EP4670698A1

EP4670698A1 - SACHET CONTAINING A PHARMACEUTICAL ACTIVE WITH A FEMALE TUBE-SHAPED CONNECTOR

Info

Publication number: EP4670698A1
Application number: EP24185428.0A
Authority: EP
Inventors: Christine Janas; Sophie BAUMEISTER; Annemarie HAVEMANN; Leonard Medico; Raphael Vallotton
Original assignee: B Braun Melsungen AG
Current assignee: B Braun Melsungen AG
Priority date: 2024-06-28
Filing date: 2024-06-28
Publication date: 2025-12-31
Also published as: WO2026003781A1

Abstract

A bag comprising a liquid comprising a pharmaceutical ingredient, wherein the bag comprises an opening comprising a female connection part of a male-female tubular connector system, wherein the pharmaceutical ingredient is selected from the list consisting of a parenteral nutrition preparation, an electrolyte, and an active pharmaceutical ingredient (API).

Description

Technical Field of the Invention

The present invention is located in the technical field of bags for storing pharmaceutical ingredients, in particular active pharmaceutical ingredients, and for providing for and transporting said pharmaceutical ingredient, in particular active pharmaceutical ingredient, to a downstream device or downstream storage container.

Background of the Invention

Pharmaceutical ingredients have an intended application purpose, for which they need to be inserted in specific downstream devices, such as syringes. To enhance sterility and handling, syringes are often provided prefilled and sterilized with a pharmaceutical solution. However, also these solutions may be prone to oxidation as set out above.
However, the production of prefilled syringes is complex, time-consuming and expensive. Furthermore, prefilled syringes usually comprise stoppers, which are not bound to the barrel, but constitute a movable part in relation to the barrel of the syringe. During sterilization and storage, tightness of the interface is challenged by deformation of the barrel material around the position of the stopper. Such a deformation can lead to loss of tightness and problems arising therefrom, i.e. concentration variation of the API in the solution and degradation of the API.
As a solution, pharmaceutical ingredients and solutions thereof are commonly stored prior to use and are transferred to respective downstream devices or storage containers shortly before usage.
Typically, such pharmaceutical solutions are stored in glass or plastic vials, glass or plastic ampoules, or plastic pouches. Historically, vials, glass bottles, and plastic pouches were accessed through elastomeric stoppers using needles, spikes, or other types of sharp transfer devices for puncturing said elastomeric stoppers. Accessing vials, ampoules or pouches and transferring the pharmaceutical solution using needles has the drawback of potential risks using sharp devices, such as piercing of the container walls, creation of fragments of elastomeric stopper or plastic membrane, needle-stick injuries, and general difficulty of pushing the needle through the elastomeric stopper.
To overcome the problem of handling the solution with a needle, other kinds of containers such as glass ampoules and later plastic ampoules were developed over the years, which provide access to their content through an open neck after breaking off an ampoule head. Such ampoules can be accessed using a needle, similar to those used to pierce elastomeric stoppers or blunt needles. In addition, also plastic needles of transfer devices, as well as semi-flexible straws could be used to transfer the pharmaceutical solution. Moreover, for withdrawing the content of glass ampoules, needles or straws are typically equipped or combined with inline filters to prevent glass particles from being directed into the withdrawing devices and later being administered to the patient.
Needle-free connectors have been developed to overcome the above-mentioned problems, cf. WO 9600556 A1 . The most common needle-free connector is the LUER connector, as currently defined in ISO 80369-7. This connector allows liquid-tight connection of two devices and transfer of a pharmaceutical solution in between these devices.
Ampoules and vials typically used for storing and/or transporting APIs are typically available in a certain size range, for example volumes of between 5 ml and 30 ml. Hence, to be able to store larger amounts of APIs without unnecessarily increasing the demand of packaging material, typically pouches have been implemented.
However, plastic pouches for storing pharmaceutical ingredients prior to use, which are compatible with syringes, and which can transfer the liquid in a needle-free manner, have not been described in the prior art.

Summary of the Invention

Hence, there is the need for pharmaceutical ingredients to be provided, stored, and made available shortly before usage by transfer to downstream devices, wherein these pharmaceutical ingredients are prevented to be delivered to wrong downstream devices.
It has now surprisingly been found that above-mentioned object can be achieved by a bag comprising a liquid comprising a pharmaceutical ingredient, wherein the bag comprises an opening comprising a female connection part of a male-female tubular connector system, wherein the pharmaceutical ingredient is selected from the list consisting of a parenteral nutrition preparation, an electrolyte, and an active pharmaceutical ingredient (API).
Moreover, it has now surprisingly been found that above-mentioned object can be achieved by a kit of parts comprising the bag according to the present invention, and a downstream device or storage container, wherein the downstream device or storage container comprises an opening comprising a male connection part of the male-female tubular connector system of the bag according to the present invention.
The bag and the kit of parts of the present invention have several advantages. One advantage is that the risk of stick injuries is reduced, as no sharp devices are needed during handling. Furthermore, reduced effort in time and costs is needed for preparation. The risk of wrong dosages is reduced, as the solution comprising the pharmaceutical ingredient can be ready for use (i.e. premixed). Finally, the risk of degradation of the pharmaceutical ingredient is reduced..

Brief Description of the Drawings

Figure 1: shows a schematic drawing of an embodiment of the bag of the present invention connected to a syringe, therefore together forming a preferred embodiment of the kit of parts of the present invention.
Figure 2: shows a picture of an embodiment of the bag of the present invention together with a syringe, therefore forming a preferred embodiment of the kit of parts of the present invention.
Figure 3: is a schematic drawing of the non-interconnectability of connectors according to ISO 80369-6 (NRFit) and ISO 80369-7 (LUER).

Definitions

The term 'polymer' as used herein denotes an organic polymer, preferably a polymer selected from polyolefins, polyethylene terephthalate, polystyrene, polyvinyl chloride, or mixtures thereof, more preferably a polyolefin selected from the list consisting of polyethylene, polypropylene, or mixtures thereof.
The term 'liquid-tight' as used herein denotes a quality of an object to function as a barrier for a liquid, preferably for a water-based liquid.
The term 'barrier layer' as used herein denotes a material, which can slow down the process of oxygen permeation. Preferably, it comprises, more preferably consists of, a based barrier material, most preferably ethylene-vinyl alcohol (EVOH), or a metal oxide material, most preferably a silicon oxide layer or an aluminum oxide layer. Such barrier layer can require a supporting or binding layer to adhere to the liquid-tight film of the bag, such as in particular the EVOH layer. Metal oxide-based layers can be deposited directly onto the polymer material (e.g., by chemical vapor deposition).
The term 'nominal volume' is the declared volume of the liquid that shall, as per pharmacopeial requirements, at least be possible to be extracted from the bag during the shelf life of the product.
The term 'total volume' is the maximum volume which can be contained in the bag at pressure equilibrium with the surrounding environment. The total volume of an bag is measured by filling said bag with water at 23±2 °C and at zero-gauge pressure, wherein the water is filled in the bag without any further pressure other than provided by the gravity until the bag is completely filled with water without any visible introduced gas, wherein the volume of the bag cavity is the volume of the water.
The term 'additive' as used herein denotes further components, which can be present in polymer compositions to modify their physical properties. Examples of additives are antioxidant(s), stabilizer(s), such as process stabilizers and UV stabilizers, acid scavenger(s), metal deactivators, crosslinking agents, such as free radical generating agent(s), e.g., organic peroxide(s), scorch retarder(s), crosslinking booster(s), processing aid(s), flame retardant additive(s), water tree retardant additive(s), inorganic filler(s), and voltage stabilizer(s). These groups of additives and the individual additive compounds therein are usually well known in the polymer field.
The term 'sterile' as used denotes the status of an object having a significantly reduced number of bacteria and/or viruses on its surface to reduce the risk of an infection. In particular, the term 'sterile' denotes an object or substance, which has a bioburden load of lower than 10^-6. The bioburden load can be measured i.e., according to ISO 11737-1:2018.
The term 'sterilization' as used herein denotes a method to destroy all forms of living microorganisms from a substance. As there is always a certain probability of at least one microorganism to survive such procedure, the aim of sterilization is the reduction of initially present microorganisms or other potential pathogens. Generally, sterilization is accepted to be achieved if the bioburden load of the substance of object to be sterilized is lower than 10^-6. The bioburden load can be measured i.e., according to ISO 11737-1:2018. Sterilization can be achieved using several methods. In one sterilization process the object is heated up to at least 105 °C to achieve a sterile object. Thereby, the object should not be deformed by the elevated temperature. Preferably, the heating step is performed in an autoclave. In another sterilization process, the object is brought into contact with toxic gases such as a mixture of ethylene oxide and carbon dioxide. Filtration methods are also used to sterilize liquids, i.e., by using membrane filters, Seitz filters, and/or candle filters. Finally, sterilization can be achieved by indirect energy import into or onto the object, e.g., by ultrasonic waves, ultraviolet light, as well as by high energy particles (such as electrons, gamma- or X-rays).
The term 'seam' as used herein denotes an area of at least two connected walls including at least one edge of each wall, of a bag, at which the two walls are connected, i.e., by gluing or welding, thereby forming a seam area, a seam edge, and an inner boundary of the edge.
The term 'seam width' as used herein denotes the distance between the seam edge and the inner boundary of the seam in a direction perpendicular to the seam edge. Usually, the seam width is substantially homogeneous, i.e., does not vary in the direction of the seam edge. However, variation of the seam width can be part of the overall design of the bag.
The term 'oxygen depleted gas' denotes a gas, which has a lower concentration of oxygen than air, preferably no or only trace amounts of oxygen. Hence, preferably, the oxygen depleted gas comprises, preferably consists of, a gas selected from nitrogen, carbon dioxide, a noble gas, or mixtures thereof. Most preferably, the oxygen depleted gas comprises, preferably consists of, nitrogen.

Detailed Description of the Invention

As indicated above, the present invention relates to a bag and a kit of parts comprising said bag. Each of these embodiments will be described in more detail in the following.

Bag of the Invention

As set out above, the most general embodiment of the present invention is concerned with a bag comprising a liquid comprising a pharmaceutical ingredient, wherein the bag comprises an opening comprising a female connection part of a male-female tubular connector system, wherein the pharmaceutical ingredient is selected from the list consisting of a parenteral nutrition preparation, an electrolyte, and an active pharmaceutical ingredient (API).
Preferably, the male-female tubular connector system defining the female connection part of the bag according to the present invention is selected from the list consisting of a system according to ISO 80369-7, a system according to ISO 80369-6, and a system according to ISO 80369-3. These systems have the advantage that they are commonly used and therefore ensure broad and convenient compatibility with downstream devices or storage containers. Preferably, the male-female tubular connector system defining the female connection part of the bag according to the present invention is system according to ISO 80369-7.
Hence, preferably, the female connection portion of the bag according to the present invention is compatible with a male connector according to ISO 80369-6, compatible with a male connector according to ISO 80369-7, or compatible with a male connector according to ISO 80369-3. Preferably, the female connection portion of the bag according to the present invention is compliant with the female connector of ISO 80369-6, compliant with the female connector of ISO 80369-7, or compliant with the female connector of ISO 80369-3. Male and female connectors according to ISO 80369-6, ISO 80369-7, and ISO 80369-3 are in particular different from each other. An example for a connector according to ISO 80369-7 is the so-called LUER connector. Likewise, an example for a connector according to ISO 80369-6 is the NRFit^® connector and an example for a connector according to ISO 80369-3 is the ENFit^® connector, both tradenames registered by GEDSA.
In all three cases the male connector comprises a conical tube. To ensure tightness, the male connector is designed to enter the female connector while creating radial compression. The end position is defined by the design of the outer features (collar, threads, etc.). The inner space of the conical tube is connected with the flow path of the respective device of the connector. Likewise, the female connector comprises in both cases also one conical tube. The conical tube of the female connector is designed to accommodate the outer surface of the conical tube and of the male connector in order to establish a liquid-tight flow path therebetween. In a preferred embodiment of the present invention, the male-female tubular connector system of the bag according to the present invention is a lockable male-female tubular connector system.
However, for example, the diameters of the connectors according to ISO 80369-6 are 20% smaller than the respective diameters of the connectors according to ISO 80369-7. Furthermore, the lengths of the tubes of the connectors according to ISO 80369-6 are 3 mm longer than the lengths of the respective tubes of the connectors according to ISO 80369-7. In addition, the taper angle of the conical part of the connectors specified in ISO 80369-3, ISO 80369-6 and ISO 80369-7 are different. As a result, neither a male connector according to ISO 80369-7 fits a female connector according to ISO 80369-6 nor a female connector according to ISO 80369-7 fits a male connector according to ISO 80369-6. Consequently, a connector according to ISO 80369-7 could not be accidentally connected to a connector according to ISO 80369-6 and vice versa (cf. Figure 5).
The particular advantage of the bag of the present invention is that the connection part is a female connection part. Thereby, it is ensured that compatibility with downstream devices or storage containers intended to be used downstream in a process or system comprising several parts of devices being connected by male-female tubular connector system according to the bag of the present invention. Downstream devices can be any devices used after storage of the pharmaceutical ingredient of the bag of the present invention has ended and application should start. Preferred downstream devices are syringes. Syringes typically comprise male connection portions of the male-female tubular connector system. Hence, the bag of the present invention ensures secure, complete, and accurate transfer of the liquid comprising the pharmaceutical ingredient to such a syringe.
In a preferred embodiment of the present invention, the bag is made from at least one liquid tight film, wherein the liquid tight film preferably comprises, more preferably consists of, a polymer material. The polymer material is preferably selected from the list consisting of polyethylene, polypropylene, polyethylene terephthalate, polyamide, ethylene vinyl alcohol, or mixture thereof. More preferably the polymer material is selected from polyethylene or polypropylene. These materials have an ideal balance of material properties, processability, inertia in view of the neuraxial drug, and low price. Additionally, the liquid tight film can preferably comprise one or more additives.
Preferably, the liquid tight film has a haze value measured according to ASTM D1003, Procedure B, of less than 60%, preferably less than 30%, more preferably less than 25%, and most preferably less than 15%. This ensures that the user can easily control the filling status of the bag according to the present invention.
Preferably, the polymer material of the liquid-tight film has a glass transition temperature T_g measured according to ASTM D3418, of not more than 80 °C, preferably not more than 60 °C, more preferably not more than 40 °C, and most preferably not more than 20 °C. This ensures thermal stability in particular in view of the sterilization conditions used.
In a preferred embodiment, the liquid-tight film of the bag according to the present invention comprises, preferably consists of, is a multilayer polymer material. The multilayer polymer material can be prepared by coextrusion, e.g., in a blown-extrusion process, in cast-extrusion process, or in an extrusion-laminating process, optionally after deposition, preferably chemical vapor deposition, of a barrier layer onto one of the films. Hence, the bag can have an innermost layer, wherein the innermost layer denotes the layer forming at least parts, preferably all of, the inner surface of the bag, and the bag can have an outermost layer, wherein the outermost layer denotes the layer forming at least parts, preferably all of, the outer surface of the bag.
The innermost layer usually has the function of providing inertia of the bag material in view of the pharmaceutical ingredient, preferably active pharmaceutical ingredient.
Hence, preferably, the material of the innermost layer is a material, which prevents or at least reduces migration of compounds of the multilayer polymer material of the bag into the liquid in the bag. Furthermore, the material of the innermost layer is preferably a material which prevents or at least reduces migration of compounds from the liquid, such as the pharmaceutical ingredient, preferably active pharmaceutical ingredient, into the multilayer polymer material of the bag according to the invention. Particularly preferably, the material of the innermost layer is a material which prevents or at least reduces migration of the pharmaceutical ingredient, preferably active pharmaceutical ingredient, into the multilayer polymer material of the bag according to the invention. Hence, most preferably, the material of the innermost layer of the bag according to the present invention is selected from the list consisting of a polypropylene, a polyethylene, or a cyclic olefin, more preferably is a cyclic olefin.
The function of the outermost layer of the multilayer polymer material of the bag according to the invention is to provide impact protection from the environment to protect the bag wall. Hence, preferably, the material of the outermost layer is preferably a polymer material having improved mechanical properties, such as tensile strength, impact strength, and/or toughness. Hence, preferably, the material of the outermost layer of the bag according to the present invention is a polyolefin material, most preferably is selected from a polyethylene or a polypropylene.
The multilayer polymer material of the bag according to the present invention preferably further comprises a barrier layer.
In a prefilled syringe, oxygen can migrate through the barrel, the plunger stopper, and/or the tip cap of the syringe. The tip of a syringe usually has only a very small surface in comparison to the volume of the syringe and is thus considered as being not too problematic in view of oxygen permeation. However, the plunger stopper and the barrel have a bigger diameter, hence surface, and are thus more prone to oxygen migration through said surfaces.
The function of the barrier layer in the preferred embodiment of the multilayer polymer material of the bag of the present invention is to slow down the process of oxygen permeation through the bag wall into the liquid in the bag. Furthermore, a barrier layer can also reduce water migration from the liquid in the bag to the environment, thereby increasing shelf life, as the concentration of the pharmaceutical ingredient, preferably active pharmaceutical ingredient, in the liquid is maintained for a longer time. Hence, shelf life could be increased by the barrier layer, as oxidative degradation of the pharmaceutical ingredient, preferably active pharmaceutical ingredient, could be delayed. Hence, preferably, the barrier layer of the bag according to the present
invention comprises, more preferably consists of, a material selected from ethylene vinyl alcohol (EVOH) or a metal oxide, preferably aluminum oxide or silicon oxide, most preferably the barrier layer of the bag according to the present invention comprises, more preferably consists of, ethylene vinyl alcohol (EVOH). If the barrier layer is made from EVOH, the barrier layer is preferably included in the multilayer material of the bag according to the present invention by being coextruded in between inner and outer layers. Additionally, typically intermediate tie layers are extruded at the same time. If the barrier layer is made from a metal oxide, preferably silicon oxide (SiO_x) or aluminum oxide (AlO_x), it is preferably deposited on a surface of the film, preferably via chemical vapor deposition, preferably prior to the production of the bag. Even more preferably, the film is laminated after the deposition step to protect the deposited barrier layer. In case the barrier layer is also made from a polymer material, the polymer material of the barrier layer has a glass transition temperature T_g measured according to ASTM D3418, of not more than 80 °C, preferably not more than 60 °C, more preferably not more than 40 °C, and most preferably not more than 20 °C.
In an especially preferred embodiment of the present invention, the barrier layer of the multilayer polymer material of the bag according to the present invention is implemented in that the bag according to the present invention comprises a barrier label layer, preferably an outermost barrier label layer.
The bag according to the present invention comprises at least one liquid-tight film. However, the bag according to the present invention may contain several liquid-tight films, which are connected to form a liquid-tight cavity. Most preferably, the bag according to the present invention comprises two liquid-tight films, which are connected at their edges to form the liquid-tight cavity. Usually, these connections are called seams. Usually, the seams of the bag of the present invention can be formed by any method allowing for a liquid-tight connection. Preferably, the seams are formed by gluing or by welding. Most preferably, the seams are formed by welding, i.e., by plastic welding. Usually, the seams are present as a plane, i.e., a flat area, in which the two entities to be connected, i.e., two liquid-tight films, constantly are in contact with each other. Depending on the use case, this area can be enlarged, i.e., to attach further equipment, print information thereon, or stance orifices therein. Usually, the seams, which are used for forming the liquid-tight connection and definition of the liquid-tight cavity only, should not be too small, as the liquid tight seam depends on the size of the area of contact, but also not too large, as otherwise the size of the bag gets too large without any further volume increase wasting space in the storage areas and increasing the amount of material consumption and waste. Hence, preferably, the seam has a seam width of equal to or more than 2 mm, preferably equal to or more than 3 mm, and most preferably equal to or more than 6 mm. Usually, the seam has a seam width of not more than 10 mm.
Preferably, the seam width of the bag of the present invention is chosen to not allow attaching further equipment or stamping orifices therein. Reason is that the bag of the present invention does not need to be attached somewhere in their intended use case. In particular, the bag according to the present invention does not need to be hung on an IV pole but can be handled manually. Thus, in a preferred embodiment, the seam width of the bag according to the present invention is substantially constant, preferably constant, and is in the range of from 2 to 10 mm, preferably in the range of from 3 to 6 mm.
In another preferred embodiment, the shape of the two liquid-tight films of the bag of the present invention is rectangular. Preferably, both liquid tight films have the same shape.
Thus, in a most preferred embodiment of the bag of the present invention, the bag comprises two liquid-tight films, which have a rectangular shape, therefore forming linear edges, and which have the same shape, wherein the two liquid-tight films are connected by seams at their edges and wherein the seam width is constant and is in the range of from 1 to 10 mm, preferably in the range of from 2 to 6 mm. Such a design allows for saving material in the seam area of the bag, therefore enhancing the sustainability of the bag. Furthermore, such design does not allow for attaching further equipment or stamping holes therein. Hence, the bag according to the present invention does not comprise any hanging means. This further improves safety, as it might not accidentally be used in hanging position for the wrong purpose.
Even more preferably, the rectangular shape of the liquid-tight films is defined by two edge lengths, wherein the edge lengths are in the range of from 50 to 150 mm, preferably 60 to 130 mm, more preferably 70 to 120 mm, and even more preferably 80 to 110 mm. The shape of the bag according to the present invention, if filled with a liquid at zero-gauge pressure, is defined by a thickness in the range of from 8 to 30 mm, preferably 10 to 20 mm.
The bag according to the present invention preferably has a nominal volume of equal to or more than 10 ml, preferably equal to or more than 20 ml, even more preferably equal to or more than 30 ml, still even preferably equal to or more 40 ml, and most preferably equal to or more than 45 ml. Likewise, the bag according to the present invention preferably has a nominal volume of equal to or less than 100 ml, more preferably equal to or less than 75 ml, even more preferably equal to or less than 60 ml, and most preferably equal to or less than 55 ml. Moreover, the bag according to the present invention preferably has a total volume of equal to or more than 12 ml, preferably equal to or more than 22 ml, even more preferably equal to or more than 33 ml, still even preferably equal to or more 44 ml, and most preferably equal to or more than 50 ml. Likewise, the bag according to the present invention preferably has a total volume of equal to or less than 110 ml, more preferably equal to or less than 84 ml, even more preferably equal to or less than 66 ml, and most preferably equal to or less than 55 ml.
Generally, the opening of the bag can be positioned at either any point of the liquid-tight film or at any point of the seam. Preferably, however, the opening is positioned at the seam as it facilitates the production process of the bag of the present invention. The opening is preferably a tube, more preferably an extruded tube or a molded tubular component welded into the seam of the bag, whereby the tube or tubular component may or not may extend from the seam. Preferably, the tube or tubular component of the opening extends from the seam. This facilitates attaching the female connection portion of the bag and further improves handling. Nevertheless, the tube preferably does not extend more than 4 cm, more preferably not more than 3 cm, and most preferably not more than 2 cm from the seam. This reduces the amount of material needed and as such the cost and sustainability of the bag. If the opening is formed by a tube or tubular component, the female connection portion is preferably attached at the end of the tube or tubular component extending outside the bag of the invention. The advantage of the tube or tubular component, in particular of the extending tube or tubular component, is to facilitate the handling of the connection of the male-female tubular connector system. By the extension, the bag is spatially separated from the connection part, thereby providing space for handling.
In another preferred embodiment, the opening of the bag comprises a openable closure before the female connection portion. More preferably, the openable closure is located in the tube or tubular component. This further ensures that the shelf life is enhanced, as contamination via the female connection portion can be reduced. The openable closure is preferably selected from a break-off section within the opening, or a resealable valve. Most preferably, the openable closure is a resealable valve. In a most preferred embodiment, the opening, of the bag, preferably the tube or the tubular component, comprise a break-off section and a resealable valve. This embodiment has the advantage that the break-off section protects the liquid in the bag from direct contact with the stopper-material of the valve during the storage. Furthermore, the valve hinders spilling before the transfer and especially after the transfer.
In a preferred embodiment of the invention, the bag comprises only needle-free openings. This ensures that handling with needles is not needed, and the risk of needle injury is reduced. More preferably, the bag of the invention does not comprise any administration port, such as spike-based connections. This ensures that the bag cannot be connected to an IV set (with an IV spike). In an even more preferred embodiment of the invention, the bag does not comprise any further opening besides the opening comprising the female connection portion. Likewise, in an evenly more preferred embodiment of the invention, the bag does not comprise any further connection portion. Thus, most preferably, the bag does not comprise any further opening and the bag does not comprise any further connection. This reduces complexity of the production process of the bag. Furthermore, this reduces the risk of leakage or entrance of components. Finally, it further reduces the risk of wrong application of the liquid to downstream devices.
In a preferred embodiment, the bag of the present invention is at least partially filled with the liquid. Thus, preferably, the bag of the present invention comprises the liquid and a headspace filled with gas, wherein the gas could be air but also other gases such as inert gases, i.e., nitrogen, noble gases, or oxygen depleted gases. Preferably, the volume of the headspace is smaller than the volume of the liquid filled part of the bag. More preferably, the volume of the headspace is less than 10% of the total volume of the bag, preferably less than 5%, more preferably less than 2%, and most preferably less than 1%. Usually, the volume of the headspace is larger than 0.5 ml, preferably in the range from 0.5 to 2 ml. Hence, it should be understood that preferably a minimal headspace is beneficial independently of the size of the bag. Hence, preferably, the minimal headspace is not lower than 0.5 ml. Such a minimal headspace ensures optimal transfer of the liquid from the bag.
The volume of the headspace can be controlled by either adding further gas through the inlet (increasing the volume) or by removal of the gas (decreasing the volume), either before, during or after the liquid filling process. The removal of the gas can be preferably carried out by mechanical pressing on the bag or by vacuuming the bag in a position to allow the gas from the headspace to leave the bag.
Usually, the bags can be sterilized after filling or are pre-sterilized and aseptically filled. One typical process of sterilization comprises the step of heating the bag up to at least 105 °C, preferably up to at least 121 °C. Thereby, the partial pressure of the gas is increased. If the volume of the headspace is too large, the partial pressure might be able to deform the bag.
Hence, preferably, the bag has a headspace filled with gas, wherein the ratio of the volume of the liquid in the bag to the volume of the head space is in the range of from 1:1 to 1000:1, preferably in the range of from 12:1 to 100:1, and most preferably in the range of from 16:1 to 50:1.
Preferably, the bag according to the present invention further comprises a secondary packaging, wherein the secondary packaging preferably is selected from an overwrap, a pouch, or a flow-wrap. The overwrap has the advantage that the bag is protected from being cut by other objects. Other advantages are protection from dust or external contamination, even gas permeation from external, such as moisture, oxygen, etc. The volume between the bag and the secondary packaging is usually denoted as secondary headspace. In one preferred embodiment of the bag according to the present invention, the secondary headspace is filled with an oxygen depleted gas. In another equally embodiment of the bag as used in the API for use in a treatment of a patient according to the present invention, an oxygen absorber is positioned with the secondary headspace. More preferably, both embodiments are combined.
Most preferably, the bag according to the present invention is a monochamber bag.
As set out above, the bag of the present invention is filled with a liquid, wherein the bag comprises, preferably consists of, a pharmaceutical ingredient. If the pharmaceutical ingredient is a solid or needs to be present in a certain concentration, the liquid further comprises a solvent. Preferably, the solvent is water and may include a buffer and/or other excipients.
The pharmaceutical ingredient as comprised in the liquid comprised in the bag according to the present invention is selected from the list consisting of a parenteral nutrition preparation, an electrolyte, and an active pharmaceutical ingredient (API).
Electrolytes are water soluble salts, which regulate chemical reactions in the human body, provide communication channels, and maintain the balance between fluids inside and outside of cells. Electrolytes are comprised of a cation, preferably selected from sodium, potassium, calcium, and magnesium ions, and an anion, preferably selected from chloride, phosphate, and bicarbonate ions. The electrolyte as may be comprised in the liquid comprised in the bag of the present invention is preferably potassium chloride.
The parenteral nutrition preparation as may be comprised in the liquid of the bag of the present invention is preferably selected from the list consisting of a lipid emulsion, preferably comprising long chain triglycerides, medium-chain triglycerides, or omega-3 oil, an amino acid preparation, and a carbohydrate preparation.
As set out above, the API comprised in the liquid comprised in the bag of the present invention is selected from the list consisting of anesthetics, antiarrhythmics, anticoagulants, sedatives, antihypertensives, antihypotensives, inotropes, vasodilators, and hormones.
Anesthetics are used to induce anesthesia and therefore their application results in a temporary loss of sensation or awareness. Anesthetics may be divided into general anesthetics, the application of which resulting in a reversible loss of consciousness, and local anesthetics, the application of which causing a reversible loss of sensation for regions of the body and not necessarily affecting consciousness. The anesthetics as may be comprised in the liquid comprised in the bag of the present invention are preferably intravenous anesthetics, preferably opioid or non-opioid intravenous anesthetics. Non-opioid intravenous anesthetics as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of barbiturates, benzodiazepines, etomidate, ketamine, and propofol. Opioid intravenous anesthetics as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of alfentanil, fentanyl, remifentanil, sufentanil, buprenorphine, butorphanol, diamorphine, hydromorphone, levorphanol, pethidine, methadone, morphine, codeine, nalbuphine, oxycodone, oxymorphone, and pentazocine. Most preferably, the anesthetics as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of fentanyl, sufentanil, diazepam, and propofol.
Antiarrhythmics are used to suppress abnormally fast rhythms (tachycardias) of the heart, e.g. atrial fibrillation, supraventricular tachycardia, and ventricular tachycardia. The antiarrhythmics as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from the list consisting of ajmaline, disopyramide, procainamide, quinidine, sparteine, lidocaine, mexiletine, phenytoin, tocainide, encainide, flecainide, moricizine, propafenone, atenolol, bisoprolol, carvedilol, esmolol, metoprolol, nebivolol, propranolol, timolol, amiodarone, dofetilide, dronedarone, ibutilide, sotalol, vernakalant, diltiazem, verapamil, adenosine, digoxin, and magnesium sulfate. Most preferably, the antiarrhythmics as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of esmolol and amiodarone.
Anticoagulants prevent or reduce the coagulation of blood, thereby prolonging the clotting time of the blood. The anticoagulants as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from the list consisting of coumarin and derivatives thereof, heparin and derivatives thereof, fondaparinux, idraparinux, idrabiotaparinux, rivaroxaban, apixaban, and edoxaban.
Most preferably, the anticoagulant as may be comprised in the liquid comprised in the bag of the present invention is heparin.
Sedatives induce sedation by reducing irritability or excitement, wherein they interact with brain activity causing deceleration thereof. Sedatives can be selected from the list comprising intravenous anesthetics, barbiturates, benzodiazepines, opioids, herbal sedatives, antipsychotics, antidepressants, muscle relaxants, and antihistamines. Preferred sedatives as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of fentanyl, sufentanil, diazepam, midazolam, and dexmedetomidine.
Antihypotensives, also known as vasopressors, can raise the blood pressure of a human being. The antihypotensives as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from the list consisting of epinephrine, noradrenaline, phenylephrine, dobutamine, dopamine, dopexamine, ephedrine, midodrine, amezinium, metaraminol, vasopressin, angiotensinamide, difetur, izoturon, hydrocortisone, prednisone, prednisolone, dexamethasone, betamethasone, fludrocortisone, strophantink, convallatoxin, digoxin, amrinone, enoximone, milrinone, and levosimendan. Most preferably, the antihypotensives as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of epinephrine and vasopressin.
Antihypertensives can lower the blood pressure of a human being, therefore can prevent complications of high blood pressure, such as stroke, heart failure, kidney failure and myocardial infarction. The antihypertensives as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from the list consisting of thiazide diuretics, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs), alpha blockers, beta blockers, and mixed alpha and beta blockers. Most preferably, the antihypertensives as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of clonidine and urapidil.
Inotropes can alter the force or energy of muscular contractions. The inotropes as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from the list consisting of digoxin, berberine, calcium, calcium sensitizers (such as levosimendan), catecholamines (such as dopamine, dobutamine, dopexamine, adrenaline (epinephrine), isoproterenol (isoprenaline), and noradrenaline (norepinephrine)), angiotensin II, eicosanoids (such as prostaglandins), phosphodiesterase inhibitors (such as enoximone, milrinone, amrinone, and theophylline), glucagon, and insulin. Most preferably, the inotropes as may be comprised in the liquid comprised in the bag of the present invention are selected from the list consisting of dobutamine, dopamine, milrinone and insulin.
Vasodilators can cause relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Vasodilators as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from milrinone and glyceryl trinitrate.
Hormones are the chemical messengers of the endocrine system and represent signals which adjust the internal working of the body. Hormones can be selected from the list of steroid hormones (cholesterol derived), lipid hormones, amino acid derived hormones, and proteinic hormones. Hormones as may be comprised in the liquid comprised in the bag of the present invention are preferably selected from the list consisting of oxytocin, insulin, dopamine, adrenaline, and vasopressin.
More preferably, the pharmaceutical ingredient comprised in the liquid in the bag according to the present invention is an active pharmaceutical ingredient. Even more preferably, the pharmaceutical ingredient comprised in the liquid in the bag according to the present invention is selected from the list consisting of anesthetics, antiarrhythmics, anticoagulants, sedatives, antihypertensives, antihypotensives, inotropes, vasodilators, and hormones. Most preferably, the pharmaceutical ingredient comprised in the liquid in the bag according to the present invention is selected from the list consisting of esmolol, heparin, potassium chloride, midazolam, propofol, noradrenaline, dexmedetomidine, amiodarone, adrenaline, fentanyl, milrinone, clonidine, dobutamine, oxytocin, insulin, sufentanil, dopamine, vasopressin, uradipil, and glyceryl trinitrate.

Kit of parts of the Invention

The present invention is further concerned with a kit of parts comprising the bag according to any of the preceding claims 1 to 13, and a downstream device or storage container, wherein the downstream device or storage container comprises an opening comprising a male connection part of the male-female tubular connector system.
It should be understood that each preferred feature as described above for the bag of the present invention equally can be present in the bag of the kit of parts of the present invention.
The advantage of this kit of parts is that the pharmaceutical ingredient is safely stored in the bag according to the invention and can be delivered directly with the downstream device. The downstream device is compatible with the bag. Thus, the pharmaceutical ingredient can be safely and easily transported from the bag to the downstream device without any risk of needle injury or connecting to the a downstream device having a connector designed for a route of a different application as the one the drug is meant to be administered through.
Preferably, the downstream device is a syringe. More preferably, the downstream device is a syringe for a syringe pump. Most preferably, the downstream device is a syringe and a syringe pump.

Claims

A bag comprising a liquid comprising a pharmaceutical ingredient, wherein the bag comprises an opening comprising a female connection part of a male-female tubular connector system, wherein the pharmaceutical ingredient is selected from the list consisting of a parenteral nutrition preparation, an electrolyte, and an active pharmaceutical ingredient (API).
The bag according to claim 1, wherein the liquid comprising the pharmaceutical ingredient is suitable for direct administration without further modification.
The bag according to claims 1 or 2, wherein the pharmaceutical ingredient is an active pharmaceutical ingredient and wherein the pharmaceutical ingredient is selected from the list consisting of anesthetics, antiarrhythmics, anticoagulants, sedatives, antihypertensives, antihypotensives, inotropes, vasodilators, and hormones.
The bag according to claim 3, wherein the active pharmaceutical ingredient is selected from the list consisting of esmolol, heparin, potassium chloride, midazolam, propofol, noradrenaline, dexmedetomidine, amiodarone, adrenaline, fentanyl, milrinone, clonidine, dobutamine, oxytocin, insulin, sufentanil, uradipil, dopamine, vasopressin, and glyceryl trinitrate.
The bag according to any of the preceding claims 1 to 4, wherein the male-female tubular connector system is selected from the list consisting of a LUER system according to ISO 80369-7, an NRfit system according to ISO 80369-6, and an ENFit system according to ISO 80369-3.
The bag according to any of the preceding claims 1 to 5, wherein the bag is made from a liquid tight film, wherein the liquid tight film preferably comprises, more preferably consists of, a polymer material, wherein the polymer material is preferably selected from the list consisting of polyethylene, polypropylene, polyethylene terephthalate, polyamide, ethylene vinyl alcohol, or mixture thereof, preferably is selected from polyethylene or polypropylene.
The bag to claim 6, wherein the liquid tight film has a haze value measured according to ASTM D1003, Procedure B, of less than 60%, preferably less than 30%, more preferably less than 25%, and most preferably less than 15%.
The bag according to any of the preceding claims 1 to 7, wherein the bag has a nominal volume of 100 ml or lower, preferably 75 ml or lower, and most preferably 60 ml or lower.
The bag according to any of the preceding claims 1 to 8, wherein the bag has a total volume of 110 ml or lower, preferably 84 ml or lower, and most preferably 66 ml or lower.
The bag according to any of the preceding claims 1 to 9, wherein the bag has a head space filled with gas, wherein the ratio of the volume of the liquid in the bag to the volume of the head space is in the range of from 1:1 to 1000:1, preferably in the range of from 12:1 to 100:1, and most preferably in the range of from 16:1 to 50:1.
The bag according to any of the preceding claims 1 to 10, wherein the bag further comprises a secondary packaging, wherein the secondary packaging preferably is selected from an overwrap, a pouch, or a flow-wrap.
The bag according to any of the preceding claims 1 to 11, wherein the bag is a monochamber bag.
A kit of parts comprising the bag according to any of the preceding claims 1 to 12, and a downstream device or storage container, wherein the downstream device or storage container comprises an opening comprising a male connection part of the male-female tubular connector system.
The kit of parts according to claim 13, wherein the downstream device is a syringe.
The kit of parts according to claim 14, wherein the kit of parts further comprises a syringe pump.