PL178101B1 - Method of mixing together liquid products in aseptic manner - Google Patents

Abstract

The invention relates to an apparatus for mixing aseptically three or more liquid products (51, 53, 55) and includes at least two pointed connection devices (1, 21, 41) which are provided with through-passing flow passageways (3, 4, 24, 25, 43, 44) and are connected in series by means of a connecting line (61) and are intended to be inserted through penetrable closure means (58, 59, 60) of product containers (52, 54, 56). A first of these connection devices (1) functions to place the first container (52) in communication with the surroundings via a sterilizing filter (7), and connects the first container with the second container (54) through the connecting line (61), wherein the product containers are mutually connected together successively by means of respective subsequent connection devices down to the last product container (56) in line in which the final mixture of products, including the product (55), is collected. A subpressure prevails in the last container in line, this subpressure constituting the force by means of which the products are driven through the system. The invention also relates to a connection device (21) and to a system for aseptically mixing three or more liquid products, and also to a method of mixing the products. The invention is primarily intended for application when mixing the liquid components of a preparation for parenteral nutrient supply.

Description

The present invention relates to an aseptic liquid mixing set.

More particularly, the invention relates to a kit for the aseptic mixing of three or more liquid products for pharmaceutical or nutritional purposes, and also to liquid products added to formulations for parenteral, especially intravenous administration.

For one reason or another, patients who are unable to absorb nutrients in the normal way are often given parenterally. Typically, nutrition involves the administration of three main types of nutrients namely carbohydrates, amino acids and fat. However, if nutrition is to be right, the patient must receive about fifty different supplements a day. Carbohydrates and amino acids are administered in the form of solutions, and the fat in the form of an emulsion. These preparations also contain other essential nutrients, such as electrolytes, trace elements, and water- and fat-soluble vitamins. However, in the normal situation it is not possible to prepare mixtures containing all three liquid components in stock since such mixtures do not show sufficient stability during storage. Various reactions result in inappropriate products, which can sometimes be harmful to the patient when administered parenterally. For example, carbohydrates and amino acids can generate Maillard reaction products that can cause secondary toxic effects. The Maiłlard reaction products often give the solution a yellowish color, which is undesirable and in many cases unacceptable from the point of view of national healthcare institutions. The other ingredients are able to make the fat emulsion unstable and cause the emulsion to crumble and the formation of large fat particles, i.e. cream formation or the complete separation of the fat phase.

Attempts to solve this problem have been to administer the three components separately to the patient and to join them together at a location only a short distance from the application site by means of a manifold coupling device. However, it is difficult to measure the correct doses of the individual components with this connecting device.

You can also mix the three ingredients in the right proportions just before administering them, and then administer them immediately to the patient before any adverse reaction occurs. However, in such a case it is very often necessary to mix these ingredients in a completely aseptic manner without access to sterilization areas and without the assistance of personnel specially trained for this purpose. It has been found that the task of mixing these solutions properly, both physically and chemically, while preventing microbial contamination, is a serious problem for hospital staff.

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One of the known solutions is a coupling device for aseptically mixing together two liquid products, which is used to aseptically mix a fat emulsion with a ready-made mixture of amino acids and carbohydrates in an aqueous solution. For the aforementioned reasons, however, stock mixtures of amino acids and carbohydrates are not suitable. There is no coupling device for aseptically mixing three or more liquid products.

The assembly for aseptic mixing of liquids according to the invention is characterized in that it comprises a first coupling device having one arm ending with a blade adapted to pierce the closure member of the first container with the first liquid, the first coupling device having two separate, essentially parallel, first passage channels. and a second, the first channel having one end located in the spike and the other end communicated to the surrounding atmosphere by a sterilizing filter. The second channel has one end located in the blade and the other end is connected to a connecting conduit to which is connected a second connecting device having two oppositely projecting arms and two separate, substantially parallel, first and second through channels. One arm ends with a first blade adapted to pierce the closure member of the second container with the second liquid. The first channel has one end located in the first blade and its other end is connected to a connecting wire. The second channel has a first end thereof located in the first blade and its second end located in the second blade which is adapted to pierce the closure member of the third container with the third liquid and mixing space.

In a preferred variant, attached to the connection conduit is at least one third connection device having one arm which ends with a blade adapted to pierce the closing member of the liquid container and two separate, essentially parallel first and second through channels, the first ends of which are situated in the blade. and the second ends are connected to sections of the connecting wire from the first connecting device and the second connecting device, respectively.

The assembly for aseptic mixing of liquids, in another variant of the invention, is characterized in that it comprises a second connecting device having two oppositely projecting arms ending in first and second blades adapted to pierce the closing members of the liquid containers and having two separate, substantially parallel first and second through channels, the first ends of which are located in the first blade, the first channel being connected to the fluid supply connector and the second channel opening in the second blade.

The assembly for aseptic mixing of liquids, in a further embodiment of the invention, is characterized in that it comprises a first container with a first liquid closed by a closure member, through which a spiked arm of the first connecting device passes and has a first passageway. The first end of the first channel is positioned in the blade and the second end is connected to the surrounding atmosphere by a sterilizing filter medium. The first connection device has a second conduit through which is parallel to and separated from the first conduit, the first end of the second conduit being located in the spike of the first connection device and the second end connected to a connector thereof connected to the connection conduit to which it is connected. a connector of a second connecting device connected on the other side.

The second linking device has two arms terminated in blades and includes a through-first channel the first end of which is disposed in the first blade and the second end of which is connected to the link. Its second channel, which is parallel to the first channel, has a first end located in the first blade and a second end located in the second blade. The first blade of the second coupling device passes through the closure member of the second container with the second liquid and is placed in the second container, and the second blade passes through the closure member of the third container containing the third liquid.

178 101 at reduced atmospheric pressure; and a mixing space the volume of which is at least equal to the volume of the first and second liquids.

In a preferred modification of the invention, attached to the connection conduit is at least one third connection device having one arm tipped with a blade which is inserted into the additional liquid container through its closure member, and having two separate first and second parallel through channels, the first ends of which are are located in the blade and the second ends are connected to connectors extending from the arms and connected to lengths of connecting wire extending from the first connecting device and the second connecting device respectively.

The present invention provides a simple aseptic liquid mixing kit that solves the problem of mixing two or more liquid products under aseptic conditions without risk of contamination. It comes to an end, especially when mixing all the nutrients needed for complete intravenous nutrition.

The subject matter of the invention is illustrated in the drawing in which Fig. 1 shows the first coupling device of a set for aseptic mixing of liquids according to the invention in longitudinal section; Fig. 2 is a side view of the connecting device of Fig. 1; Fig. 3 is a longitudinal section of a second coupling device of the aseptic mixing of liquids according to the invention; Fig. 4 is a side view of the apparatus of Fig. 3; Fig. 5 shows a third connection device of the aseptic mixing set according to the invention in longitudinal section; and Fig. 6 is a schematic view of an embodiment of a kit for aseptic mixing of liquids with each other according to the invention.

1 and 2 show the first coupling device 1 of the set for aseptic mixing of liquids together. The connecting device 1 has an arm which ends with a blade 2 and has two separate, approximately parallel, first 3 and second 4 through channels. One end 5 of the first channel 3 has an opening located in the spike 2 of the arm, while the second end 6 of the first channel 3 is connected to the surrounding atmosphere. through the sterilizing filter 7. As shown in Fig. 1, the sterilizing filter 7 is mounted in the chamber 8 of the connecting device 1 and is held in position by a cover 9 with openings 10 connecting the chamber 8 with the surrounding atmosphere. Of course, the sterilizing filter 7 may be of a different design.

The second channel 4 has one end 11 located in the spike 2 of the arm, while the other end 12 of the second channel 4 is connected to a connecting conduit (not shown) via a connector 13.

Figures 3 and 4 show a second aseptic mixing device consisting of a second connecting device 21. The second connecting device 21 has a first blade 22 and a second blade 23, the blades 22, 23 being disposed on opposing arms. first and second, although this is not absolutely necessary. The second connecting device 21 comprises two separate and approximately parallel channels 24 and 25. One end 26 of the first channel 24 opens into a blade 22 of the first arm, and the second end 27 of the first channel 24 is connected to a connecting conduit (not shown) coming from the first connecting device. 1, via the connector 28 of the second connecting device 21.

The first end 29 of the second channel 25 is also located in the blade 22 of the first arm, and the second end 30 of the second channel 25 opens into the blade 23 of the second arm.

In one embodiment, the assembly for aseptic mixing of liquids comprises a first connecting device 1 and a second connecting device 21 connected to each other by a connecting conduit.

Figure 5 shows a cross-sectional view of a third coupling device 41 according to the invention that is used in an assembly for mixing four or more liquids together. The third linking device 41 comprises an arm terminated in a blade 42 having two separate and approximately parallel first 43 and second 44 through channels. One ends 45 and 46 of the respective first 43 and second 44 channels open into the blade 42 while the other ends 47

1718101 and 48 of the respective first 43 and second 44 channels are connected to first 49 and second 50 connectors via which an intermediate connection device 41 is connected to a connection wire (not shown) between devices 1 and 21 according to the previous embodiments.

It goes without saying that several connecting devices like the third connecting device 41 may be successively connected to the connecting line with one device for each additional liquid product to be mixed over the first three products to form an aseptic liquid mixing set as needed.

The blades of the devices shown in Figs. 1 to 5 and the channels therein are protected against mechanical damage and mainly against microbial contamination by means of protective caps or caps placed on the respective blades. Preferably, the protective caps are airtight and also contain elements that are damaged upon removal, so that the cap cannot be replaced without leaving any traces that it has already been removed (content tampering). The design of such protective caps and such security elements is known to those skilled in the art. The protective cap should not be removed from the respective blade until immediately prior to insertion of the blade through the piercing closure member of the product container. For simplicity, the protective caps are not shown in the drawings.

Figure 6 shows schematically an embodiment of an assembly for aseptic mixing of three liquids according to the invention. The kit, in addition to the previously discussed kit embodiment, comprises a first container 52 containing a first liquid 51, a second container 54 containing a second liquid 53 and a third container 56 containing a third liquid 55. In the third container 56, an empty mixing space 57 is provided above the third liquid 55. the volume of which is at least equal to the volume of the first 51 and second 53 liquids supplied there from the first 52 and second 54 containers, respectively.

The three containers 52, 54 and 56 are closed by pierceable closure members 58, 59 and 60, respectively. The closure members 58, 59 and 60 are preferably members including a rubber membrane closing the container opening and held in place by a metal capsule. In the central part of the capsule there is an opening which exposes the rubber diaphragm, which enables it to be pierced by the blade of the connecting device according to the invention. The opening in the metal capsule is protected against damage and bacterial contamination during storage and transport by means of an additional metal or plastic protective cover. It is obvious to all those skilled in the art that other pierceable closing elements can also be used.

As shown in figure 6, the first connecting device 1 according to figures 1 and 2 is inserted through the closure member 58 of the first container 52. Channels 3 and 4 of the first connecting device 1 are connected at one end in a blade 2 to the interior of the first container 52. The second end 6 of the first channel 3 is connected to the surrounding atmosphere by a sterilizing filter, and the second end 12 of the second channel 4 is connected to a connection line 61 extending to a second connecting device 21 of the type shown in figures 3 and 4.

The first blade 22 of the second connecting device 21 is inserted into the second container 54 through its closure member 59, and the second blade 23 of the second connecting device 21 is inserted into the third container 56 through its closing member 60. The second end 27 of the first passage 24 of the second connecting device 21 is connected to a connecting conduit 61 extending from the first container 52. The second channel 25 connects the interior of the second container 54 to the interior of the third container 56. Thus, an open connection to the surrounding atmosphere is obtained via the sterilizing filter 7 (Fig. 1) and then successively through first 52, second 53 and third 56 containers, the last in the case shown. Thus, under the action of the respective driving force, the liquid first product 51

178 101 flows from the first container 52 and through the second container 54, mixing simultaneously with the liquid second product 53 therein, and finally into the third container 56, where all three products mix together to form the final mixture. .

In the event that four or more liquid products have to be mixed together, at least one third connecting device 41 of the type shown in Figure 5 engages with the connecting conduit 61 by means of two ends 49 and 50 thereof. The arm of the third tip 42 is then inserted. a connecting device 41 in which the first and second channels 43 are provided through a closure member of a container of a similar type to the first and second containers 52.

The capacity of the last container in the series for the final blend of said liquid products, also containing one of the liquid products, should be sufficient to contain the final blend. Thus, the final container should have a considerable void space before the ingredients of the blend flow into it. In this void there is preferably a vacuum or subatmospheric pressure which just creates the driving force in the mixing process, as described later.

Preferably, the products contained in the first and second containers 52 and in any other additional container located upstream of the flow end container, in the shown case of the third container 56, are also preferably under vacuum or underpressure, although this is not necessary and they may contain atmospheric pressure or a slight overpressure. In the event of overpressure or underpressure in one or more containers, except the latter, such overpressure must be compensated by a sterilizing filter. For this purpose, the blades of the devices are preferably located above the liquid surfaces in suitable containers. Liquid products of this type are often packed such that the packages are filled with a suitable protective gas such as nitrogen, rather than air, to eliminate the possibility of oxidation of sensitive ingredients.

The connecting line 61 extending between the two first and second connecting devices 21 is preferably in the form of a connecting hose between the connectors 13 and 28 of the respective devices 1,21, optionally with additional connecting devices 41 coupled thereto. However, it is preferred that the connection line 61 and the two connection devices 1 and 21 are permanently connected to each other during the production stage of the mixing arrangement, so as to constitute one arrangement. This combination of devices and a connecting line is then connected to a suitable connecting device for holding the containers, which holds the three containers 52, 54 and 56 with the products 51, 53, 55 and their respective connections and connecting lines as a single system. This type of kit is easier to handle in the mixing process than separate product containers.

The operation of the aseptic mixing set for three liquid products is as follows:

The two connecting devices, the first 1 and the second 21, are connected by a connecting conduit 61, and the arms of the connecting devices 1 and 21 ending with a blade 2, 22 and 23 are all covered with protective caps (not shown) impermeable to air and bacteria, preventing air and bacteria from flowing into the channels. 3, 4 and 24, 25 devices 1 and 21 as previously described. The protective cap is removed from the tip of the blade 2 of the first connecting device 1 and the blade 2 is inserted by piercing the closure member 58 of the first container 52 containing the first liquid 51. If the first liquid 51 in the first container 52 is under a negative pressure, it is generated therein. the atmospheric pressure due to the ambient air flowing into the first connecting device 1 through the sterilizing filter 7 and the first conduit 3.

The protective cap covering the blade 22 of the connecting device 21 should not be removed before the vacuum has been equalized in the first container 52. This is important for maintaining aseptic conditions in the first container 52. If the cap covering the first blade 22 is removed prematurely, when in the first

101 of the container 52, there is still a negative pressure, through the first channel 24 of the second connecting device 21 and the connecting line 61, unfiltered air will be sucked in, which will flow into the first container 52 and the contamination of the first product 51 therein.

After the vacuum in the first container 52 has been equalized, the cap covering the first blade 22 of the second connecting device 21 is removed and the blade is inserted through the closure member 59 of the second device 54. The negative pressure in the second container 54 is compensated by the air flowing into the first connecting device 1 through the sterilized filter 7 and from there to the first container 52 with the first product 51, simultaneously displacing a portion of the first product 51 to the second container 54. The cap covering the second blade 23 of the second coupling device 21 cannot be removed until the pressures are equalized. This is important to prevent unfiltered air from entering the second container 54 with the second product 53 through the first channel 24 and the possibility of contamination of the second product 53 in the second container 53.

After the vacuum in the second container 54 has been equalized, the cap is removed from the second blade 23 of the second connecting device 21 and the blade is inserted through the closure member 60 of the last, third container 56. The negative pressure in the mixing chamber 57 of the third container 56 now draws the second product 53 from the second container 54 at the same time as the first liquid 51 from the first container 52 flows through the second container 54 and enters the third container 56 where the three liquids mix together. The negative pressure in the third container 56 is also compensated for by the air drawn in by suction through the sterilizing filter 7 and flowing through the first and second containers 52 and the connecting line 61.

If four or more liquid products are mixed together, the mixing process is analogous to that described above. The containers are connected sequentially by the pointed arms of the devices according to the invention, ensuring that the vacuum is equilibrated in the receptacle to be connected before the protective cap is removed from the blade of the next in line device, and a fluid connection is established with the next container.

As already mentioned, the negative pressure should only necessarily be in the last container. Its value should be sufficient to force the remaining liquid products to flow to the last container. The pressure in the previous containers is preferably initially equal to atmospheric pressure, so that there is no risk of unfiltered air being sucked into these containers. Nevertheless, it is advisable to remove the protective caps from the respective blades of the devices immediately before the insertion of the blade through the closure member of the respective container. This gives an additional guarantee that unfiltered air will not come into contact with one of the products and contaminate it.

After the liquid has been mixed and the pressure equalized in the third container 56, the container is disconnected from the second coupling device 21 and the final mixture is administered in a conventional manner, such as by intravenous infusion or injection. In order to provide additional security, it is recommended to give the mixture as soon as possible after its production. This reduces the risk of reactions occurring between the constituent products, which may result in an increase in the amount of undesired reaction products. Moreover, it is preferred to store the finished mixture in a dark and cool place until it is administered.

Of course, the mixing process must be hygienic and impeccable. Thus, preferably, the pierceable closure member must be cleaned with a disinfectant, for example alcohol, before the spike of the connecting device is inserted therethrough. Preferably, the use of the connecting device and the associated connecting cable should be disposable, i.e. only used once, and stored in sterile packaging, for example sterilized by ionizing radiation, before use. The simple joining devices according to the invention allow the products to be mixed by personnel

178 101 hospital, with no special training in this field, with virtually no risk of bacterial infection.

The components of the kit of the invention can be made of material normally used in known techniques for aseptic handling of liquids. The product containers are preferably conventional glass or plastic bottles intended for injection or infusion preparations. Preferably the blade-tipped joining devices are made of metal and / or plastic commonly used in the field. It is important to be able to sterilize the materials, for example in autoclaves, with gas or radiation. Since these fastening devices are preferably disposable items, their cost is also important.

The embodiments shown in the figures are only exemplary and are not intended to be limiting. Within the scope of the invention, following from the appended claims, further variations and modifications are possible and will be obvious to those having the appropriate basic knowledge in this field.

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Publishing Department of the UP RP. Circulation of 70 copies. Price PLN 4.00.

Claims (5)

Patent claims An assembly for aseptic mixing of liquids, characterized in that it comprises a first connecting device (1) having one arm ending with a blade (2) adapted to pierce the closure member (58) of the first container (52) with the first liquid (51), the first being the connecting device (1) has two separate, essentially parallel, first (3) and second (4) through channels, of which the first channel (3) has one end (5) located in the blade (2) and the other end (6) ) connected to the surrounding atmosphere by a sterilizing filter (7), and the second channel (4) has one end (11) of it located in the blade (2) and the other end (12) is connected to a connecting conduit (61) to which it is connected a second connecting device (21) having two oppositely projecting arms and two separate first (24) and second (25) essentially parallel through channels, one arm terminating in a first blade (22) adapted to pierce the closing element ( 59) of the second container (54) with a second liquid (53), and the first channel (24) has one end (26) of it located in the first blade (22) and its other end is connected to the connecting line (61) and the second channel (25) has a first end thereof (29) disposed in the first blade (22) and its second end (30) disposed in the second blade (23) which is adapted to pierce the closure member (60) of the third container (56) with the third liquid (55) and space. mixing valve (57). 2. The kit according to claim A connecting device according to claim 1, characterized in that attached to the connecting conduit (61) is at least one third connecting device (41) having one arm tipped with a blade (42) adapted to pierce the closing member of the liquid container and having two separate, essentially parallel through channels. first (43) and second (44), the first ends (45, 46) of which are disposed in the blade (42) and the second ends (47, 48) are connected to sections of connecting wire (61) extending respectively from the first connecting device ( 1) and to the second connecting device (21). A set for aseptic mixing of liquids, characterized in that it comprises a second connecting device (21) having two oppositely projecting arms ending in first (22) and second (23) blades adapted to pierce the closing members of the liquid containers and having two separate, substantially parallel, first (24) and second (25) through channels, the first ends (26, 29) of which are located in the first blade (22), the first channel (24) being connected to the feed fitting (28) liquid and the second channel (25) opens out in the second blade (23). A set for aseptic mixing of liquids, characterized in that it comprises a first container (52) with the first liquid (51) closed by a closure member (58), through which the arm of the first connecting device (1) ends with a blade (2) passes. which has a through first channel (3), the first end (5) of which is located in the blade (2) and the second end (6) is connected to the surrounding atmosphere - by a sterilizing filter medium (7), and has a through second channel ( 4) which is parallel to and separated from the first channel (3), the first end (11) of the second channel (4) being located in the blade (2) of the first connecting device (1), and the second end (12) is connected to its connector (13) connected to the connecting conduit (61) to which is connected on the other side the connector (28) of the second connecting device (21) having two arms terminated in blades (22, 23) and including a through first channel ( 24), whose first end (26) eats st positioned in the first blade (22) and the second end is connected to the coupler (28), and the second channel (25) which is parallel to the first channel (24) has a first end (29) thereof located in the first blade (22). and a second end (30) thereof located in the second blade (23) of the second connecting device (21), the first blade (22) passing through the closure member (59) of the second container (54) with the second liquid (53) and being 178 101 placed in the second container (54) and the second blade (23) passes through the closure member (60) of the third container (56) containing the third liquid (53) under atmospheric pressure and the mixing space (57), the volume of which is equal to at least the first (51) and second (53) fluid volumes. 5. Set according to A connecting device according to claim 4, characterized in that at least one third connecting device (41) is attached to the connecting conduit (61) having one arm tipped with a blade (42) which is placed in the additional liquid container through its closure member and having two separate, parallel first (43) and second (44) through channels, the first ends (45, 46) of which are disposed in the blade (42) and the second ends (47, 48) are connected to connectors (49, 50) protruding from arms and connected to sections of connecting wire (61) extending from the first connecting device (1) and the second connecting device (21) respectively.