GB2117733A - Sterilized liquid mixing system - Google Patents

Abstract

A sterilized system for mixing liquid and powder includes a first container (10) for holding liquid and an attached container (18) for holding dry solid material. A sealed connection (20, 22) between the containers is breachable to permit mixing whilst maintaining the container interiors sealed from the atmosphere. At least the first container and the connection are sealed in an overpouch (54) to protect the container and to reduce water vapour loss through the container walls. Sterilized liquid can be admitted to the container 10 from a container 62 via a tube 44 which passes through the sealed periphery of the overpouch 54. <IMAGE>

Description

SPECIFICATION Sterilized liquid mixing system Technical Field and Prior Art In U.S. Patent No. 4,223,675 entitled "SO- LUTION CONTAINERS SUCH AS BLOOD BAGS AND SYSTEMS FOR PREPARING SAME", packages and containers are formed in which auto-claved liquids such as anticoagulents may be added to the system after sterilization of at least part of the system by a means other than high temperature sterilization. After the sterilization step has taken place, the auto-claved liquids may be joined to the remainder of the system by a sterile connection technique. Thus by the above cited patent containers such as blood bags may be sterilized by a system other than heat sterilization, and may thereafter be charged with a sterile liquid such as anticoagulentpreservative for blood.

Systems are available to provide reliable, sterile mixing of dry solids with liquids. For example, it is common to add drugs such as antibiotics or any other desired drug to an intravenous solution container for administration to hospitalized patients. At the present time this is commonly done in the hospital pharmacy. After the drug admixture with the parenteral solution has been accomplished, the mixed product should be either promptly administered to the patient after the admixture has been performed or refrigerated to inhibit bacterial growth, since it is commonly considered that sterility has been breached by the admixture process, although the process naturally takes place under as clean conditions as possible to minimize the possibility of bacterial contamination.

As the result of this, hospital pharmacies are burdened with the requirement of preparing frequent batches of drug-admixed solutions, since only relatively fresh solutions should be used. It is not commonly considered good practice to prepare a large number of drug admixed solutions and store them for a period of days or until needed by the patient, since that raises the possibility that contaminating bacteria injected into the system during the admixture process might have time to multiply.

A need, therefore, exists for a drug admixture system in which a solid drug or the like can be admixed with a parenteral solution without significant risk of bacterial contamination Such drug-admixed solutions can be stored at room temperature after their admix ture without concern about the proliferation of bacteria within the system. The stability and shelf life of such an admixture system, therefore, may be extended to the shelf life of the drug itself in solution.

This can substantially eliminate the current efforts of the hospital pharmacies to maintain an inventory of drug admixed solutions. Such a solution system in accordance with this invention can remain on the shelf until it is needed. Then it can be prepared without risk of bacterial contamination, by the nurse on the floor of the ward, if desired. On the other hand, the drug can be admixed into the solution, and then the solution can be stored at room temperature for a longer period of time without the fear of bacterial contamination.

Problems in the manufacture of such a system arise because solutons are typically autoclaved or otherwise heat sterilized. Solutions cannot be effectively sterilized with ethylene oxide, and are commonly not sterilized with gamma rays. On the other hand, many dry solids, including large numbers of drugs, are sensitive to heat, and thus cannot be heat sterilized. Accordingly, the problem remains: how does one bring together into sterile relationship a container of solution which must be heat sterilized, and a container of dry solid which cannot be heat sterilized? In accordance with this invention a method is provided for bringing together into potentially sterile connection relationship a container of dry solid, even if the solid may not be heat sterilized, and a container of liquid which must be heat sterilized, and appropriate apparatus which can be so sterilized is disclosed.

Typically, the apparatus of this invention is used for the admixture of drugs into parenteral solutions, but it may be used in any field desired.

Description of the Invention In this invention, a method is provided of sterilizing a first container for holding liquid and an attached container holding a dry solid, the containers having connection means for mixing their contents while remaining sealed from the exterior. At least the first container in the connection means is sealed in an overpouch (to protect the container and to reduce water vapor loss through the walls of the container).

By this invention, sterilizing gas is passed through a first, porous, sealed, bacteria-blocking port into the interior of the overpouch to sterilize at least portions of the exterior of the first container and the connection means. The exterior of the attached container is also sterilized in the event that it is contained within the overpouch.

Sterilizing gas is also passed through a second, porous, sealed, bacteria-blocking port into the dry interior of the first container to sterilize the interior.

Thereafter, the sterilizing gas is allowed to diffuse from the interiors of the overpouch and first container, out of the first and second ports, without permitting bacterial access into the overpouch and first container.

After this, the second port is typically sealed, and an open, sterile connection is effected between a sealed tube communicating with the interior of the first container and a source of sterile liquid.

The sterile liquid is passed into the interior of the first container, and then the sealed tube is resealed.

The result of this is to provide a sterile liquid container, in sealed, potentially sterile communication with its attached container which holds the dry solid under conditions wherein a dry solid is never exposed to sterilizing temperatures.

The container of dry solid may be presterilized in its interior by any desired conventional means. For example, the dry solid may be a glass or plastic ampule of a type which is presently commercially available in the drug industry. Alternatively, the dry solid may be contained in a plastic bag, having been presterilized by any desired technique.

By the process of this invention, heat sensitive dry powders such as commercially available antibiotic drugs, for example Gentamicin sulfate or Cefazolin sodium, may be packaged with sterile, intravenous solution and admixed therewith in sterile manner. Similarly, other drugs such as Cimetidine or 5-fluorouracil, or any other appropriate drug, may be utilized in the system of this invention.

Suitable solutions for placement in the system of this invention may be accomplished by the use of a known sterile connector system.

For example, sterile connectors as disclosed in U.S. Patent Nos. 4,157,723 or 4,265,280 may be used in accordance with this invention. These sterile connectors are each preconnected with a membrane, at least one of which is opaque, the membranes abutting one another in a sealed area. Intense radiation, for example infrared, is then applied to melt the membranes and cause them to fuse together, opening a sterile hole between the connectors. The particular membranes which are preferably used are as described in Boggs et al. Application Serial No. 027,575, filed April 6, 1979.

The attached container and connection means are preferably positioned substantially within an isolated compartment of the first container, being completely enclosed within the overpouch. In this instance, the sterilizing gas is passed from the overpouch interior through a third, porous, sealed bacteria-blocking port between the overpouch interior and the isolated compartment to sterilize the exterior of the attached container as well as the connection means. Afterward, time is, of course, given to allow sterilizing gas to diffuse out of the isolated compartment through the third port.

It is also preferred for the sealed tube to communicate through the overpouch through sliding seal means to permit pullinq free of the first container and the tube from the overpouch upon opening of the overpouch.

The sliding seal means can include a tube of high melting plastic such as polypropylene, positioned in the sealed periphery of the overpouch so that the tube slides relative to the sealed periphery of the overpouch.

It is also desirable for the second porous, sealed, bacteria-blocking port to be carried at a position outside of the overpouch so, after the sterilization process has taken place, it can be removed by transverse sealing of the tubing on which it is carried, and cutting through the seal.

The first container is preferably a collapsible bag having one or more access tubes to its interior, each closed with a pierceable diaphragm. The outer end of the access tube is sealed with a removable seal member carrying a fourth porous sealed bacteria-blocking port.

As the result of this, sterilizing gas from the overpouch interior can also pass into contact with the outer end of the access tube to sterilize its interior and the outer side of the pierceable diaphragm.

Description of the Drawing Referring to the drawing, Fig. 1 is a plan view of the container system of this invention in the process of being filled and sterilized.

Fig. 2 is a plan view of system of Fig. 1 after completion of filling and sterilization, with various portions utilized in the sterilization removed.

Description of Specific Embodiment In the drawing, a first plastic container 10 is disclosed which may be made of a pair of plastic sheets, for example, polyvinyl chloride plastic sealed together about its periphery 1 2 by a heat seal in a manner well known to the art. Container 10 also carries a second heat seal 14 to seal off an area 1 6 within the container, enclosing glass or plastic ampule 1 8 which constitutes the attached container holding a dry solid such as an antibiotic or Cimetidine, for example.

Ampule 1 8 may be of conventional commerical design, defining latex diaphragm 20 across its mouth. Hollow piercing needle or spike 22 is positioned in seal line 14 to penetrate diaphragm 20 when ampule 1 8 is pressed upon it for communication between the interior portion 24 of bag 10 and the interior of ampule 18. Needle 22 may be made of stainless steel, and carried by plastic hub 23, through which at least its lumen passes. Hub 23 may be sealed in seal line 14.

The opposite end of hollow needle 22 may be closed with a breakaway seal member 26 carried on hub 23 which may, for example, be of a design as disclosed in U.S. Patent Nos. 4,181,140 or 4,294,247, or U.S. Patent Application Serial No. 86,102, filed October 18, 1979.

Flexible bag 10 also carries at its lower end one or more access tubes 28 projecting through sealed periphery 1 2 in conventional manner, and carrying a pierceable diaphragm 30 blocking its interior. An outer end of tube 28 is sealed with removable seal 32 which carries a porous, sealed, bacteria-blocking port 34 including a wad of cotton, as is conventional. The other end of bag 12 carries a seal flap 36 having hanger hole 38.

Container 10 also carries vent port 40, which is also sealed with a porous, bacteriablocking member 42 of conventional design to permit the bacteria-free exchange of gases between interior space 1 6 and the exterior thereof through port 40.

Bag 10 also carries sealed tube 44 which is sealed in flow communication through the seal line of periphery 1 2 and which extends outwardly. Sealed tube 44 may define a branch 46 which serves as a vent member, and also contains a porous bacteria-blocking member 48, such as a wad of cotton. A second branch 50 is also provided to tube 44 which terminates in a sterile connector 52, which may be of a design as previously described.

Bag 10 may be made of a thermoplastic material, typically polyvinyl chloride or a polypropylene copolymer containing a small amount of ethylene units in the copolymer molecule, for example. To reduce the loss of water vapor on storage from bag 10, it is covered with an overpouch 54, which may also be made of polypropylene if desired or a copolymer therewith, with a minor amount of ethylene units, or any other desired plastic material. Overpouch 54 is also sealed with a heat seal about its periphery 56 to seal bag 10 in its interior. Overpouch 54 may be designed to be easily opened by tearing, using any conventional design, for ready access by the user.

Overpouch 54 also carries a port 58 of thermoplastic material extending through periphery 56. Within the outer end of port 58 is another porous bacteria-blocking member 60, once again typically a wad of cotton.

In accordance with this invention, the above assembly is put together in nonsterile manner with ampule or vial 1 8 being sealed within area 1 6. If desired, vial 18 may be retained in a conventional manner with an appropriate spring or breakaway retainer so that it does not accidentally thrust against spike 22 for accidental opening. As a further alternative, spike 22 may be an integral part of the ampule system and in communication therewith, so that communication between the area 24 of bag 10 and the interior of ampule 1 8 may be effected simply by opening breakaway seal 26. In that instance, there is no spike to penetrate a diaphragm of ampule 1 8.

For sterilization of the system, sterilizing gas such as ethylene oxide is passed into port 58 to flow into the interior of overpouch 54, sterilizing the exterior of bag 1 0. Similar sterilizing gas is passed into branch 46, from where it flows through sealed tube 44 into the interior of bag 10, which at this time is preferably dry. Furthermore, ethylene oxide gas from the interior of the overpouch 54 migrates through port 40 into sealed area 16, to sterilize all exposed surfaces there, including the interior of tubular needle 22 and the exterior of ampule 1 8. Ethylene oxide gas also migrates through outer closure 32, to sterilize the outer face of membrane 30 and the outer portions of access port 28.

After the application of ethylene oxide gas, the system of overpouch 54 and bag 10 is stored in a manner permitting venting of ethylene oxide gas outwardly through pots 28, 40, 44 and 58 so that the ethylene oxide gas is removed from the system. This storage generally requires a number of days to take place, but sterility is not broken because of the porous bacteria-blocking seals 48 and 60.

After the ethylene oxide gas has vented from the system, a bag 62 of conventionally sterilized solution may be connected to the system by the connection between sterile connectors 52 and 52a. These sterile connectors of a design previously described may be locked together and exposed to infrared radiation, for example from infrared source 64 until a sterile aperture is formed between the two connectors 52, 52a. The desired solution, for example normal saline, may then flow from bag 62, through connectors 52, 52a and sealed tube 44, into the interior 24 of bag 10. Branch 46 may be sealed during this process.

Following this, sealed tubing 44 may be sealed with a transverse heat seal 66 (which may be provided by a HEMATRON(g) heat seal, sold by the Fenwal Division of Travenol Laboratories, Inc.). Thereafter, tube 44 may be severed as at location 67, or through the heat seal 66 itself, to separate branches 46, 50 and bag 62 from the system. Port 58 may also be sealed with a transverse heat seal 68.

As the result of this, container 10 now contains, within its overpouch 54, a measured amount of sterile liquid within space 24 along with the dry solid contents of ampule 18, which have not been subjected to the heat needed for the necessary sterilization of the liquid.

When it is desired to admix the contents of ampule 1 8 with the liquid, hollow needle 22 penetrates diaphragm 20 of ampule 1 8 and breakaway seal 26 is snapped away. Then bag 10 is manipulated to force liquid into ampule 1 8 and to allow the liquid to flow again out of ampule 1 8 through hollow spike 20 back into the main body of liquid within space 24. Thus admixture can take place without breach of sterility. If desired, it can take place without opening overpouch 54.

This permits nurses in the ward to admix the various mixtures immediately before use, simply selecting the desired admixture system and preparing it for the patient, without the need of the supervision of a pharmacist.

Tubing 44 is in sliding, sealed relationship with the heat sealed periphery 56 of overpouch 54. This can be accomplished by sealing within heat seal 56 a tube 70 of high melting polypropylene or the like, which does not melt during the heat sealing process which forms periphery 56, but is preferably compatible with the material of overpouch 54 so as to adhere to the seal line 56. Thus tubing 44 can pass through sleeve 57 in a sliding fit relationship, so that when overpouch 54 is opened by peeling away an area for access to bag 10, tube 44 can slide out of its telescoping engagement with sleeve 57 by pulling, so that bag 10 may be separated from the overpouch.

Claims (14)

1. The method of sterilizing a first plastic container for holding liquid and an attached container holding a sterile dry solid, said containers having connection means for mixing their contents while remaining sealed from the exterior, at least said first container and said connection means being sealed in an overpouch, said method comprising:: passing sterilizing gas through a first porous, sealed, bacteria-blocking port into the interior of said overpouch to sterilize at least portions of the exterior of said first container and said connection means; passing sterilizing gas through a second, porous, sealed, bacteria-blocking port into the dry interior of said first container to sterilize said interior; allowing said sterilizing gas to diffuse from the interiors of the overpouch and first container out of said first and second ports without permitting bacterial access into said overpouch and first container; effecting an open sterile connection between a sealed tube communicating with the interior of said first container and a source of sterile liquid and passing said sterile liquid into the interior of the first container; and resealing said sealed tube.

2. The method of Claim 1 in which said attached container and connection means are positioned substantially within an isolated compartment of said first container, said method including the step of passing sterilizing gas from the overpouch interior through a third porous, sealed, bacteria-blocking port between the overpouch interior and the iso lated compartment, and thereafter allowing said sterilizing gas to diffuse out of the iso lated compartment through the third port.

3. The method of Claim 1 in which said sealed tube communicates through said over pouch through sliding seal means to permit pulling free of said first container and tube from the overpouch upon opening of the overpouch.

4. The method of Claim 1 in which said second, porous, sealed, bacteria-blocking port is carried at a position outside of said overpouch.

5. The method of Claim 4 in which said sealed tube is released by heat-sealing its bore permanently shut at a point nearer the first container than said second port and open, sterile connection, and thereafter severing said tube to remove said second port and open sterile connection without opening the resealed second tube.

6. The method of Claim 1 in which said first container is a collapsible bag having at least one access tube to its interior closed with a pierceable diaphragm, the outer end of said access tube being sealed with a removable seal member carrying a fourth porous, sealed bacteria-blocking port, whereby sterilizing gas from the overpouch interior can pass into contact with the outer end of said access tube.

7. The method of Claim 1 in which said attached container is a rigid vial.

8. The method of sterilizing a first flexible container for holding liquid and an attached container holding a dry solid, said containers having connection means for mixing their contents while remaining sealed from the exterior, said first container and attached container being sealed in an overpouch, the attached container being sealed in an isolated compartment of the first container, said method comprising:: passing sterilizing gas through a first porous, sealed bacteria-blocking port into the interior of said overpouch to sterilize the exteriors of said first and attached containers and the sealed connection means; passing sterilizing gas through a second, porous, sealed bacteria-blocking port carried at a position outside said overpouch into the dry interior of said first container to sterilize said interior; allowing said sterilizing gas to diffuse from the interiors of the overpouch, isolated compartment, and first container out of said first and second ports without permitting bacterial access into said overpouch and first container; effecting an open, sterile connection between a sealed tube communicating with the interior of said first container and a source of sterile liquid, and passing said sterile liquid into the interior of the first container; resealing said sealed tube; and severing said sealed tube to remove said source of sterile liquid without opening said resealed tube.

9. A sterile system which comprises a first container holding a liquid and an attached container holding a dry solid, connection means between said container for mixing their contents while permitting the containers to remain sealed from the exterior, at least said first container and connection means being sealed in an overpouch, and a sealed tube communicating with the interior of said first container, said sealed tube communicating through said overpouch and sealed thereto by sliding seal means, to permit opening of the overpouch and pulling free of the first container and tube by sliding the tube out of sliding, sealed relationship with the overpouch.

10. The apparatus of Claim 9 in which said attached container and connection means are positioned substantially within an isolated compartment of said first container, and port means carrying porous, bacteria-blocking means communicating between the isolated compartment and the overpouch interior.

11. The apparatus of Claim 10 in which said attached container is a rigid vial.

1 2. The apparatus of Claim 11 in which said connection means comprises a diaphragm carried by said attached container and spike means for penetrating said diaphragm, to provide access between the interior of said first container and attached container.

1 3. The apparatus of Claim 11 in which said first container carries at least one access tube closed with a pierceable diaphragm, said access tube carrying a removable seal member carrying a porous, sealed, bacteria-blocking port, whereby sterilizing gas from the overpouch interior can pass into contact with the outer end of the access tube.

14. The apparatus of Claim 1 3 in which said spike means is hollow and is closed at one end with a breakaway seal member.