9450) and Kraton B G1652 from Shell (styrene / ethylene / butadiene / styrene copolymer (SEBS));

b) the middle bonding layer of the KratonB G1652 material itself; and

c) the outer layer made of Ecdel ™ B 9965 (or 9566 or 9967) material from Eastman Chemical Co., which is a cycloaliphatic thermoplastic copolyester-ether, condensation product of the trans 1,4-dimethyl-cyclohexanedicarboxylate trans isomer, cyclohexanedimethanol and polytetramethylene glycol terminated ).

[0041] Other types of multilayer polymeric films can also be used according to the present invention. Other types are made of at least two different polymer layers, wherein

EP 1 773 277 wewnętrzna1 the inner layer is a sealant layer that is capable of forming both permanent and peelable welds, which are described in documents EP 0 893 982, EP 0 700 280 and WO 01/42009, as well as methods for their production and peel welding welds.

[0042] The container or bag with peelable seams, as previously described, can be enclosed in an outer package with a high oxygen barrier. The outer packaging film is preferably a multilayer structure comprising PET, a thin glass coating and polypropylene. Useful outer packaging is described, for example, in document EP 0 893 982. An oxygen absorber may be placed between the container and the outer packaging.

[0043] The present invention in a further embodiment also relates to a method for forming a container according to the invention, and in particular a method for forming the peel seal described above. In general, hot rod welding or pulse hot welding can be used to perform the permanent or peelable seal of the present invention.

[0044] Appropriate peel seal welding temperatures for the Biofine ™ films mentioned above are in the range of 122 - 130 ° C. Such welds appear to be sufficiently tight after conventional mechanical packaging tests and are objectively easy to open, also after subjecting the container to steam sterilization. Appropriate welding temperatures to create permanent welds using Biofine ™ are in the range of 130 - 160 ° C.

[0045] When Excel ™ is used as the multilayer film for the production of containers, the sealing temperature of the peel welds is 113-120 ° C, and the welding temperature for permanent welds is 130-160 ° C.

[0046] In another embodiment, the present invention relates to the use of the containers described above for storing pharmaceutical substances, dialysis solutions, infusion solutions and / or nutrients.

[0047] Illustrative embodiments of the invention and of the prior art container are shown in the figures, which are explained below, Figure 1 is a schematic top view of a first type of container according to the present invention, Figure 2 is a schematic top view of a second type of the container according to the present invention, Fig. 3 is a schematic top view of a third type of container according to the present invention in fig. 4 is shown a straight peel-off seal according to the prior art, Fig. 5 shows a weld with a V-shaped crack zone according to the prior art, Fig. 6 shows a first preferred embodiment of a weld with a rupture zone according to the present invention, Fig. 7 shows a second preferred example of performing a weld with a rupture zone according to the present invention, in Fig. 8 shows a third preferred embodiment of a weld with a rupture zone according to the present invention,

Fig. 9 shows a fourth preferred embodiment of a weld with a rupture zone according to the present invention, Fig. 10 is a sample illustration that shows the positions W1, T1, F1, W2, T2, F2 of the peelable weld for stress testing with with the container of Fig. 3 (see example 1), Fig. 11 is a sample illustration that shows the positions S1, S2, S4 and S4 of the peel seal for the stress test with the container of Fig. 1 (see example 2).

[0048] Particularly preferred embodiments in the figures are to illustrate the principle of the invention compared to the prior art, and not to limit the scope and idea of ​​the invention described above.

[0049] Referring to Fig. 1, a first preferred container according to the present invention is illustrated. This container contains a first chamber 20, a second chamber 21 and a third chamber 22. These three chambers are filled with three different parenterally administered liquid nutrients that should be mixed homogeneously just before being administered to the patient to produce a full parenteral nutrient solution ( TPN). In a particularly preferred embodiment, the first chamber 20 is filled with an aqueous solution containing carbohydrates, e.g. glucose, the second chamber 21 is filled with an aqueous solution containing amino acids and / or electrolytes, and the third chamber 22 is filled with a lipid emulsion i.e. a fat component. It should be noted that although three chambers are present in this embodiment, more chambers may be used. It should also be noted that the contents of these three chambers may be different and other possible contents are also possible. It is possible according to the invention to change the assignment of ingredients to these three chambers. This means that each of the components can be placed in any of the chambers. In another embodiment, chamber 22 contains an amino acid solution and chamber 21 contains a lipid emulsion. In addition, electrolytes may be contained in an aqueous solution containing carbohydrates.

[0050] The flexible container is preferably formed from a blown film 280 mm or 320 mm wide, so that only the upper border zone and the lower border zone are glued together. The upper border zone 23 comprises a hanger assembly 24 in the form of an opening, so that the container can be hung near the bed to administer the mix to the patient. The lower boundary zone 25 has a system of delivery holes 26 for separating the medical fluid and introducing additional components, depending on the patient's requirements.

[0051] The delivery opening system 26 comprises three holes located in the lower border zone 25 of the container. All holes can be used to fill the chambers. Furthermore, opening 26a is also present as an additional inlet opening for injecting additives directly into the chamber / chambers using a needle or syringe under aseptic conditions. An opening 26b is also present as an infusion opening for administering the product to the patient. The opening 26c, after filling the chamber, is closed in this preferred embodiment with a cap.

[0052] Which opening should be connected to which chamber depends on the set of compartments. In a particular embodiment, the opening 26a is located in the lower limit zone below the second chamber 21, the opening 26b below the first chamber 20 and the opening 26c below the third chamber 22. In another preferred embodiment below the third chamber 22 there is an additional opening 26a. The holes belong to the state of the art and are described, for example, in EP-A-0 811560.

EP 1 773 277 Β1 [0053] The container is made of a multilayer film based on polypropylene, for example described in document EP-A-0 228 819 or EP-A-0 739 713 (Biofine ™), which can form both peelable seams and and permanent welding using rod welding or pulse welding.

[0054] The container as the main bag is contained in an outer package with a high oxygen barrier. The outer packaging is a multilayer structure containing PET, a thin glass coating and polypropylene. A thin glass coating gives oxygen barrier properties. There is an oxygen absorber between the main bag and additional packaging.

[0055] The first chamber 20 has a larger volume than the second and third chambers 21, 22, respectively. The first chamber 20 is located in the horizontal upper part as well as in the vertical right part of the container, the upper part extending a distance of about 1/3 of the total distance between the upper and lower border zone and the right side extends about 1/3 of the total width of the container between the right and left side. The second chamber 21 is located in the vertical central portion of the container below the upper portion of the first chamber, the central portion extending about 1/3 of the total width of the container. The third chamber 22 is located in the vertical left part of the container below the upper part of the first chamber, the left part extending about 1/3 of the total width of the container. [0056] The three chambers of the container are separated by three highly tight welded seams. The first chamber 20 is separated from the second chamber 21 by a first tight seam 27 (weld 1), the second chamber 21 is separated from the third chamber 22 via a second tight seam 28 (weld 2), and the first chamber 20 is separated from the third chamber 22 by third airtight seam 29. [0057] The first seam 27 includes a horizontally extending portion 27a as well as the vertically extending portion 27b, while the second seam 28 comprises a vertically extending portion and the third seam 29 only includes the horizontally extending portion. The first, second and third seams have a common upper end 30. [0058] In a particular embodiment, starting from the left border zone 31, the horizontal third seam 29 extends about 1/3 of the width of the container about 1/3 of the length of the container between the first chamber and the third chamber. Starting from the end of the third seam 29, the second seam 28 extends vertically to the lower border zone 25 of the container separating the second chamber and the third chamber. Also starting from the end of the third seam 29, the horizontal portion 27a of the first seam 27 extends about 1/3 of the container width in about 1/3 of the container length, and the vertical portion 27b of the first seam extends from the end of the horizontal portion in a vertical direction to the lower border zone 25, separating the first chamber and the second chamber.

[0059] The first seam and the second seam are formed in the form of peelable seams comprising rupture zones 32, 33. The third seam 29 is preferably also formed in the form of a peelable seam, its opening strength being equal to or higher than the opening strength of the first and second seams respectively seamless. However, the seam 29 may be formed as a permanent weld.

[0060] In a particular embodiment, the first peel seal 27 comprises a first rupture zone 32 and the second peel seal 28 includes a second rupture zone 33 to avoid ripping the film when opening these welds. Curved opening zones are formed so that the welds open slowly in two stages, i.e. in the first stage in the opening zone and in the second stage in their other parts.

[0061] The transition zone 34 between the horizontal and vertical parts 27a, 27b of the first seam 27 is also formed as a rupture zone 34, but the transitional rupture zone preferably has a larger

EP 1 773 277 Β1 radius of curvature than the outer rupture zone 32 of the first tear weld 27. The larger radius generally results in a greater opening force of the tear weld, so that generally the rupture zone 32 opens before the rupture zone 34. The function of the pouch is, however, intact if the zone the cracks 34 will open before the rupture zone 32, as long as the weld 27b opens all the way to the bottom of the pouch before the rupture zone 33 opens.

[0062] The rupture zones of both welds may be located everywhere from the lower limit zone up to the fluid level. The preferred location is at least 50 millimeters above the border zone 25 (lower weld) and at least 50 millimeters below the mixed bag fluid level. However, the optimal location of the rupture zone is approximately halfway between the lower border zone and the fluid level.

[0063] The flexible container according to the present invention is easy to control manipulation. In order to mix solutions for the preparation of parenteral fluid, the container is rolled from the upper limit zone 23 towards the lower limit zone 25. As the container is rolled up, the fluid pressure increases in the chambers. When the pressure is high enough, the first peelable seal 27 opens in the fracture zone 32, i.e. the zone with the smallest radius. As a result of further rolling upwards, the fluid pressure increases even more and further parts of the first tear weld 27 begin to open, from the fracture zone 32 in both directions. The weld opens down to the lower limit zone and up to the fluid level. When the fluid level is reached, the weld is no longer pressurized and the weld will not open further. After opening the first weld 27, the second weld 28 is opened in the rupture zone 33. As with the first weld, the opening of the second weld propagates up and down. Therefore, the first solution and the second solution from the first and second chambers 20, 21, respectively, are mixed in the first stage, while the mixture of the first solution and the second solution and the third solution are mixed in the second stage. This is guaranteed by the advantageously greater strength of the third weld compared to the second weld and the first weld. However, if the third weld and the first weld had the same strength, the curved opening zone of the first weld guarantees the opening of the first weld before the second weld opens.

[0064] Even if the horizontal parts of the welds would have a lower strength than the vertical parts, the transitional rupture zone 34 of the first weld guarantees the opening of the first weld 27 before opening the second weld 28.

[0065] Fig. 2 shows another preferred embodiment with the peelable welds of the present invention. The container contains a first chamber 36, a second chamber 37 and a third chamber 38, which are separated from each other via hermetic seams 40 and 41. The first chamber is intended to be filled with its first solution, the second chamber is to be filled with the second solution, and the third chamber will be filled third solution. The first chamber 36 is separated from the second chamber and the third chamber 37, 38 via an airtight seam 40. The second chamber and the third chamber are separated from each other via a second airtight seam 41, both seams 40, 41 intersecting at intersection 43. W in the preferred embodiment of Fig. 2, the seams 40 and 41 are perpendicular to each other and form the shape of the letter "T".

[0066] At least part of the first seam 40 is provided with a rupture zone 39 according to the present invention which has been described in detail earlier and which can be opened to obtain

EP 1 773 277 Β1 of a fluid connection between the first and at least the second or third chamber. The entire hermetic seam 40 may also be formed as a separation zone.

[0067] The first chamber 67 preferably has a larger volume than the second chamber and the third chamber, respectively 37, 38. The first chamber 36 is preferably located in the horizontal upper part of the container, the upper part extending about the entire width of the container between the right border zone and left border zone, 31a and 31b. In the particular embodiment of Fig. 2, the volume of the first chamber 36 is approximately half the volume of the entire container. The peelable seal 40 with a rupture zone 39 extends horizontally between boundary zones 31a and 31b and at an almost equal distance to the upper boundary zone 23 and the lower boundary zone 25, thereby dividing the container into two halves and separating the first chamber 36 from the second chamber and the third chamber 37 , 38.

[0068] The second chamber and the third chamber 37, 38 are located in the lower half of the container and separated by a peel weld 41 which is perpendicular to the weld 40 and extend vertically between the peel weld 40 and the lower border zone 25. Weld 41 can be located in such a way that the chambers 37 and 38 have the same volume. In the preferred embodiment shown in Figure 2, however, the second chamber 37 has a larger volume than the third chamber 38.

[0069] The peel seal 40 includes a rupture zone 39 to avoid peeling the film when opening the seal. The rupture zone 39 is in the preferred embodiment of Fig. 2 located between the chambers 36 and 37. The preferred location is at least 50 mm from the border zones 31a and 31b. When the first chamber 36 is filled with an aqueous solution containing electrolytes and / or carbohydrates, i.e. glucose, the second chamber 37 is filled with an aqueous solution containing amino acids, and the third chamber 38 is filled with lipid emulsion, the rupture zone is preferably located between the chambers 36 and 37, according to as shown in Fig. 2.

[0070] The three chambers are filled with three different parenteral nutrients, in the form of liquids, which should be mixed homogeneously just before administration to the patient to form a full parenteral nutrient solution (TPN). In this particular embodiment, the first chamber 36 is filled with an aqueous solution containing carbohydrates, i.e. glucose, the second chamber 37 is filled with an aqueous solution containing amino acids and / or electrolytes, and the third chamber 38 is filled with a lipid emulsion i.e. a fat component. It should be noted that although three chambers are present in this embodiment, more chambers can be used. It should also be noted that the contents of the three chambers may be different and other possible contents are also possible. It is possible according to the invention to change the assignment of ingredients to these three chambers. This means that each of the ingredients can be placed in any of the chambers. In addition, electrolytes may also be contained in an aqueous solution containing carbohydrates.

[0071] The flexible container in the preferred embodiment of Fig. 2 is formed from a blown film so that only the upper border zone and the lower border zone are glued together. The upper border zone 23 comprises a hanger assembly 24 in the form of an opening, so that the container can be hung near the bed to administer the mix to the patient. Each of the chambers 36, 37 and 38 includes one opening (42a, 42b, 42c), which are located in the upper and lower border zone 23, 25, respectively. Openings 42a, 42b, 42c serve to fill the pouch, isolate the medical mix and / or introduce additional ingredients, depending on the patient's requirements.

EP 1 773 277 Β1 [0072] In the preferred embodiment of Fig. 2, the opening 42a serves for filling, the opening 42b serves for administering the contents of the pouch to the patient, and the opening 42c is an additional opening for injecting the pouch additives. Which hole should be connected to which chamber depends on the set of compartments. The holes belong to the state of the art and are described, for example, in EP-A-0 811 560.

[0073] Both hermetic seams are formed in the form of peelable welds. According to the invention, the hermetic seams are arranged together with the formed crack zones so that when the container is used to prepare a mixed medical solution, the first seam 40 and the second seam 41, which are formed in the form of peelable welds, open successively, with the opening beginning in the zone cracks in the first seam 40. Thanks to this, the components of the cells are mixed one after the other.

[0074] According to the embodiment of Fig. 2, the hermetic seams 40, 41 are arranged together with the formed rupture zone 39 so that when the container is used to prepare a mixed medical solution, the rupture zone opens as a result of applying pressure to the container starting from top down to the bottom of the container. According to another embodiment, the rupture zone 39 and the seams 40, 41 are peelable seals that are opened by rolling the container up.

[0075] By rolling the container from the top downwards, the fluid pressure in the first chamber increases. When the fluid pressure is high enough, the tear welds 40, 41 open one after the other so that the fluids mix. The arrangement of the peelable welds according to the invention allows controlled mixing and the problem of container damage is reduced.

[0076] The flexible container according to the preferred embodiment of Figure 2 is easy to control manipulation. In order to mix the solutions and prepare the parenteral fluid, the container is rolled up from the upper limit zone 23 towards the lower limit zone 25. By rolling the container, the fluid pressure increases in the chambers. When this pressure is high enough, the peelable seal 40 begins to open in the zone of rupture 39, i.e. in the zone with the smallest radius. Weld 40 continues the process of opening towards boundary zone 31 a and towards the intersection with weld 41. Then, the intersection between welds 40 and 41 opens and the opening process runs towards the lower boundary zone 25. Part of weld 40 between weld 41 and weld 31 b it can remain closed even if it is tearable.

[0077] As a result, the contents of chambers 36 and 37, which are preferably an aqueous solution containing an electrolyte and / or carbohydrates, and an aqueous solution containing an amino acid, are mixed in the first stage, and the chamber 38, which preferably contains a lipid emulsion remains closed. In the second stage, when the cut between weld 40 and 41 opens, the third chamber 38 also opens. Therefore, the first and second solutions of the first chamber and the second chamber 36, 37 are mixed in the first stage, and the mixture of the first solution and the second solution and the third solution from the chamber 38 are mixed in the second stage.

[0078] In principle, all previously described polymer films (e.g. Excel) can be used. The container of Fig. 2 is made of a multilayer film based on polypropylene, for example described in document EP-A-0 228 819 or EP-A-0 739 713 (Biofine ™), which can form both peelable welds and permanent welds with using thermal welding with a hot rod or pulse welding.

[0079] The container as the main bag is contained in the outer packaging with a high oxygen barrier. The outer packaging is a multilayer structure containing PET, a thin coating

EP 1 773 277 Β1 glass and polypropylene. A thin glass coating gives oxygen barrier properties. There is an oxygen absorber between the main bag and additional packaging.

[0080] Fig. 3 shows another preferred container with peelable welds according to the present invention. All reference numbers in this figure have the same meanings as in Figure 2. This container is divided into three chambers 36, 37, 38 by two tear welds 40 with crack zones 39. Both tear welds extend horizontally between border zones 31a and 31b . All three chambers also extend between the border zones 31 aa 31 b and are arranged on top of each other. By rolling the container from the upper limit zone 23 towards the lower limit zone 25, fluid pressure increases in the chamber 36. When this pressure is high enough, the upper peel seal 41 between chambers 36 and 37 opens in the rupture zone 39 and the contents of both chambers can mix in the first stage. As a result of further rolling, the lower peel seal is also opened, which separates the chamber 38, after which the mixture of the first solution and the second solution and the third solution in the chamber 38 mix in the second stage.

[0081] Fig. 4 shows a rectilinear peel seal according to the prior art that does not include a rupture zone (type A seal). The width of the 14 welds is 20 mm.

[0082] Fig. 5 shows a peelable seal with two straight sections 7, 8 and a V-shaped crack zone 5 according to the prior art (type B seal). The width of the 14 welds is 5 mm, the width of the crack zone 17 is 150 mm, and the height of the 9 crack zone is 30 mm. Reference number 13 means the total length of the weld.

[0083] Fig. 6 shows in detail the preferred shape of the peelable seal according to the present invention (C-type seal) with two straight sections 7, 8 and a rupture zone 5. The width of the weld 14 is 7 mm and the radius 15 is 90 mm. The width of the crack zone 17 is 145 mm and the height of the crack zone 9 is 43 mm.

[0084] Fig. 7 shows another preferred shape of the peel seal (type D seal) in which the fracture zone 5 is formed as an arc of a circle with a central angle of 18 ° 145 °. Radius 15 is 20 mm. Straight sections 7, 8 are parallel to each other with an offset of 15 mm. The width of the 14 welds is 7 mm. Reference number 13 means the total length of the weld.

[0085] Figure 8 illustrates another preferred shape of the peel seal of the present invention (E-type seal) with a fracture zone 5 that is S-shaped between end points 6a and 6b. The S-shaped rupture zone is formed of two semi-circles with a radius of 15 mm. Straight weld sections 7, 8 are parallel to each other with an offset 16 of 60 mm. The width of the 14 welds is 7 mm. Reference number 13 means the total length of the weld.

[0086] Fig. 9 shows another preferred shape of the peel seal (F type seal), in which the fracture zone 5 is in the form of a circular arc with a central angle 18 of 90 °. Radius 15 is 20 mm. The straight sections 7, 8 are located parallel to each other with an offset of 20 mm. The width of the 14 welds is 7 mm. Reference number 13 means the total length of the weld.

Examples [0087] The following part of the invention is illustrated by examples which are to be understood not to limit the scope or idea of ​​the invention.

EP 1 773 277 Β1

Example 1

A) General procedure for making the container according to Fig. 3 [0088] The containers shown in Fig. 3 were made of cast polyolefin film (Excel). Tear welds were welded at various temperatures ranging from 113 to 120 ° C in order to obtain different weld strengths, for 3 seconds at 4 bar pressure.

[0089] Permanent welds were welded at 130 ° C for 1.5 seconds under 4 bar pressure. Welding was carried out using the hot rod technique.

B) Tests performed [0090] The pouches according to Fig. 3 were made according to the above procedure with different shapes of the peelable seals shown in Figs. 4-8. Three different strengths of the peelable seals were used, which were about 10 N, 20 N and 30 N.

[0091] Each sample group contained 20 bags. 10 bags were filled with water and seven of them were wrapped from the outside and sterilized in an autoclave with a water shower (F_about = 12, temperature 121 ° C). The following tests were performed on each group of samples.

Stress test:

[0092] The stress test was performed on 30 mm wide strips using an Instron stress tester. Test strips were taken from the F1, T1, W1 and F2, T2, W2 sites (see positions in Figure 10). The initial grip distance was 50 mm. The test speed was set to 500 mm / min. Maximum strength was measured.

Non-sterilized bags: the weld strength was measured on 5 bags.

Sterilized bags: the weld strength was measured on 2 bags.

Burst test:

[0093] Restrictive plates with an opening of 50 mm were used. The pressure was measured directly inside the bag using a pressure sensor. The input pressure was set to 0.3 bar. Weak welds were opened towards the apex, i.e. weld 1 was opened before weld 2.

[0094] Non-sterilized bags: the break test was performed on 5 bags.

Sterilized bags: the crack test was performed on 2 bags.

Manual opening of the pouch [0095] Tear welds are manually opened by rolling. The degree of difficulty was rated on a scale of 5 according to the definition below.

EP 1 773 277 Β1 = very easy = easy = some resistance, but opening without problems = high resistance, but opening is possible with great effort

5 = not open

Non-sterilized bags: the manual opening test was performed on 3 bags.

Sterilized bags: manual opening was done on 3 bags.

C) Test results for different weld designs [0096] Tests were carried out on bags with different weld shapes, from A to E, as shown in Fig. 4. 8. Shapes C to E were inventive examples, and shape A was a straight-line reference weld, and shape B was a reference example according to the prior art of document EP 0 893 982.

Shape A (Figure 4 - reference example) [0097] The table below shows the total average value of the weld strength, measured in 6 positions.

<td>Identifier samples</td><td>Welding strength of non-autoclaved bags (N / 30 mm)</td><td>Welding strength of autoclaved bags (N / 30 mm)</td>

<td>10N</td><td> 11</td><td> 43</td>

<td>20 N.</td><td> 16</td><td> 42</td>

<td>30 N.</td><td> 27</td><td> 43</td>

[0098] The table below shows the average burst test values.

<td rowspan="2">Identifier samples</td><td colspan="2">The tear value of the bags is not autoclaved (bar)</td><td colspan="2">Value of tearing of treated bags autoclaving (bar)</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td>10N</td><td> 0,13</td><td> 0,12</td><td> 0,44</td><td> 0,44</td>

<td>20N</td><td> 0,20</td><td> 0,18</td><td> &gt;0,55</td><td> &gt;0,55</td>

<td>30N</td><td> 0,30</td><td> 0,28</td><td> &gt;0,55</td><td> &gt;0,55</td>

Shape B (Fig. 5 - reference example) [0099] The table below shows the total average value of the weld strength, measured in 6 positions.

<td>Sample ID</td><td>Welding strength of non-autoclaved bags (N / 30 mm)</td><td>Welding strength of autoclaved bags (N / 30 mm)</td>

<td>10N</td><td> 10</td><td> 35</td>

EP 1 773 277 Β1

<td>20 N.</td><td> 19</td><td> 36</td>

<td>30 N.</td><td> 31</td><td> 39</td>

[0100] The table below records the average burst test values.

<td rowspan="2">Sample ID</td><td colspan="2">The tear value of the bags is not autoclaved (bar)</td><td colspan="2">Value of tearing of treated bags autoclaving (bar)</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td>10N</td><td> 0,07</td><td> 0,06</td><td> 0,26</td><td> 0,29</td>

<td>20 N.</td><td> 0,15</td><td> 0,13</td><td> 0,29</td><td> 0,28</td>

<td>30 N.</td><td> 0,24</td><td> 0,23</td><td> 0,29</td><td> 0,27</td>

Shape C (Fig. 6) [0101] The table below shows the total average value of the weld strength, measured in 6 positions.

<td>Sample ID</td><td>Welding strength of non-autoclaved bags (N / 30 mm)</td><td>Welding strength of autoclaved bags (N / 30 mm)</td>

<td>10N</td><td> 13</td><td> 36</td>

<td>20 N.</td><td> 19</td><td> 36</td>

<td>20 N.</td><td> 29</td><td> 37</td>

[0102] The table below records the average burst test values.

<td rowspan="2">Sample ID</td><td colspan="2">The tear value of the bags is not autoclaved (bar)</td><td colspan="2">Value of tearing of treated bags autoclaving (bar)</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td>10N</td><td> 0,08</td><td> 0,09</td><td> 0,30</td><td> 0,30</td>

<td>20 N.</td><td> 0,14</td><td> 0,16</td><td> 0,31</td><td> 0,31</td>

<td>30 N.</td><td> 0,24</td><td> 0,23</td><td> 0,33</td><td> 0,32</td>

Shape D (Fig. 7) [0103] The table below shows the total average value of the weld strength, measured in 6 positions.

<td>Identifier samples</td><td>Welding strength of non-autoclaved bags (N / 30 mm)</td><td>Welding strength of autoclaved bags (N / 30 mm)</td>

<td>10N</td><td> 10</td><td> 37</td>

<td>20 N.</td><td> 20</td><td> 37</td>

<td>30 N.</td><td> 28</td><td> 41</td>

EP 1 773 277 Β1 [0104] The table below shows the average values ​​of the burst test.

<td rowspan="2">Sample ID</td><td colspan="2">The tear value of the bags is not autoclaved (bar)</td><td colspan="2">Value of tearing of treated bags autoclaving (bar)</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td>10N</td><td> 0,04</td><td> 0,05</td><td> 0,16</td><td> -</td>

<td>20 N.</td><td> 0,06</td><td> 0,07</td><td> 0,20</td><td> 0,21</td>

<td>30 N.</td><td> 0,10</td><td> 0,11</td><td> 0,22</td><td> 0,25</td>

Shape E (Fig. 8) [0105] The table below shows the total average value of the weld strength, measured in 6 positions.

<td>Sample ID</td><td>Welding strength of non-autoclaved bags (N / 30 mm)</td><td>Welding strength of autoclaved bags (N / 30 mm)</td>

<td>10N</td><td> 14</td><td> 46</td>

<td>20 N.</td><td> 21</td><td> 47</td>

<td>30 N.</td><td> 35</td><td> 52</td>

[0106] The table below records the average burst test values.

<td rowspan="2">Sample ID</td><td colspan="2">The tear value of the bags is not autoclaved (bar)</td><td colspan="2">Value of tearing of treated bags autoclaving (bar)</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td>10 N.</td><td> 0,05</td><td> 0,05</td><td> -</td><td> -</td>

<td>20 N.</td><td> 0,07</td><td> 0,08</td><td> 0,19</td><td> 0,19</td>

<td>30 N.</td><td> 0,14</td><td> 0,12</td><td> 0,22</td><td> 0,20</td>

Comparison and discussion [0107] The table below summarizes the shapes from A to E. The degrees of difficulty of manually opening the bags are summarized. This table also shows the maximum weld strength measured for different welds and the appropriate burst pressure. The burst pressure values ​​for the weld strength of 20 N / 30 mm and 40 N / 30 mm were extrapolated to give a better comparison between different weld shapes.

<td>Shape weld</td><td>Manual assessment of opening</td><td>Maximum weld strength with easy manual opening (N / 30 mm)</td><td>Burst pressure at maximum weld strength for opening (bar)</td><td>Burst pressure at 20 N / 30 mm (bar)</td>

<td>A (ref.)</td><td> 2-4</td><td> 10</td><td> 0,13</td><td> 0,23</td>

<td>B (ref.)</td><td> 3</td><td> 30</td><td> 0,23</td><td> 0,15</td>

EP 1 773 277 Β1

<td>c</td><td> 3</td><td> 30</td><td> 0,25</td><td> 0,15</td>

<td>D</td><td> 2-3</td><td> 41</td><td> 0,21</td><td> 0,08</td>

<td>E</td><td> 2-3</td><td> 52</td><td> 0,22</td><td> 0,07</td>

[0108] The results show that the rectilinear peel weld (shape A), to remain easily opened, is limited to the low weld strength. Welds B (reference example according to the state of the art of EP 0 893 982) and C can be easily opened at higher strengths, while the weld shapes according to the invention D and E can be easily opened even at high strengths. A weld that is easily opened at high strengths is advantageous from a manufacturing point of view, as the high strength of the weld increases process and transport capabilities. An infusion bag with a weld strength as low as in Reference Example A requires some kind of welding support during transport, i.e. curl along the weld line.

[0109] Comparison of C and D welds shows that by reducing the radius of the rupture zone and at the same time adapting one of the straight sections of the peelable weld parallel to the other, creating a gap, higher strength welds can be opened.

Example 2

A) General procedure for making the container according to Fig. 1 [0110] The containers shown in Fig. 1 were made of blown tubular film (Biofine) based on polyolefins. Tear welds were welded at various temperatures ranging from 122 to 128 ° C in order to obtain different weld strengths, for 3 seconds at 4 bar pressure using the hot rod technique. The rupture zone (apex) was placed 40 mm, 100 mm and 160 mm from the lower weld. The total length of the bag was 400 mm, width was 280 mm, and the total length of the peel was 260 mm. The total volume of fluid in the bag was 1500 ml.

[0111] Permanent welds were pulse welded.

B) Tests performed [0112] Purses according to Fig. 1 with different apex positions were made according to the above procedure. Tear welds were welded at 122, 124, 126 and 128 ° C. Each sample group contained 10 bags. These bags were not autoclaved. The following tests were performed on each group of samples.

Stress test:

[0113] The stress test was performed on 30 mm wide strips using the Instron stress tester. Test strips were taken from S1, S2, S3 and S4 (see positions in Figure 11). The initial grip distance was 50 mm. The test speed was set to 500 mm / min. Maximum strength was measured. [0114] Weld strength was measured on 3 bags.

EP 1 773 277 Β1

Burst test:

[0115] Restrictive plates were not used. The pressure was measured directly inside the bag using a pressure sensor. The input pressure was set to 0.3 bar. Weak welds were opened towards the apex, i.e. weld 1 was opened before weld 2.

[0116] The crack test was performed on 3 bags.

Manual bag opening [0117] Tear welds are manually opened by rolling. The degree of difficulty was rated on a scale of 5 according to the definition below.

= very easy = easy = some resistance but trouble-free opening = high resistance but opening possible with great effort = impossible to open [0118] The manual opening test was carried out on 4 bags.

C) Test results for various weld designs

Top aperture 40 mm [0119] The table below shows the values ​​of weld strength, tear and assessment of the difficulty of manual opening for different welding temperatures.

<td rowspan="2">Temperature welding (° C)</td><td rowspan="2">Tear Strength weld (N / 30 mm)</td><td colspan="2">Burst pressure (bar)</td><td colspan="2">Manual opening rating</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td> 122</td><td> 16</td><td> 0,17</td><td> 0,12</td><td> 1,5</td><td> 1,9</td>

<td> 124</td><td> 21</td><td> 0,20</td><td> 0,14</td><td> 2,3</td><td> 3,0</td>

<td> 126</td><td> 26</td><td> 0,25</td><td> 0,17</td><td> 3,0</td><td> 3,3</td>

<td> 128</td><td> 37</td><td> 0,32</td><td> 0,28</td><td> 3,5</td><td> 4,7</td>

<td> 130</td><td> 46</td><td> &gt;0,30</td><td> &gt;0,30</td><td> 5,0</td><td> 5,0</td>

100 mm apex position [0120] The table below presents the values ​​of weld strength, tearing and assessment of the difficulty of manual opening for different welding temperatures.

<td rowspan="2">Temperature welding (° C)</td><td rowspan="2">Strength weld (N / 30 mm)</td><td colspan="2">Burst pressure (bar)</td><td colspan="2">Manual opening rating</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td> 122</td><td> 16</td><td> 0,12</td><td> 0,09</td><td> 1,0</td><td> 1,0</td>

<td> 124</td><td> 21</td><td> 0,16</td><td> 0,11</td><td> 1,8</td><td> 2,0</td>

EP 1 773 277 Β1

<td> 126</td><td> 27</td><td> 0,19</td><td> 0,12</td><td> 1,8</td><td> 20</td>

<td> 128</td><td> 37</td><td> 0,28</td><td> 0,16</td><td> 2,5</td><td> 2,7</td>

<td> 130</td><td> 45</td><td> &gt;0,30</td><td> &gt;0,30</td><td> 4,0</td><td> 4,0</td>

160 mm apex location [0121] The table below shows the strength of the welds, tears and an assessment of the difficulty of manual opening for different welding temperatures.

<td rowspan="2">Temperature welding (° C)</td><td rowspan="2">Weld strength (N / 30 mm)</td><td colspan="2">Burst pressure (bar)</td><td colspan="2">Manual opening rating</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td> 122</td><td> 16</td><td> 0,14</td><td> 0,09</td><td> 1,3</td><td> 2,3</td>

<td> 124</td><td> 21</td><td> 0,17</td><td> 0,10</td><td> 2,0</td><td> 3,5</td>

<td> 126</td><td> 28</td><td> 0,21</td><td> 0,13</td><td> 2,4</td><td> 4,3</td>

<td> 128</td><td> 37</td><td> 0,28</td><td> 0,19</td><td> 3,0</td><td> 5,0</td>

<td> 130</td><td> 45</td><td> &gt;0,30</td><td> &gt;0,30</td><td> 5,0</td><td> 5,0</td>

[0122] The table below shows a summary of results for apex positions 40, 100 and 160. The degrees of difficulty of manually opening the pouches for different weld strengths are summarized.

<td rowspan="2">temperatures and welding (° C)</td><td rowspan="2">Tensile strength weld (N / 15 mm)</td><td colspan="2">Manual assessment opening for position apex 40 mm</td><td colspan="2">Manual assessment opening for position top 100 mm</td><td colspan="2">Manual assessment opening for position apex 160 mm</td>

<td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td><td>Weld 1</td><td>Weld 2</td>

<td> 122</td><td> 16</td><td> 1,5</td><td> 1,9</td><td> 1,0</td><td> 1,0</td><td> 1,3</td><td> 2,3</td>

<td> 124</td><td> 21</td><td> 2,3</td><td> 3,0</td><td> 1,8</td><td> 2,0</td><td> 2,0</td><td> 3,5</td>

<td> 126</td><td> 27</td><td> 3,0</td><td> 3,3</td><td> 1,8</td><td> 2,0</td><td> 2,4</td><td> 4,3</td>

<td> 128</td><td> 37</td><td> 3,5</td><td> 4,7</td><td> 2,5</td><td> 2,7</td><td> 3,0</td><td> 5,0</td>

<td> 130</td><td> 45</td><td> 5,0</td><td> 5,0</td><td> 4,0</td><td> 4,0</td><td> 5,0</td><td> 5,0</td>

[0123] These results show that peel-off welds with a high apex position are easier to open than peel-open welds with a low apex position. When the apex position is too high, close to the fluid level of the mixed bag, such as in the 160 mm weld position 2, the weld becomes more difficult to open. A comparison of the vertex positions made in this example shows that the preferred vertex location is 100 mm.