Container containing selectively dissolved gas content

Abstract

The present invention relates to a flexible container / multi-chamber container with selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product having a selective gas requirement to remain stable, comprising a solution containing at least one compound and a packing material from which the container is made to provide a high gas barrier for said gas. The at least one compound may be selenium in the form of Se(IV), preferably selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide. The selective gas may be oxygen, and the oxygen headspace maintains the solution to contain a level of dissolved oxygen (DO) of 0.5 ppm to 8 ppm.

Description

[Technical Field]

[0001] explanation This invention generally relates to the field of IV solutions, and more particularly to the field of clinical nutrition and corresponding pharmaceutical products.

[0002] The present invention relates to a pharmaceutical product having, preferably, a plurality of chambers, each having a selective and controllable dissolved gas (e.g., oxygen) content.

[0003] In certain embodiments, the present invention relates to a flexible container or multi-chamber container in which a selective dissolved gas content is contained in one or more compartments to stabilize at least one compound sensitive to the gas level. In certain embodiments, such a compound may be a compound delivered intravenously, such as a certain vitamin or micronutrient (e.g., a selenium compound in the form of Se(IV)). In certain embodiments, the present invention relates to a flexible container or multi-chamber container in which a selective dissolved gas content is contained in one or more compartments, and the headspace of a compartment having a particular gas requirement is filled with the required gas (e.g., ambient air, oxygen-rich air, or oxygen). In the case of selenium, the selenium compound in the form of Se(IV) is preferably selected from the group consisting of sodium selenite, selenite, and selenium dioxide, and the headspace of the compartment containing the selenium-containing solution contains ambient air, oxygen-rich ambient air, or oxygen as part of the oxygen, thereby maintaining, for example, the level of dissolved oxygen (DO) in the solution at an intended level, such as oxygen from 0.5 ppm to 8 ppm. We can imagine other compounds that have specific gaseous requirements.

[0004] In certain embodiments of the present invention, the solution of the pharmaceutical product of the present invention contains at least one additional trace element, such as selenium. As used herein, the term “pharmaceutical product” encompasses IV solutions as well as parenteral and nutritional solutions. The term “parenteral nutritional solution” refers to a solution for providing nutritional support delivered entirely intravenously via an IV pump through the bloodstream. The solution contains amino acids, carbohydrates, lipids, electrolytes, vitamins, and / or minerals. The pharmaceutical solution may be ready for immediate use. The solution may be contained in one chamber of a multi-chamber container having at least two, at least three, at least four, at least five, at least six, or more chambers. The solution may also be contained in a monobag. Multiple solutions contained in a multi-chamber bag may have specific gas requirements, such as high oxygen levels, which may differ from the remaining compartments of the multi-chamber bag, for example, which may require particularly low levels of oxygen. Furthermore, the present invention relates to a method for providing a pharmaceutical product in a multi-chamber container according to the present invention, or, if possible, in a monobag according to the present invention. [Background technology]

[0005] Background of the Invention Solutions for intravenous administration, including parenteral nutrition (PN) products, are intended to deliver certain compounds to a patient via venous access. For example, parenteral nutrition products may consist of macronutrients (lipids, amino acids, or proteins, and dextrose, or carbohydrates), micronutrients (vitamins and trace elements), and / or electrolytes. IV solutions and PN products are often supplied in flexible bags of varying volumes. PN products, in particular, are often supplied in multi-chamber bags, as various formulations, such as the lipid preparations, carbohydrate preparations, or amino acid preparations mentioned, must be kept separate from each other during production, filling, sterilization, and storage to remain stable. Various formulations often have different requirements, for example, regarding pH, the presence of certain active ingredients or excipients that may affect stability or interact with each other, and the presence or absence of certain gases, such as oxygen, which tends to react with and inactivate many pharmaceutically active ingredients.

[0006] Furthermore, while various formulations may be placed in various compartments of a multi-chamber bag, as is typically done in parenteral nutrition, the various requirements regarding specific gases that must or must not be present in the various formulations of the same MCB are difficult to fulfill. As is readily apparent, a multi-chamber bag is prepared from a single film material. The various compartments are introduced by welded sealing between the various compartments, which is (partially) permanent or can be peeled off, for example, by hand pressure. Therefore, it is also difficult to accommodate one or more formulations that require the use of a certain film material, for example, an oxygen-semipermeable film material that allows oxygen to be slowly removed from a given formulation using an oxygen absorber in an overpouch to keep the oxygen level low in the formulation, for example, compartments and formulations that require high oxygen levels, and consequently, a high oxygen barrier film that prevents oxygen from leaving the compartment, especially if an oxygen absorber is also present in the overpouch.

[0007] Further challenges arise when compounds have selective gas requirements for their stability, such as compounds that require high dissolved oxygen levels. Oxygen may be consumed by the formulation's components and / or lost when using high oxygen barrier materials by diffusion through the film. This is particularly evident in the presence of oxygen absorbers that can be placed in the overpouch of the MCB, which will also slowly deplete the dissolved oxygen solution in the case of high oxygen barrier materials. Once oxygen is lost from the compartment, the compound will begin to lose stability and decompose. Therefore, simply using film materials for containers with high oxygen barriers to reduce the loss of DO from the solution through the container may not be sufficient to address the long-term problems of such compounds, i.e., the typical shelf life requirements for ready-to-use pharmaceutical formulations, which should generally be at least 6, 12, 18, or best 24 months at temperatures up to 25°C.

[0008] Parenteral nutritional solutions, such as one or more solutions, may also be provided in the form of a single flexible bag containing glucose, amino acids, or lipids, or, for example, vitamins and / or trace elements, with or without electrolytes, and which can be mixed together before administration. This flexible bag may also be in the form of a multi-chamber flexible bag providing individual macronutrients and electrolytes in a ready-to-use format. Thus, the same challenges of unsuitable gas level requirements in various formulations can also arise in MCBs providing parenteral nutritional formulations.

[0009] Such headspace is known to be created when a liquid composition is introduced into a container, for example, into a container discussed herein, meaning that air is trapped at the top of the container before it is sealed. Generally, the goal of industry is to reduce headspace for a variety of reasons. Methods have been developed to monitor the oxygen level in the headspace of pre-filled containers, where requirements arise to ensure the stability and potency of oxygen-sensitive products, and are used for inspecting finished sterile products, such as headspace oxygen analysis (HOA) or non-destructive laser headspace inspection. As also described in WO2009021094A1, headspace can be reduced by a variety of methods, including "topping off" the container with a sufficient amount of composition to prevent air from remaining at the top of the container, or evacuating a liquid-filled container. Another technique involves providing an elaborate passage in the closure, thereby allowing gas to escape the system while minimizing liquid loss. Another system utilizes one or more small orifices in a rubber, metal, or plastic diaphragm that makes the material permeable to gas. In common cases where headspace cannot be completely avoided, the headspace is filled with an inert gas such as nitrogen.

[0010] In summary, for example, the conventional headspace in a container for a pharmaceutical solution needs to be reduced or avoided, or controlled in a way that avoids the presence of any inert gas, such as oxygen, if possible.

[0011] Typical pharmaceutical solution containers, including those used for parenteral nutritional solutions, must meet several performance criteria, including flexibility, transparency, gas barrier properties, drug compatibility, heat sterilization resistance, and drop impact resistance. Various types of pharmaceutical solution containers are currently available, such as double bags with an inner bag and an outer bag, where the inner bag contains the functional pharmaceutical solution and the outer bag (also called an "overpouch") covers the inner bag and has gas or oxygen barrier properties.

[0012] The bags are typically made from synthetic or plastic materials, such as polypropylene (PP), polyethylene (PE), ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), and all possible copolymers, and are essentially made from any synthetic material suitable for containing the administered component.

[0013] As mentioned above, current technology does not allow for stable formulation into one of the compartments of the MCB; therefore, typically, micronutrients, but also certain drugs, are added directly to the nutrition bag before administration. For this purpose, vitamins can be provided in glass vials in the form of lyophilized or solution products that will be reconstituted and / or mixed into the nutrition / infusion bag. Trace elements are also provided in glass vials or polypropylene ampoules, meaning they will be mixed in the infusion bag before administration. The same applies to certain drugs that can or may be added to parenteral nutritional solutions for administration.

[0014] Before use, when initiating administration of the formulation to a patient, micronutrients or drugs are sometimes added to the mixture or macronutrients via the infusion port of the container or bag (septum), or added to the infusion line via a Y-connector. This process is time-consuming and involves several handling steps, increasing the risk of error or contamination.

[0015] To avoid these potential problems, for example, products have been developed that already contain some trace elements in a nutritional multi-chamber bag. For example, Pediaven, a two-component parenteral nutrition solution for infants, children, and adolescents, contains trace elements in the glucose chamber. However, the trace element selenium, which is provided as selenium dioxide in the product, has been reported to be absent in the finished product, presumably due to degradation, as published in July 2014 (http: / / www.pharmacovigilance-tours.fr / 490.html). Another product, Elneopa from Otsuka Pharmaceutical, contains certain specific trace elements in a small dedicated chamber as part of a multi-chamber bag. However, this product does not contain selenium.

[0016] For example, EP2080501A1 seeks to reduce the dissolved oxygen content in the formulation by using a plastic material that has an oxygen permeability of 200 cm at a temperature of 25°C and a humidity of 60% RH within 12 hours after the steam sterilization process or hot water sterilization process 3 / m 2 ·24h·atm or more, and a steady-state oxygen permeability of 100 cm at a temperature of 25°C and a humidity of 60% RH 3 / m 2 ·24h / atm or less, discloses a multi-chamber bag containing a formulation for parenteral nutrition that also includes micronutrients (trace elements). In such cases, the dissolved oxygen level will be significantly reduced over time, especially over the shelf life, which is beneficial to oxygen-prone components, but may lead to the degradation of Se(IV) when present as a micronutrient.

[0017] KR10-2019-0105737 relates to an intravenous solution preparation containing fat-soluble vitamins and trace elements, and more specifically, to an intravenous solution preparation containing multiple chambers internally, thus separately storing reducing sugars, amino acids, lipids, and fat-soluble vitamins and trace elements. The publication describes preferred concentrations of selenium ions and selenium cations, ranging from 3 μg / mL to 7.0 μg / mL, among other trace elements contained in the chambers of the multi-chamber nutritional product. No method for stabilizing specific ions or such selenium ions in the preparation is described. For example, it is well known in the art that selenium, iodine, and copper—especially in combination—are difficult to include in nutritional bags because they may undergo chemical reactions and must be subjected to extreme conditions such as heat sterilization and long-term storage life (e.g., Allwood et al. Compatibility and Stability of Additives in Parenteral Nutrition Admixtures. Nutrition 1998, Vol. 14, No. 9, pp. 697-706; Eisenberg et al. Stability of selenium sources reviewed. Feedstuffs, June 18, 2012). (Furthermore, in various formulation studies, when attempting to introduce trace elements into a nutritional multi-chamber bag, severe stability issues have been encountered, and loss of selenium in particular has been observed. This can be attributed to the fact that selenium in the Se(IV) form, especially selenium in the form of sodium selenite, selenous acid, or selenium dioxide, tends to adsorb onto, for example, plastic materials or iron oxides; may be reduced to elemental selenium in the presence of reducing agents such as ascorbic acid; may be reduced to hydrogen selenide, which is a volatile substance; and / or may be converted at low pH to selenium dioxide, which is also a volatile substance under certain specific conditions. In short, the conditions for certain specific compounds such as selenite are not suitable in the MCB to be provided in a stable manner. Such challenges can now be addressed as disclosed herein. As a result of the disclosure made herein, it is finally possible to stably provide a ready-to-use pharmaceutical product or a flexible container / multi-chamber container for a pharmaceutical product, including those directed to parenteral administration that contain solutions for parenteral administration to a patient in need thereof, which comprise compounds with selective gas requirements that may be further in contrast to the requirements of other formulations in the same MCB. For example, selenium in the Se(IV) form can finally be stably provided over an extended period of time. The technology disclosed herein can also be used with respect to other compounds or combinations of compounds having selective gas requirements, particularly in the context of multi-chamber bags containing formulations that have conflicting requirements regarding various gas levels in solution. [Prior Art Documents] [Patent Documents]

[0018] [Patent Document 1] International Publication No. 2009021094A1 [Patent Document 2] European Patent Application Publication No. 2080501A1 Specification [Patent Document 3] Korean Patent Application Publication No. 10-2019-0105737 Specification [Non-Patent Documents]

[0019] [Non-Patent Document 1] Allwood et al. Compatibility and Stability of Additives in Parenteral Nutrition Admixtures. Nutrition 1998, Vol. 14, No. 9, pp. 697-706 [Non-Patent Document 2] Eisenberg et al. Stability of selenium sources reviewed. Feedstuffs, June 18, 2012 [Overview of the Initiative] [Problems that the invention aims to solve]

[0020] Therefore, there remains a need to provide solutions that contain sensitive compounds that require the presence of a selective gas in a formulation, particularly in formulations that are part of an MCB encompassing further formulations with various gas level requirements. [Means for solving the problem]

[0021] Summary of the Invention In one embodiment, the present invention relates to a flexible container having a selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product having a selective gas requirement for remaining stable, the flexible container comprising: a solution containing at least one compound; a film material from which the container is fabricated, providing a high gas barrier with respect to the gas; and a gas headspace.

[0022] In another embodiment, the present invention relates to a flexible container having a selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product, wherein the flexible container: (a) A solution containing at least one compound having a selective dissolved gas requirement; and (b) Gas headspace Includes.

[0023] In another embodiment, at least one compound is a compound that requires a high level of oxygen, and the selectively dissolved gas is oxygen.

[0024] In another embodiment, the flexible container is a multi-chamber bag containing at least one chamber in which a compound having selective dissolved gas requirements is disposed.

[0025] In another embodiment, the flexible container has a headspace volume of about 5% to about 100% of the volume of the solution inside the flexible container.

[0026] In another embodiment, the headspace volume is approximately 35% to 45% of the volume of the solution in the flexible container.

[0027] In another embodiment, the container is ultimately heat-sterilized.

[0028] In another embodiment, at least one compound is a selenium compound in the form of Se(IV).

[0029] In another embodiment, at least one selenium compound is selected from the group consisting of sodium selenite, selenite, and selenium dioxide.

[0030] In another embodiment, the solution contains dissolved oxygen (DO) equal to or greater than 0.5 ppm throughout the entire shelf life of the pharmaceutical product.

[0031] In another embodiment, the solution contains approximately 0.5 ppm to approximately 8 ppm of dissolved oxygen (DO).

[0032] In another embodiment, the solution contains dissolved oxygen (DO) equal to or greater than 1 ppm.

[0033] In another embodiment, the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm.

[0034] In another embodiment, the gas headspace stabilizes at least one compound for a period selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months, when stored at a temperature between about 1°C and about 40°C.

[0035] In another embodiment, the flexible container is stored at a temperature between approximately 18°C ​​and approximately 30°C.

[0036] In another embodiment, the solution has an acidic pH value in the range of about 1 to about 4, preferably about 2.5 to about 3.2.

[0037] In another embodiment, the multi-chamber container includes at least two chambers.

[0038] In another embodiment, the multi-chamber container is selected from the group consisting of 2-chamber containers, 3-chamber containers, 4-chamber containers, 5-chamber containers, 6-chamber containers, 7-chamber containers, and 8-chamber containers.

[0039] In another embodiment, a multi-chamber container is: (a) A first chamber containing a carbohydrate preparation; (b) A second chamber containing an amino acid preparation; (c) A third chamber containing a lipid preparation; and (d) A fourth chamber containing a solution containing a compound having selective dissolved gas requirements. Includes.

[0040] In another embodiment, the solution contained in the fourth chamber comprises at least one selenium compound, and the headspace is filled with ambient air, oxygen-rich ambient air, or oxygen.

[0041] In another embodiment, the flexible container holds 1 cc / m³ 2 Less than 0.5 cc / m³ per day, preferably 0.5 cc / m³ 2 It is made from materials with an oxygen barrier of less than 1 day.

[0042] In another embodiment, the compartment of a flexible container in which a compound having selective dissolved gas requirements is located may or may not include an airtight port tube.

[0043] In another embodiment, the present invention relates to a multi-chamber container having a selective dissolved gas content for stabilizing at least one micronutrient of a pharmaceutical product, wherein the multi-chamber container: (a) A first chamber containing a carbohydrate preparation, an amino acid preparation, or a lipid preparation; (b) A solution containing at least one micronutrient having selective dissolved gas requirements; and a second chamber including a gas headspace. Includes.

[0044] In another embodiment, at least one micronutrient is at least one micronutrient compound, which is selenium in the form of Se(IV), and the dissolved gas is dissolved oxygen (DO).

[0045] In another embodiment, the multi-chamber vessel includes at least five chambers.

[0046] In another embodiment, at least one selenium compound is selected from the group consisting of sodium selenite, selenite, and selenium dioxide.

[0047] In another embodiment, at least one selenium compound is sodium selenite or selenium dioxide.

[0048] In another embodiment, the solution in the second chamber contains dissolved oxygen (DO) equal to or greater than 0.5 ppm throughout the entire shelf life of the pharmaceutical product.

[0049] In another embodiment, the solution in the second chamber contains dissolved oxygen (DO) at a concentration of approximately 0.5 ppm to approximately 8 ppm.

[0050] In another embodiment, the solution in the second chamber contains dissolved oxygen (DO) equal to or greater than 1 ppm.

[0051] In another embodiment, the container is ultimately heat-sterilized.

[0052] In another embodiment, the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm.

[0053] In another embodiment, the headspace volume is approximately 5% to 100% of the volume of the solution in the multi-chamber container.

[0054] In another embodiment, the volume of oxygen headspace is approximately 35 to 45% of the volume of the solution in the flexible container.

[0055] In another embodiment, the gaseous headspace, when stored at temperatures between approximately 1°C and approximately 30°C, stabilizes at least one micronutrient for a period of time selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months.

[0056] In another embodiment, the multi-chamber container is stored at a temperature between approximately 18°C ​​and approximately 25°C.

[0057] In another embodiment, the multi-chamber container has a capacity of 1 cc / m³ 2 Less than 0.5 cc / m³ per day, preferably 0.5 cc / m³ 2 It is made from materials with an oxygen barrier of less than 1 day.

[0058] The present invention is further described by the following figures. These are not intended to limit the scope of the invention, but rather to represent preferred embodiments of the invention provided for a broader illustration of the invention as described herein. [Brief explanation of the drawing]

[0059] [Figure 1] Figure 1 is a set of graphs showing the changes in dissolved oxygen (DO) over time at 40°C for samples in EU-2S batches (semipermeable) and EU2-F bags (oxygen-impermeable).

[0060] [Figure 2A] Figure 2 (Figures 2A and 2B) is a set of graphs showing the selenite recovery levels for selenite batch EU2-S (semipermeable film) (Figure 2A) and selenite batch EU2-F (oxygen-impermeable film) (Figure 2B). [Figure 2B] Figure 2 (Figures 2A and 2B) is a set of graphs showing the selenite recovery levels for selenite batch EU2-S (semipermeable film) (Figure 2A) and selenite batch EU2-F (oxygen-impermeable film) (Figure 2B).

[0061] [Figure 3] Figure 3 is a set of graphs showing an analysis of the effects of combining the presence of headspace and port tubes with an oxygen-impermeable bag.

[0062] [Figure 4] Figure 4 is a set of graphs showing the change in dissolved oxygen (DO) over time as an effect of headspace volume.

[0063] [Figure 5] Figure 5 shows an exemplary multi-chamber container.

[0064] [Figure 6] Figure 6 is a graph showing the change in dissolved oxygen (DO) over time at 40°C for chamber C of the multi-chamber container shown in Figure 5.

[0065] [Figure 7]Figure 7 is a graph showing the change in dissolved oxygen (DO) over time at 40°C in chamber C of the multi-chamber container shown in Figure 5, after a 5 mL air headspace has been added to chamber C.

[0066] [Figure 8] Figure 8 shows another exemplary multi-chamber container, similar to the one in Figure 5, but with a sealing material added to isolate any filling tube from chamber C.

[0067] [Figure 9] Figure 9 shows the change in dissolved oxygen (DO) over time at 40°C for chamber C of the multi-chamber container shown in Figure 8, and is a graph that shows the dissolved oxygen level remains around 5 to 6 ppm even after 6 months of storage at 40°C.

[0068] [Figure 10] Figure 10 is a set of graphs showing the variation in dissolved oxygen (DO) over time at 40°C, indicating that the dissolved oxygen level is still above 5 after 6 months of storage at 40°C with a high-barrier primary film, a small headspace of air (5 ml), and the port tube removed (operation 5).

[0069] [Figure 11] Figure 11 is a set of graphs showing the stability of low levels of dissolved oxygen in a chamber filled with a low-dissolved-oxygen medium.

[0070] [Figure 12] Figure 12 is a pH / redox diagram showing the conversion of SeO3 in these volatile species in a medium that does not contain oxygen as a whole.

[0071] [Figure 13] Figure 13 is a graph showing a fitted line plot between Se dose and log oxygen content. Figure 13 shows approximately 80% fit between Se dose and log oxygen content. [Mode for Carrying Out the Invention]

[0072] Detailed Description of the Invention Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following terms used herein shall have the meanings set forth below.

[0073] As used herein, the terms "comprising" or "comprises" mean that the compositions and methods include the recited elements, but do not exclude others.

[0074] The term "about", when used before a numerical designation, e.g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by (+) or (-) 10%, 5%, or 1%.

[0075] In the context of the present invention, the terms "flexible bag" and "flexible container" may be used interchangeably. The terms "solution" and "formulation" are also used interchangeably in the context of the present invention.

[0076] As used herein, the term "micronutrient" refers to any essential element required by an organism in varying amounts throughout its lifespan to regulate a range of physiological functions for maintaining health. Important micronutrients include iodine, iron, zinc, calcium, selenium, fluorine, copper, chromium, molybdenum, manganese, as well as vitamins A, B6, B 12 , B1, B2, B3, B8, B9, K, D, E, and C. With respect to human nutrition, micronutrient requirements may generally be in amounts of less than 100 milligrams per day, whereas macronutrients may be required in gram amounts daily. Calcium is sometimes also referred to as an electrolyte.

[0077] As used herein, the term “macromutants” refers to types of compounds that humans consume in relatively large quantities compared to vitamins and minerals, and that provide energy to humans. There are three main types of macronutrients: carbohydrates, proteins, and fats.

[0078] The term “pharmaceutical product” as disclosed herein refers to any product intended for use for medical purposes, preferably for clinical nutrition purposes. The pharmaceutical products of the present invention are intended and designed for the medical purpose of preventing or correcting selenium deficiency in patients.

[0079] As disclosed herein, the term “dissolved oxygen” (DO) refers to the level of free, non-compound oxygen present in water or other liquids or solutions, for example, in solutions for parenteral nutrients. Oxygen saturation (symbol SO2) is a relative measure of the concentration of oxygen dissolved or retained in a given medium, as the percentage of the maximum concentration that can be dissolved in that medium. In liquid media, typically in water, it can be measured with an oxygen sensor or dissolved oxygen probe such as an Optoid.

[0080] Dissolved oxygen is usually reported in milligrams per liter (mg / L) or as a percentage of air saturation. However, studies also report DO in parts per million (ppm) or micromoles (μmol). 1 mg / L is equal to 1 ppm. The relationship between mg / L and air saturation % changes with water temperature, pressure, and salinity. 1 micromol of oxygen is equal to 0.022391 milligrams. Therefore, 100 μmol / L of O2 is equal to 2.2 mg / L of O2. To calculate the dissolved oxygen concentration from air saturation, it is necessary to know the temperature and salinity of the sample. Atmospheric pressure has already been taken into account as the partial pressure of oxygen involved in the air saturation percentage. Then, using Henry's Law with the salinity and temperature, it is possible to calculate what the DO concentration would be at 100% air saturation. However, it is easier to use oxygen solubility charts. These charts show the dissolved oxygen concentration at 100% air saturation at various temperatures and salinity concentrations. Next, this value can be multiplied by the measured air saturation percentage to calculate the dissolved oxygen concentration [Fondriest Environmental, Inc. "Dissolved Oxygen." Fundamentals of Environmental Measurements. 19 Nov. 2013.].

[0081] Oxygenation of a liquid occurs, for example, through exposure of the liquid to an oxygen-containing gas. For instance, exposure of a liquid sample to an atmosphere containing approximately 21% O2 results in oxygenation through the diffusion of gaseous oxygen into the liquid. This process can be accelerated, for example, by stirring, flushing the liquid with an oxygen-containing gas, or by similar techniques known to those skilled in the art.

[0082] Several methods are available in the art for measuring dissolved oxygen concentration. Modern techniques involve either electrochemical or optical sensors, with dissolved oxygen sensors attached to meters for spot sampling and laboratory applications, or attached to data loggers, process monitors, or transmitters for deployed measurement and process control. An example is the Microx TX3 fiber optic oxygen meter from PreSens Precision Sensing GmbH (Germany) for gaseous and dissolved O2. Colorimetric methods provide a basic approximation of dissolved oxygen concentration in a sample. There are two methods designed for high and low ranges of dissolved oxygen concentration. These methods are quick and inexpensive for basic projects, but have a limited range and are susceptible to errors due to other redox agents that may be present in water. A traditional method is the Winkler titration.

[0083] As used herein, the term "shelf life" refers to the length of time that the pharmaceutical product in the flexible container / multi-chamber container of the present invention can be stored without becoming unsuitable for use or consumption under specified storage conditions after sealing and sterilization. The shelf life may vary depending on the storage conditions.

[0084] As used herein, the terms “stable,” “stable,” or “stable” mean that at least 50%, at least 60%, at least 70%, or at least 80% of the amount of components, particularly compounds having selective gas requirements, provided in the product when generated, is still available at a temperature of 1°C to 40°C, e.g., 1°C to 30°C, preferably after final heat sterilization, for at least 6 months, preferably at least 12 months, more preferably at least 18 months, and even more preferably at least 24 months. Preferably, at least 80%, at least 85%, at least 90%, and at least 95% of the components are still available when generated, preferably after final heat sterilization, for at least 6 months, preferably at least 12 months, at a temperature of 1°C to 40°C, and / or at least 18 months, preferably at least 24 months, at a temperature of 1°C to 30°C. The expression “when generated” refers to the time immediately before final heat sterilization.

[0085] In light of the prior art, the underlying technical problem of the present invention is to provide a flexible container / multi-chamber container having a selective dissolved gas content for stabilizing at least one compound having such selective gas requirements (e.g., the aforementioned selenium compounds in the form of Se(IV)). In particular, the problem relates to providing a multi-chamber bag containing at least two formulations having various dissolved gas requirements for the stability of each formulation or compound contained therein, such as one having the requirement to maintain a very low level of gas for an extended period, and another having the requirement to maintain a high or higher level of the same gas for an extended period. As described above, MCBs are generally prepared from a single film material that cannot be individually adapted to the diverse gas requirements. Therefore, in certain cases, the film material is selected so that the gas can diffuse from the formulation and be captured by a scavenger placed outside the primary container, such as an oxygen scavenger that will consume any oxygen still present to some extent in the formulation where oxygen is unwanted. However, this likely contradicts the need to retain the same gas in the second compartment, for example, oxygen, which must remain above a certain concentration threshold to ensure that at least one compound contained in the first compartment remains stable.

[0086] The challenge of various selective gas requirements for housing a formulation in a single multi-chamber bag has not been addressed or resolved in the prior art. Therefore, compounds requiring selective dissolved gas content in the formulation, contrary to the requirements of other formulations, are not provided in a single MCB, but are generally added to the MCB after reconstitution and before administration to the patient, or provided in a second pharmaceutical solution.

[0087] This problem is resolved by the features of the independent claim. Preferred embodiments of the present invention are provided by the dependent claim.

[0088] A relatively simple but highly efficient method has been found for stabilizing compounds with certain selective gas requirements in the aforementioned containers. The method can be used in monobags made from rigid, semi-rigid, or flexible containers and is particularly suitable for multi-chamber containers where formulations with very different selective gas requirements are stored.

[0089] Accordingly, the present invention relates to a flexible container / multi-chamber container having a selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product contained in one or more compartments of the container / multi-chamber container, wherein the container is prepared from a gas barrier film material relating to the selective dissolved gas in question and a headspace containing the gas, the gas headspace acting as a reservoir of the gas required by the at least one compound to be stabilized in the container.

[0090] As used herein, the term "headspace" refers to the unfilled space within a container holding a liquid or solid.

[0091] In conventional technology, headspace, such as the headspace in a container for pharmaceutical solutions, needs to be reduced or avoided, and where possible, it needs to be controlled in a way that avoids the presence of any non-inert gases such as oxygen.

[0092] Therefore, particularly when meeting the needs of other formulations that can be placed in the same MCB using gaseous scavengers such as oxygen absorbers, stabilizing compounds that require a certain dissolved gas level for stability by providing them in a solution contained in a container or compartment of a container having a deliberately created headspace, filled with a reservoir gas that can replenish the dissolved gas lost through the film material, is a very different non-trivial method.

[0093] The headspace, filled with the required gas or mixture of gases, can be advantageously combined with a film material that has a high barrier to the gas in question. According to one embodiment, a flexible container / multi-chamber container is 5 cc / m 2 Less than / day, 2cc / m³ 2 Less than / day, 1cc / m³ 2 Less than 0.5 cc / m³ per day, preferably 0.5 cc / m³ 2 Less than / day, for example, 0.2cc / m³ 2 Less than / day, 0.3cc / m³ 2 Less than / day, or 0.4cc / m³ 2 It is made from oxygen-impermeable materials with an oxygen or carbon dioxide barrier of less than 1 / day. If the film material has a somewhat low oxygen or carbon dioxide barrier, the corresponding headspace and / or selective gas concentration can be increased to preserve more of the selective gas and keep the dissolved gas level above the desired threshold for a longer period of time. By using a film material with a higher oxygen barrier, the headspace and / or the concentration of the selective gas within the headspace can be reduced.

[0094] In particular, it is possible to accommodate one or more formulations having selective gas requirements by intentionally using headspace, which acts as a reservoir for the required gas or gas mixture, to replenish the used dissolved gas in a solution containing compounds that require gas for stability, such as a multi-chamber container having at least two compartments within the container, and at the same time, the film is used to produce a container with low permeability with respect to the gas, especially when the container contains further compartments and formulations that require low or at least lower levels of the same gas, and therefore often includes a gas scavenger inside the package, for example, in an overpouch that encloses the primary container containing the various formulations.

[0095] As is easily understood, some gases will permeate container films used over long periods of time, even when the material creates a high gas barrier. This is even more pronounced when the container has an overpouch containing a gas scavenger that utilizes dissolved gases. This may be desirable to a certain extent, as other formulations in the MCB require that gas, such as oxygen, including oxygen generated in the formulation over time, and must be removed from the solution by allowing the oxygen to pass through the barrier and be absorbed by such a scavenger.

[0096] According to one embodiment, the selective dissolved gas is oxygen, which is typically avoided as a dissolved gas in a pharmaceutical solution because it can lead to the oxidation and decomposition of the active ingredients contained therein. However, the present invention can be equally and fully applied to other selective gases required to maintain the stability of compounds provided in a pharmaceutical solution. The present invention clearly does not refer to and / or include dissolved gases such as nitrogen or other inert gases used to replace any non-inert gas. Therefore, the present invention clearly rejects nitrogen. In a preferred embodiment, the selective dissolved gas is oxygen.

[0097] Those skilled in the art will notice that the concentration of dissolved oxygen (DO) in water is affected by several factors, including water temperature, salinity, and atmospheric pressure. Table I provides the solubility of oxygen as a function of temperature in ppm (760 mmHg, salinity = 0.0 ppt). Thus, an DO concentration of approximately 8 ppm corresponds to a solution saturated with oxygen at approximately room temperature (approximately 21°C).

[0098] According to one embodiment of the present invention, the DO in the pharmaceutical solution is greater than 6 ppm, preferably 6 ppm to about 8 ppm at the time of filling and before sterilization, and the solution has a temperature of about 18°C ​​to about 25°C, preferably about 21°C. [Table 1]

[0099] According to certain embodiments, the compound to be stabilized by the present invention is selenium in its Se(IV) form. In particular, selenium in its Se(IV) form can be provided in pharmaceutical solutions for parenteral nutrition. In the art, it is known that selenium, iodine, and copper, for example, are difficult to include in nutritional bags because they may undergo chemical reactions under particularly extreme conditions, such as heat sterilization steps, and during their shelf life. See, for example, Allwood et al. Compatibility and Stability of Additives in Parenteral Nutrition Admixtures. Nutrition 1998, Vol. 14, No. 9, pp. 697-706; Eisenberg et al. Stability of selenium sources reviewed. Feedstuffs, June 18, 2012. Therefore, in one embodiment, at least one compound is selenium in the form of Se(IV), preferably selected from the group consisting of sodium selenite, selenite, and selenium dioxide, and the oxygen headspace is maintained so that the solution contains dissolved oxygen (DO) at a level of 0.5 ppm to 8 ppm.

[0100] In one embodiment, the present invention also relates to a pharmaceutical product in a flexible container / multi-chamber container for preventing or correcting selenium deficiency in patients, comprising a solution delivered in an oxygen-impermeable flexible container for parenteral administration, and containing at least one selenium compound, preferably in the form of Se(IV) selected from the group consisting of sodium selenite, selenite, and selenium dioxide, and characterized in that the solution contains dissolved oxygen (DO) preferably at 0.5 ppm to 8 ppm DO.

[0101] In certain embodiments of the present invention, when other oxygen-sensitive compounds such as trace elements or vitamins are present in the same compartment as the selenium compound according to the present invention, it is considered preferable to target an oxygen range of 0.5 to 2.0 ppm. In certain embodiments, an oxygen range of 1.0 ppm to 2.0 ppm is considered preferable for stably formulating the composition according to the present invention.

[0102] In certain embodiments of the present invention, the solution of the pharmaceutical product of the present invention contains sodium selenite. In some embodiments, the solution of the pharmaceutical product of the present invention contains selenite. In some embodiments, the solution of the pharmaceutical product of the present invention contains selenium dioxide.

[0103] In one preferred embodiment, a solution of the pharmaceutical product of the present invention contains sodium selenite having a selective gas requirement for remaining stable in such solution for extended periods. Surprisingly, we have found that the presence of oxygen headspace on a solution containing at least one selenium compound in the form of Se(IV) to maintain a stable concentration of dissolved oxygen (DO) in the solution from about 0.5 ppm to about 8 ppm results in the stabilization of sodium selenite, selenite, and / or selenium dioxide in solution, which would normally be protected from gas exchange with its surroundings, since oxygen is generally expected to be involved in redox reactions and often detrimental to the stability of macronutrients and micronutrients in solution. In particular, certain trace elements and vitamins have been reported to be sensitive to the presence or absence of oxygen when stored in sealed containers such as sealed flexible bags.

[0104] As a result, the present invention is based on the finding that the presence of a controlled concentration of dissolved oxygen in a solution, maintained by the oxygen headspace on a solution containing, for example, sodium selenite, selenite, and / or selenium dioxide, alone or in combination with other sensitive trace elements, such as iodine and / or copper, results in the stabilization of these selenium-containing compounds, which are known to be unstable when present in a solution, particularly in sealed pharmaceutical nutritional products generally provided in oxygen-impermeable containers to avoid the aforementioned redox reactions.

[0105] As mentioned above, oxygen-permeable containers are known, for example, Peditrace™, and are used to allow gas exchange between the inside of the container and the ambient air. However, most parenteral products are supplied in oxygen-impermeable containers due to the redox sensitivity of the nutrients they contain. On the other hand, oxygen-permeable containers do not provide a predetermined stable oxygen concentration, which has been found to be a prerequisite for providing long-term stability, particularly for highly sensitive compositions of various trace elements. In contrast, oxygen levels are subject to change based on, for example, temperature or height (pressure), and unfavorable conditions during, for example, sterilization, transport, or storage can lead to the decomposition and loss of sensitive compounds, such as selenium in its Se(IV) form, even if the container is then stored under better and more suitable conditions, which allows for the replenishment of lost dissolved gases, such as oxygen, within the container through an oxygen-permeable film.

[0106] In one embodiment, the headspace in the present invention refers to the space in a flexible container / multi-chamber container that is not filled with any liquid solution or an inert gas such as nitrogen, and refers to the volume of gas in such space.

[0107] In one embodiment, the applicant has surprisingly found that, when combined with an oxygen barrier film for a container, the oxygen headspace on a solution containing at least one selenium compound in the form of Se(IV) can maintain dissolved oxygen (DO) in the solution at a stable concentration of about 0.5 ppm to about 8 ppm, resulting in the stabilization of sodium selenite, selenite, and / or selenium dioxide in the solution, which would normally be protected from gas exchange with its surroundings.

[0108] To avoid any doubt, the solution in the flexible container / multi-chamber container of the present invention, which contains at least one selenium compound in the form of Se(IV), is preferably selected from the group consisting of sodium selenite, selenite, and selenium dioxide, and may be referred to as a "selenium solution," a "solution containing selenium," or a "solution containing Se(IV)."

[0109] In the context of this invention, the phrase "stable" or "controlled" concentration of the dissolved gas means that the concentration of the dissolved gas does not fall below a given threshold over the entire shelf life of the product containing the pharmaceutical solution with a component having selective gas requirements. The concentration of the selective dissolved gas does not mean that it is always the same from its formation to the end of its shelf life, and its loss or consumption can be controlled by means of maintaining a certain minimum concentration throughout its entire shelf life.

[0110] For example, "a controlled concentration of dissolved oxygen in the solution, between 0.5 ppm and 8 ppm" refers to a dissolved oxygen (DO) concentration that remains within the range of 0.5 ppm to 8 ppm throughout the entire shelf life of the pharmaceutical product of the present invention, where 8 ppm approximately corresponds to the oxygen saturation of the solution of the present invention. In other words, it is not necessarily required that the exact oxygen concentration of the solution in the pharmaceutical product remain stable, but rather that the concentration does not fall below this range, i.e., below 0.5 ppm, throughout the entire shelf life. Therefore, in a preferred embodiment of the present invention, the DO concentration in the solution is at least 0.5 ppm DO.

[0111] In one embodiment, a controlled concentration of dissolved oxygen in a solution, ranging from 0.5 ppm to 8 ppm, is maintained by the oxygen headspace above the solution in one chamber of a flexible container / multi-chamber container. In one embodiment, the chamber contains a stable (further controlled) concentration of dissolved oxygen in the solution, ranging from 0.5 ppm to 8 ppm, and the oxygen headspace above the solution is sealed.

[0112] In certain embodiments, the dissolved oxygen (DO) in the Se(IV)-containing solution is at least 0.5 ppm throughout the shelf life. In certain embodiments, the dissolved oxygen (DO) in the Se(IV)-containing solution does not drop below 0.5 ppm throughout the entire shelf life of the pharmaceutical product.

[0113] In one embodiment, the solution contains dissolved oxygen (DO) or dissolved carbon dioxide at a concentration equal to or greater than 1 ppm.

[0114] In one embodiment, the solution is a sterilization solution, such as a final heat sterilization solution.

[0115] In another embodiment, the solution comprises at least one compound that requires a certain level of oxygen to remain stable over a long period of time, particularly during sterilization and storage.

[0116] In preferred embodiments, the dissolved oxygen (DO) in a pharmaceutical solution, such as a Se(IV)-containing solution, is at least 6 ppm when the solution is filled (and sealed as necessary) in a flexible container / multi-chamber container and before sterilization. In some embodiments, the dissolved oxygen (DO) concentration in the solution is between 6 ppm and 8 ppm (8 ppm is approximately the oxygen saturation level of the solution).

[0117] In a preferred embodiment, the oxygen-sealed chamber of a flexible container / multi-chamber container containing a pharmaceutical solution includes a headspace of an oxygen-containing gaseous composition. In other words, in such an embodiment, at least one of the chambers of a flexible container / multi-chamber container containing a pharmaceutical solution having requirements regarding a certain oxygen level further includes a certain volume of an oxygen-containing gaseous composition. Such an additional gas volume or “headspace” is understood to be the space or volume within the sealed chamber that is not filled with the solution, i.e., the volume of air / gas remaining at the top of the filled container before sealing.

[0118] As already mentioned, headspace can generally be avoided or minimized to the extent that it is likely to be considered an undesirable interaction between the gas contained inside (ambient air) and the liquid (or solid) content inside the container (see, for example, US20030110736A1).

[0119] In contrast, in the context of the present invention, such headspace can be intentionally used and designed to be sufficient to store gases such as oxygen via ambient air, and thus allow for the replacement of oxygen lost through, for example, the container film material, i.e., through the primary container. Thus, for example, dissolved oxygen (DO) in a solution can be maintained above 0.5 ppm throughout the entire intended storage life, which is generally targeted to be at least 12, 18, or 24 months, depending on a typical ambient temperature of about 15°C to about 25°C, preferably about 15°C to about 30°C. Using the headspace according to the present invention, i.e., providing a sufficient gas reservoir containing ambient air or any other gas or gas mixture that may be lost or otherwise consumed in the solution of a gas-impermeable bag or chamber, but is required for the stability of the compounds contained in such a solution, is a general principle that can also be used in relation to various compounds that require a certain level of gas, such as oxygen or carbon dioxide, for long-term stability in situations where the gas is lost from the chamber of a multi-chamber bag (MCB), i.e., through the primary container.

[0120] In some embodiments, the selective gas is oxygen. In such cases, the gas composition in the headspace containing oxygen may be ambient air containing about 78% nitrogen, 21% oxygen, and about 1% other gas. However, in certain embodiments, the gas composition in the headspace containing oxygen may be an oxygen-rich gas composition consisting almost entirely of oxygen, especially when the headspace volume should be reduced. In certain embodiments, the headspace gas composition may contain about 10 to about 100% oxygen, for example, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 42, about 44, about 46, about 48, about 50, about 54, about 58, about 62, about 66, about 70, about 75, about 80, about 85, about 90, about 95, about 96, about 97, about 98, or about 99% oxygen. As is well known to those skilled in the art, higher oxygen levels are not recommended, particularly due to the risk of fire or explosion during production.

[0121] In the case of ambient air, the volume of the headspace may be the same as or greater than the normal headspace remaining in the container or compartment that provides the pharmaceutical solution. According to the present invention, the headspace may range from about 5% to about 100% of the volume of the solution containing the compound having selective gas requirements and is contained in at least one chamber of the flexible container / multi-chamber container of the present invention.

[0122] For example, in the case of a 25 ml selenium(IV) solution containing about 70 μg of selenium(IV), the ambient air headspace may be 10 ml. However, in certain embodiments, the volume of the ambient air or oxygen headspace may be in the range of more than about 10% of the volume of the selenium solution, greater than about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, or about 100%.

[0123] Generally, the volume of the headspace of the selective gas according to the present invention may be in the range of about 5% to 100% of the volume of the pharmaceutical solution containing the compound having the selective gas requirement, for example, in the range of 10% to 60%, for example, about 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23% of the volume of the pharmaceutical solution. It may be approximately 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 55, 56, 57, 58, 59, or approximately 60%.

[0124] For example, in the case of 25 ml of selenium solution sealed in a chamber of a flexible container / multi-chamber container, the headspace of ambient air or oxygen may be in the range of about 2.5 ml to about 22.5 ml, about 2.5 ml to about 20 ml, about 2.5 ml to about 17.5 ml, about 2.5 ml to about 15 ml, or about 2.5 ml to about 12.5 ml, preferably about 3 to about 12 ml, for example, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 ml, or about 12 ml. Those skilled in the art can calculate the corresponding volume of headspace based on this disclosure for other volumes of selenium solution.

[0125] As disclosed herein, the volume of the gas headspace can be adjusted accordingly when different gas compositions are used. For example, in the case of a gas with a high oxygen content, a smaller headspace may be used as will be obvious to those skilled in the art and can be calculated based on the above ratio shown with respect to ambient air and / or by conventional experiments depending on the compound that becomes stable in the pharmaceutical solution.

[0126] In certain embodiments of the flexible container / multi-chamber container of the present invention, at least one selenium compound in the form of Se(IV), such as sodium selenite, selenite, and / or selenium dioxide, is stabilized in solution for at least three months when stored at a wide range of temperatures, from about 1°C to about 50°C, with ambient air or oxygen headspace and dissolved oxygen (DO) in the solution, either alone or in combination with other trace elements. Other salt forms, such as potassium selenite, lithium selenite, calcium selenite, or magnesium selenite, may be used instead of sodium selenite. Therefore, when sodium selenite is mentioned, it should be understood simply as a preferred example of such alternatives. It was surprising and unexpected that comparative experiments were able to demonstrate that the enumerated selenium-containing compositions were stabilized in solution at various temperatures, tested in the range of about 1°C to about 50°C, over long periods of time, such as at least three months, in an oxygen-impermeable flexible container.

[0127] In certain embodiments, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solution according to the present invention stabilize sodium selenite, selenite, and / or selenium dioxide, alone or in the presence of other trace elements, in solution for at least 3 months when stored at a maximum of approximately 40°C. Furthermore, in certain embodiments, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solution stabilize sodium selenite, selenite, and / or selenium dioxide, alone or in the presence of other trace elements, in solution for at least 6 months when stored at a maximum of approximately 40°C.

[0128] In a further embodiment of the present invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solution stabilize sodium selenite, selenite, and / or selenium dioxide alone or in the presence of other trace elements in solution for at least 6 months, preferably at least 12 months, more preferably at least 18 months, and most preferably at least 24 months.

[0129] In a further embodiment of the present invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solution stabilize sodium selenite, selenite, and / or selenium dioxide alone or in the presence of other trace elements in solution for at least 6 months, preferably 12 months, more preferably 18 months, and most preferably 24 months, at a maximum temperature of about 30°C.

[0130] In further embodiments of the present invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solution stabilize sodium selenite, selenite, and / or selenium dioxide alone or in the presence of other trace elements in solution at a temperature of about 18°C ​​to about 25°C for at least 6 months, preferably at least 12 months, more preferably at least 18 months, and most preferably at least 24 months.

[0131] In yet another embodiment of the present invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solution are stabilized in solution with sodium selenite, selenite, and / or selenium dioxide alone or in the presence of other trace elements for at least 6 months, preferably at least 12 months, more preferably at least 18 months, most preferably at least 24 months, at normal storage temperatures, for example, room temperature, but not limited to, a range from about 15°C to about 30°C, more preferably about 18°C ​​to about 25°C, or under refrigerated conditions, for example, about 1°C to about 10°C, preferably about 2°C to about 8°C, or about 3°C ​​to about 7°C.

[0132] According to another embodiment of the present invention, the selective gas may be carbon dioxide, another example of a selective gas required for the stability of compounds in a pharmaceutical solution, which can be placed in an MCB where various compartments have different requirements regarding carbon dioxide. Thus, the disclosures made herein with respect to oxygen are equally applicable to and effective for carbon dioxide.

[0133] According to one embodiment of the present invention, the selective gas is carbon dioxide (CO2). According to yet another embodiment, the compound having the selective gas requirement is a bicarbonate, such as sodium bicarbonate. The bicarbonate and carbon dioxide in an aqueous solution are linked via the following formula: [ka]

[0134] For example, the loss or permeation of carbon dioxide from a sodium bicarbonate solution results in an increase in sodium carbonate content, and therefore an increased pH level. Furthermore, the loss of carbon dioxide leads to a decrease in the desired content and / or availability of bicarbonate ions in the final mixed composition of the sodium bicarbonate component solution. However, bicarbonates are required in such pharmaceutical solutions. Next, carbonates tend to form calcium carbonate or other precipitates (e.g., with magnesium) over time, which is detrimental to pharmaceutical solutions intended for administration to patients, for example. On the other hand, large amounts of dissolved carbon dioxide are considered undesirable in other compartments of the MCB, as they can lower the pH to values ​​that are not beneficial to the compounds located inside. Therefore, the loss of carbon dioxide should be avoided or controlled as much as possible. It is also important to obtain proper control of the range of CO2 transfer, particularly from and between bicarbonates and other solutions in the MCB. Improved control and limitation of the amount of CO2 gas that can escape or escapes from bicarbonate-containing solutions and compartments may also provide an opportunity to eliminate the need for top packaging.

[0135] Known methods for achieving some control include using a gas-impermeable primary film and / or overpouch. Since the volume occupied by the overpouch material is always greater than the volume of the flexible bag container containing the bicarbonate and other solutions, there is always a volume within the overpouch material that can accommodate CO2 gas escaping from the bicarbonate solution itself. As in the case of oxygen, carbon dioxide barrier materials can be used to limit the loss of carbon dioxide in the primary bag material as well as any loss through the overpouch. Thus, the primary bag can be designed to include a nylon layer. The overpouch can also be made from nylon or contain nylon. For example, the overpouch can be a laminated film composed of Al2O3, PVDC, and nylon, supported by a polypropylene copolymer and with an adhesive layer between various layers.

[0136] For example, U.S. Patent No. 7,491,411(B2) describes a multi-compartment flexible bag assembly comprising a first predetermined volume of aqueous sodium bicarbonate solution contained in at least one of the multi-compartments and a second predetermined volume of aqueous acid component solution contained in at least another of the multi-compartments. In this case, the aqueous acid component solution contains a certain amount of dissolved carbon dioxide, and the mixing of the bicarbonate component solution and the acid component solution exposes the bicarbonate solution to an environment of a CO2-containing solution rather than a CO2-free solution, and then allows carbon dioxide to migrate across the packaging material from the acid component solution into the gas-impermeable upper packaging flexible bag, thereby limiting the amount of carbon dioxide that can migrate from the bicarbonate component solution into the upper packaging flexible bag. However, in this case, both compartments are acceptable, and the presence of carbon dioxide is utilized.

[0137] According to the present invention, similar to what is described for an MCB in which one compartment contains a compound requiring a higher dissolved oxygen level (e.g., sodium selenite or selenium dioxide), the headspace can be used to provide a carbon dioxide reservoir, particularly when the second compartment cannot tolerate a higher dissolved carbon dioxide level and the methods described in the prior art cannot be used.

[0138] In particular, when contained in one compartment of an MCB containing formulations with various requirements, it is a significant advantage that a pharmaceutical solution containing compounds with selective gas requirements can be prepared, packaged in a flexible bag made of oxygen-impermeable material that can be airtight and liquid-tight without significant loss, either by itself or in the presence of other components such as further trace elements, vitamins, or macronutrients such as glucose, and then sterilized.

[0139] In certain embodiments, the solution of the present invention undergoes final heat sterilization after the preparation of the solution and filling it into a flexible container. Sterilization may occur before or after filling the flexible bag of the pharmaceutical product of the present invention with the solution, and final sterilization of the filled and sealed flexible container, particularly heat sterilization, is preferred.

[0140] A flexible container / multi-chamber container or the chamber of a flexible container / multi-chamber container containing a compound that requires a gas is very preferably impermeable to the gas. For example, if the gas is oxygen or carbon dioxide, an oxygen or carbon dioxide impermeable material should be used. For example, a flexible container / multi-chamber container or the chamber of a flexible container / multi-chamber container containing a solution containing selenium should have a capacity of 5 cc / m³. 2 Less than 4cc / m³ per day. 2 Less than / day, 3cc / m³ 2 Less than / day, 2cc / m³ 2 Less than / day, 1cc / m³ 2 Less than 0.5 cc / m³ per day, preferably 0.5 cc / m³ 2 It may be made from a material having an oxygen barrier of less than 1 day.

[0141] As previously mentioned, lower gas barriers should be accompanied by larger headspace and / or higher concentrations of selective gas. Higher gas barriers in film materials can reduce headspace volume and / or selective gas concentration.

[0142] Any port should preferably be attached to or sealed by an airtight manner to a compartment containing a headspace according to the present invention, and / or should be a gas-impermeable port to avoid selective gas loss over such port. For example, certain oxygen loss through a port seal can be addressed by the present invention with a suitable headspace used, for example, as an oxygen reservoir, to ensure the stability of the relevant compound over its intended shelf life. In a particular embodiment, a chamber containing a selenium-containing solution includes an oxygen-impermeable port. In a particular embodiment, a flexible vessel according to the present invention having at least two compartments does not have any ports attached to a compartment containing a pharmaceutical solution containing a compound having selective gas requirements.

[0143] The sterilization of the present invention may be performed by a final heat sterilization process, however, by using final filtration, gamma irradiation, or any other sterilization technique. Alternatively, the solution in the flexible container / multi-chamber container of the present invention may be filled into the flexible container / multi-chamber container by an aseptic filling process that ensures that contamination of the essentially sterilized solution does not occur during filling and before sealing of the flexible bag. In some embodiments, the solution may be sterilized, but not necessarily. For example, a sterilization process may be performed, but absolute sterility may not be achieved and / or required.

[0144] In further embodiments, the concentration of dissolved oxygen (DO) in the solution is equal to or greater than 0.5 ppm, more preferably equal to or greater than 1.0 ppm. In certain embodiments, the concentration of dissolved oxygen (DO) in the solution is 4 ppm or less. In certain embodiments, the dissolved oxygen (DO) in the solution is higher than 0.8 ppm and 2 ppm or less.

[0145] In certain embodiments of the present invention, the concentration of dissolved oxygen (DO) in the solution may be any value in the range of about 0.5, about 0.75, or from about 1 to about 2 ppm, or from about 0.5, about 0.75, about 1, or from about 2 to about 8 ppm, for example, about 0.5, about 0.75, about 1, about 1.5, about 2, about 2.5, about 3, about 3.5, about 4, about 4.5, about 5, about 5.5, about 6, about 6.5, about 7, about 7.5, or about 8 ppm. The indicated ranges include the terminal values ​​described. Any range including any combination of the disclosed values ​​is considered an embodiment of the present invention.

[0146] In some embodiments, the concentration of dissolved oxygen (DO) in the solution, maintained by ambient air or oxygen headspace, is equal to or greater than 0.5 ppm, more preferably equal to or greater than 1.0 ppm, throughout the entire shelf life of the pharmaceutical product.

[0147] In some embodiments of the present invention, the dissolved oxygen (DO) in the Se(IV)-containing solution, maintained by ambient air or oxygen headspace, is at least 0.5 ppm throughout the entire shelf life of the pharmaceutical product of the present invention. In some embodiments, the dissolved oxygen (DO) concentration in the solution, maintained by ambient air or oxygen headspace, may decrease during the shelf life but is maintained above 0.5 ppm. For example, the dissolved oxygen (DO) concentration of the solution is preferably above 6 ppm when the solution is filled into a flexible container and before sterilization. During sterilization and storage, the dissolved oxygen (DO) concentration may decrease over time but remains above 0.5 ppm throughout the entire shelf life.

[0148] In certain embodiments of the flexible container / multi-chamber container of the present invention, the concentration of dissolved oxygen (DO) in the solution is at least 6 ppm when the chambers of the flexible container / multi-chamber container containing the solution are filled, preferably when sealed.

[0149] In certain embodiments, the dissolved oxygen (DO) concentration in the solution may decrease in the pharmaceutical product after filling, sealing, and sterilization, and during the product's shelf life, even if the chamber containing the solution is completely oxygen-impermeable. In some embodiments, the oxygen in the solution may be consumed during the shelf life, possibly by slow chemical reactions such as oxidation or decomposition within the chamber over time, and therefore the oxygen concentration may decrease. Therefore, when filling and sealing the pharmaceutical solution according to the present invention in the chamber of a flexible container / multi-chamber container, it is preferable that the dissolved oxygen (DO) concentration is at least 6 ppm, for example, in the range of 6 ppm to 8 ppm. Such a high dissolved oxygen (DO) concentration at the time of filling and sealing ensures that the dissolved oxygen (DO) concentration remains stably above 0.5 ppm during the product's shelf life, meaning that the DO concentration will not fall below 0.5 ppm even if oxygen consumption and / or loss occurs through the film material in the chamber.

[0150] In a particular embodiment, a flexible container / multi-chamber container having a selective dissolved gas content for stabilizing at least one micronutrient of a pharmaceutical product, the flexible container comprises: a solution containing at least one micronutrient, such as at least one selenium compound in the form of Se(IV) disclosed herein (i.e., sealed within the chamber of the flexible container / multi-chamber container); and a headspace of gas, such as oxygen disclosed herein (i.e., sealed within the chamber of the flexible container / multi-chamber container).

[0151] In some embodiments, the sealed chamber of a flexible container / multi-chamber container containing a solution comprising at least one selenium compound in the form of Se(IV) further includes a headspace for a gaseous composition containing oxygen.

[0152] In preferred embodiments, a flexible container / multi-chamber container or its chambers containing a solution comprising at least one selenium compound in the form of Se(IV) further comprises a headspace of an oxygen-containing gaseous composition, the sealed chambers being oxygen-impermeable, and the dissolved oxygen (DO) in the solution when the chambers are filled, preferably when sealed, is at least 6 ppm. In such embodiments, it has been shown that the dissolved oxygen (DO) in the solution is equal to or greater than 0.5 ppm, or remains equal to or above 0.5 ppm, throughout the entire shelf life of the pharmaceutical product.

[0153] The fact that the dissolved oxygen (DO) content maintained by the ambient air or oxygen headspace according to the present invention is suitable for stabilizing selenium-containing compounds alone, and especially in combination with other sensitive trace elements, is a significant advantage in the context of the pharmaceutical products of the present invention, as the dissolved oxygen (DO) concentration can be easily established without complex technical measurements or manipulations of the solution.

[0154] It will be readily apparent to those skilled in the art that other parameters may need to be adjusted to further improve the stability of compounds with selective gas requirements, such as selenium in the form of Se(IV), in order to keep them stable in the pharmaceutical solution for extended periods. For example, pH may need to be adjusted and / or consideration must be given to incompatibility with other possible compounds in the formulation.

[0155] For example, a solution containing selenium in the form of Se(IV), such as sodium selenite or selenium dioxide, may also have an acidic pH, preferably in the range of about 1 to about 4, more preferably about 2 to about 3.5, and more preferably about 2.5 to about 3.2. However, with respect to long-term stability, the dissolved oxygen content is extremely important. Furthermore, a solution of the present invention that is stable not only at a nearly neutral pH in the range of about 7 to about 7.5 but also at an acidic pH in the presence of about 0.5 to about 8 ppm of dissolved oxygen (DO), particularly in the presence of about 0.8 ppm to about 4 ppm of dissolved oxygen (DO), or in the presence of about 1 ppm to about 2 ppm, is particularly advantageous. Selenium in solution in the flexible container / multi-chamber container according to the present invention is stable, even at acidic pH values, for example, in the ranges of about 1 to about 4, about 1.5 to about 3.5, about 1.8 to about 3.2, about 2 to about 3, about 2.1 to about 2.9, about 2.2 to about 2.8, about 2.3 to about 2.7, about 2.4 to about 2.6, and about 2.5. The indicated ranges include the described terminal values. Ranges including any combination of the disclosed terminal values ​​are considered embodiments of the present invention.

[0156] Such stability under acidic pH conditions is important, especially if the solution contains other trace elements that are only stable under acidic conditions and cannot be stable at neutral pH. This is particularly true for iodide (I), which has been reported to be more stable in acidic pH solutions. However, this is also likely true for nutrient solutions containing one or more trace elements such as copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), chromium (Cr), fluoride (F), and molybdenum (Mo).

[0157] In another embodiment, the stability of a solution containing selenium in the form of Se(IV), such as sodium selenite or selenium dioxide, may be further enhanced by the presence of certain acids, such as organic acids in the form of malic acid, tartaric acid, citric acid, maleic acid, and fumaric acid, more preferably malic acid, where the concentration of the organic acid is preferably in the range of about 100 mM to about 400 mM, preferably about 190 mM to about 220 mM, and more preferably about 200 mM.

[0158] In another embodiment, the present invention relates to a multi-chamber container having a selective dissolved gas content in one of its chambers for stabilizing at least one micronutrient in a pharmaceutical product, the multi-chamber container comprising: a first chamber containing a carbohydrate preparation; a second chamber containing an amino acid preparation; a third chamber containing a lipid preparation; and a fourth chamber containing a solution containing at least one micronutrient; and a gas headspace.

[0159] The present invention relates to a sterile solution in a multi-chamber container having a selective dissolved gas content for stabilizing at least one micronutrient of a pharmaceutical product, comprising a solution provided in an oxygen-impermeable flexible container containing at least one compound selected from the group comprising sodium selenite, selenite, and selenium dioxide, wherein the solution contains dissolved oxygen (DO) of about 0.5 ppm to about 8 ppm at about 20°C to about 25°C.

[0160] In the context of the present invention, oxygen-impermeable materials (e.g., 2 cc / m³) 2 Less than / day, 1cc / m³ 2 Less than 0.5 cc / m³ per day, preferably 0.5 cc / m³ 2 The solution in a multi-chamber container, preferably made from any material having an oxygen barrier of less than 1 / day, comprises at least one compound selected from the group consisting of selenites, such as sodium selenite, selenite, and selenium dioxide, and the solution contains about 1 ppm to about 8 ppm of dissolved oxygen (DO).

[0161] Sodium selenite is an inorganic compound with the formula Na₂SeO₃. This salt is a colorless solid. Na₂SeO₃(H₂O)₅ pentahydrate is the most common water-soluble selenium compound. Selenous acid (or selenious acid) is a compound with the formula H₂SeO₃. More precisely, structurally, it is written as H₂SeO₃. This is the major oxoacid of selenium; the others are selenic acid. Selenium dioxide is a compound with the formula SeO₂ and is a colorless solid. This is one of the most frequently encountered compounds of selenium.

[0162] In some embodiments, at least one micronutrient is at least one selenium compound in the form of Se(IV), and the dissolved gas is dissolved oxygen (DO).

[0163] In some embodiments, at least one selenium compound is selected from the group consisting of sodium selenite, selenite, and selenium dioxide.

[0164] In some embodiments, at least one selenium compound is sodium selenite or selenium dioxide.

[0165] In some embodiments, the multi-chamber container of the present invention has at least two, at least three, at least four, at least five, or at least six chambers. In some embodiments, the headspace configuration of the multi-chamber container may be applicable to certain existing multi-chamber containers having at least two, at least three, at least four, at least five, or at least six chambers.

[0166] For example, U.S. Patent Application Publication 2009 / 0166363(A1) (Baxter) discloses a multi-chamber bag (MCB) having at least a fourth chamber (see claim 20). EP790051A1 (B. Braun) shows a four-chamber bag including smaller chambers. EP2568947A1 (B. Braun) shows a three-chamber bag having a port tube for filling from one side. U.S. Patent No. 8,343,128(B2) (Otsuka) shows a configuration having smaller chambers. U.S. Patent No. 5,267,646A (Otsuka) includes another example of including smaller chambers that may contain special compounds (i.e., drugs, TEs) having certain requirements regarding gas levels / presence.

[0167] In some embodiments, the multi-chamber container of the present invention includes at least five chambers.

[0168] In a particular embodiment, the multi-chamber container of the present invention includes either five chambers or six chambers.

[0169] In a particular embodiment, the solution in one chamber of a multi-chamber container (e.g., the fourth chamber) contains dissolved oxygen (DO) equal to or greater than 0.5 ppm, which is maintained by the ambient air or oxygen headspace throughout the entire shelf life of the pharmaceutical product.

[0170] In a particular embodiment, the solution in the fourth chamber of the multi-chamber vessel contains dissolved oxygen (DO) of about 0.5 ppm to about 8 ppm, maintained by ambient air or oxygen headspace.

[0171] In a particular embodiment, the solution in the fourth chamber of the multi-chamber vessel contains dissolved oxygen (DO) equal to or greater than 1 ppm, which is maintained by the ambient air or oxygen headspace.

[0172] In embodiments of the present invention, the solution in the fourth chamber of the multi-chamber container is a sterile solution. In the context of the present invention, the term “sterilized” refers to a solution that has undergone a sterilization process. Sterilization refers to any process that eliminates, removes, kills, or inactivates all forms of life (in particular, referring to microorganisms such as fungi, bacteria, viruses, spores, single-celled eukaryotes, e.g., Plasmodium) and other biological agents present on a particular surface, object, or fluid, e.g., food or a biological culture medium, such as prions. Sterilization can be achieved through a variety of means, including heat, chemicals, irradiation, high pressure, and filtration. Sterilization is distinguished from disinfection, sanitization, and sterilization in that these methods reduce, rather than eliminate, all forms of life and biological agents present. After sterilization, an object is said to be sterile or germ-free.

[0173] According to certain embodiments of the present invention, sterilization may be carried out by heat. According to another embodiment of the present invention, sterilization is carried out by heating under pressure in the presence of water to generate steam; this method is recommended by various pharmacopoeias. In general, steam sterilization may be carried out in an autoclave and can be used for drug products, medical devices, plastic bags and other single-use devices, glass containers, surgical bandages, etc.

[0174] Other methods include sterilization by wet heating. Sterilization can also be achieved through dry heating. Very high temperatures (180-200°C) are required for this method. Dry heating is commonly used to sterilize glassware, metals, and other surfaces.

[0175] Exposure to radiation is another sterilization method used across industries. Gamma radiation is the most common, but other options include infrared and ultraviolet radiation, as well as fast electrons. Radiation is typically used to sterilize single-use components / systems, but can also be used for packaged pharmaceutical products.

[0176] Gaseous treatment may be an alternative to sterilization. Such gases include ethylene oxide, formaldehyde, glutaraldehyde, propylene oxide, hydrogen peroxide, and chlorine dioxide. This method may be more commonly used to sterilize cleanroom suits. Sterilization by filtration is the only option when other processes are not suitable for a particular product or component. In filtration, the final drug product solution passes through a filter that is produced under sterile manufacturing conditions and designed with appropriate pore size / surface chemistry to remove bacteria by size exclusion, capture, electrostatic attraction, and other means.

[0177] In a particular embodiment, the concentration of dissolved oxygen (DO) in the solution of the fourth chamber of the multi-chamber container during sterilization (maintained, for example, by ambient air or oxygen headspace) is at least 6 ppm.

[0178] In certain embodiments, the volume of ambient air or oxygen headspace is approximately 5% to 100% of the volume of solution in the fourth chamber of the multi-chamber vessel.

[0179] In a particular embodiment, the volume of the multi-chamber container is approximately 35% to 45% of the volume of the solution in the fourth chamber of the multi-chamber container.

[0180] In a particular embodiment, the headspace of ambient air or oxygen in the fourth chamber of a multi-chamber vessel stabilizes at least one selenium compound for a period of time selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months when stored at a temperature between about 1°C and about 30°C.

[0181] In a particular embodiment, the multi-chamber container is stored at a temperature between approximately 18°C ​​and approximately 25°C.

[0182] In the context of the present invention, the pharmaceutical solution is supplied to one sealed chamber of a multi-chamber container along with a headspace of ambient air or a selective gas such as oxygen. In a particular embodiment of the present invention, the solution is contained and sealed in one chamber of a multi-chamber container having at least two, at least three, at least four, at least five, or at least six chambers, along with a headspace of ambient air or oxygen.

[0183] Preferably, the sealing material around the compartment containing the pharmaceutical solution and headspace according to the present invention should be airtight. The filling port may form a potential gas leak through which the necessary gases according to the present invention may be lost from the pharmaceutical solution. Therefore, care should be taken in the use of airtight ports, or, for example, as pharmaceutical or injection ports according to one embodiment of the present invention, their removal after filling when they are no longer needed.

[0184] As used herein, the terms “flexible container” or “multi-chamber container” refer to a container or bag made from a flexible material, such as a bag made from a plastic film. This term does not include rigid or semi-rigid polymer containers.

[0185] The flexible container or bag of the present invention can be made from materials including, but not limited to, polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), polyethylene terephthalate (PET), and all possible thermoplastic elastomer copolymers, essentially any synthetic material, including laminated materials, that is suitable for containing the components to be administered.

[0186] Oxygen-impermeable flexible containers are well known in the art and are made of a gas barrier film that blocks the migration of oxygen to the outside of the container. Various techniques have been developed to provide an oxygen barrier to a transparent film, for example, a polyolefin film or polyethylene terephthalate film. The main techniques are as follows: (1) coating with a high barrier material, generally an inorganic oxide layer (e.g., SiOx or Al2O3); (2) multilayer films in which the inner layer consists of a barrier material, such as EVOH, polyamide, aluminum, halogenated polyvinylidene, such as PVDC, amorphous nylon or crystalline nylon or a combination of both, a copolymer of an ethylene vinyl alcohol copolymer layer (EVOH), or a polyolefin, comprising two or more combinations of the above layers; and the outer layer consists of a structural polymer (e.g., PE, PP, or PET). For example, EVOH has one of the lowest reported oxygen permeability among polymers commonly used in packaging. Chemically, EVOH is a semicrystalline copolymer of ethylene and vinyl alcohol monomer units.

[0187] In one embodiment, the flexible container or multi-chamber container has a capacity of 5 cc / m³ 2 Less than / day, 2cc / m³ 2 Less than 1 cc / m³ per day, preferably 1 cc / m³ 2 Less than / day, particularly preferably 0.5cc / m³ 2 It may also be made from a material with a high oxygen barrier of less than 1 day (30°C / 70%RH).

[0188] Oxygen permeability, also known as "OTR," is the steady-state rate at which oxygen gas can permeate through a film. OTR is the volume of oxygen that permeates a given area over a period of one day; cc / m³ 2 Expressed as / day (or 24 hours), measured at a standard temperature of 23°C and 0% relative humidity (RH).

[0189] Accordingly, the Disclosure also provides a multi-chamber container for parenteral or nutritional formulations that can be prepared from a flexible container, preferably from one of the flexible films described above. Those generally skilled in the art can select a suitable film having a sufficiently low gas barrier according to the present invention, such as a low oxygen or carbon dioxide barrier. For example, the container may be in the form of a bag having one or more compartments or chambers. The container, such as a bag, may contain at least two chambers, but may contain three, four, five, or six or more chambers, with one preferred embodiment containing two or three chambers, or another preferred embodiment containing four, five, or six chambers.

[0190] Suitable containers, including soft bags, are typically sterile, non-pyrogenic, single-use, and / or ready to use. Multi-chamber containers are particularly useful for holding parenteral nutritional products for adults, children, and neonates, and can provide a carbohydrate preparation disclosed herein in a first chamber, an amino acid preparation disclosed herein in a second chamber, and a lipid preparation disclosed herein in a third chamber of the container.

[0191] A multi-chamber container may include vertical chambers as disclosed in U.S. Patent Application Publication No. 2007 / 0092579. For example, a multi-chamber container may be configured as a bag containing two, three, four, five, or six adjacent chambers or compartments. If desired, a brittle barrier or an openable seal (e.g., a peel seal or brittle seal) is used to separate the chambers of the multi-chamber container. A multi-chamber container may include three chambers containing a lipid emulsion, a carbohydrate preparation, and an amino acid preparation, and may further include at least one, in a particular embodiment, two or three smaller chambers containing, for example, a vitamin preparation and / or a trace element preparation. In a particular embodiment, the multi-chamber container of the present invention has a first chamber containing a lipid emulsion according to the present invention, a second chamber containing an amino acid preparation, a third chamber containing a carbohydrate preparation, a fourth chamber containing a vitamin preparation, and a fifth chamber containing a trace element preparation.

[0192] A multi-chamber container or multi-chamber bag (MCB) used in the context of the present invention may be designed for parenteral administration of the reconstituted content after mixing of the formulations contained in each chamber. Such an MCB may have two, three, four, five, six, or more chambers. The chambers of the MCB may be of the same size, or may be of various sizes to accommodate various compositions and volumes. The chambers may be designed to contain volumes, for example, about 1 to about 5 ml, about 5 to about 10 ml, about 10 to about 50 ml, about 50 to about 100 ml, about 100 to about 250 ml, about 250 ml to about 500 ml, about 500 to about 1000 ml, or about 1000 to about 1500 ml. The MCB may be designed to have chambers arranged adjacent to one another. The chambers may have various shapes. The chambers may be oriented horizontally and / or vertically to one another. A particular small chamber can be designed to be located within another larger chamber, for example, a small chamber placed within another larger chamber can be housed and secured within the larger chamber by welding at least one edge of the small chamber between the welded seams of the surrounding larger chamber.

[0193] The openable seal of a multi-chamber container allows formulations to be stored separately and mixed / reconstituted immediately before administration, thereby enabling the storage of formulations in a single container that should not be stored as a mixture for extended periods. Opening the seal allows communication between chambers and mixing of the contents of each chamber. The outer seal of the multi-chamber container is a strong seal that does not open under the pressure of the supplied fluid to open weaker peel seals or brittle seals between chambers. In some embodiments, the openable seal of a multi-chamber container may be designed to mix or reconstitute only selected chambers of the multi-chamber container, for example, mixing lipid emulsions with vitamin chambers and amino acid chambers if desired.

[0194] A multi-chamber container may be provided with instructions describing a desired order in which to open the release seals so that the component fluids are mixed in the desired order. The opening strengths of two or more release seals may vary to facilitate the opening of the seals in the desired order. For example, the opening strength of the release seal to be opened first may be 1 / 3 to 1 / 2 of the opening strength required to open the release seal to be opened second.

[0195] In some embodiments, the multi-chamber vessel comprises at least a first chamber containing a carbohydrate preparation, a second chamber containing an amino acid preparation, and optionally a third chamber containing a lipid preparation, and optionally electrolytes and / or vitamins in at least the first, second, and / or third chambers. According to certain embodiments, at least one chamber containing sodium selenite, selenite, and / or selenium dioxide further comprises an ambient air or oxygen headspace.

[0196] Carbohydrate preparations provide a calorie supply, typically in the form of glucose. In particular, carbohydrate preparations provide sufficient amounts of carbohydrates to avoid adverse effects such as hyperglycemia observed in patients receiving parenteral nutrition. [Examples]

[0197] The present invention is further described by the following embodiments. These do not limit the scope of the present invention, but represent preferred embodiments of the present invention provided to further illustrate the present invention as described herein. (Example 1) Tests conducted using oxygen semipermeable and oxygen impermeable barrier films.

[0198] The tests were conducted using two different types of films: an oxygen-semipermeable film and an oxygen-impermeable film.

[0199] The semipermeable film is a co-extruded film having the following structure: PP|Tie|PA|Tie|PP / SEBS / LLDPE. Here, PP refers to polypropylene, PA refers to polyamide, SEBS refers to styrene-ethylene-butylene-styrene block copolymer, and LLDPE refers to linear low-density polyethylene. "Tie" is a special adhesive polymer or "Tie resin," typically a polyethylene copolymer with or without polar and nonpolar repeating units and functional reactive groups, used to improve adhesion between the main layers of a multilayer film. The oxygen barrier of the film is the polyamide layer (approximately 50 cc / m²). 2 Provided by ( / Japan). The applicable film is described, for example, in U.S. Patent Application Publication No. 2010 / 0247935(A1). The semipermeable film allows some oxygen to pass through.

[0200] The oxygen-impermeable film is made from a co-extruded polyolefin material laminated onto polyester by vapor deposition of silicon dioxide coated in a barrier layer to provide an oxygen barrier; that is, the oxygen barrier provided by this particular PET-SiOx has an oxygen permeability of <0.5 cc / m². 2 The concentration was per day. In the tests shown in Figures 1 and 2 (Figures 2A and 2B), sodium selenite was present at a concentration of 1 dd / 25 ml at a pH of 3.0 ± 0.2. Similarly, 100 mM malic acid was present in a 50 ml monobag with a single port tube, which was made of either the semi-permeable or oxygen-impermeable material described above.

[0201] After mixing, each solution was flushed with nitrogen to achieve a dissolved oxygen (DO) level below 0.5 ppm. A headspace of 10 ml of ambient air was left in the 50 ml bag. After filling, the oxygen was saturated (approximately 8 ppm, see Figure 1). Each container was sealed and wrapped in an oxygen-impermeable aluminum overpouch, to which the oxygen absorber was added. Each container was then subjected to wet heat sterilization.

[0202] The following results were obtained: Selenite was found to have a recovery rate of less than 80% after approximately 5 months in the EU-2S batch (semipermeable) (Figure 2A). It can be concluded that oxygen is drawn out of the solution due to the presence of an oxygen absorber in the outer pouch and a semipermeable primary film that allows oxygen to pass through. In the EU2-F bag (oxygen impermeable), this did not occur due to the oxygen barrier film (Figure 2B). Selenite remained above the 80% recovery threshold. Therefore, the oxygen barrier film is advantageous in ensuring the stability of selenite-containing solutions.

[0203] As shown in Figure 1, dissolved oxygen (DO) rapidly decreased from saturation to essentially 0 ppm within approximately 3 months in both cases, but even faster under EU2S semipermeable conditions due to the effect of the oxygen absorber. Subsequently, dissolved oxygen (DO) was essentially 0 ppm in both samples.

[0204] Therefore, dissolved oxygen (DO) decreased even when an oxygen barrier film was used. It was found that components in the solution, including other components (trace elements, malic acid), consumed dissolved oxygen (DO), even though they were no longer lost by permeating the film. This was more pronounced in the presence of malic acid. While not strictly theoretical, it is assumed that the oxidation-reduction potential in the solution favors oxygen consumption (reaction with oxygen). However, as long as the dissolved oxygen (DO) is maintained above 0.5 ppm, selenite can be recovered at a rate of over 80% over a 5-month period. This was achieved by having a dissolved oxygen (DO) above 6 ppm, preferably 6–8 ppm (essentially saturated), at the time of filling.

[0205] (Example 2) Headspace relevance

[0206] In this example, water was saturated with oxygen. The volume of the solution used was 15 ml. As shown in Figure 3, it was found that dissolved oxygen (DO) rapidly dropped below the threshold of 0.5 ppm, even when an oxygen-impermeable film was used without headspace (in contrast to the above setting which included headspace).

[0207] Therefore, it could be shown that the headspace, filled with ambient air, provides a certain "oxygen stock" to replace the oxygen lost from the container. The oxygen from the headspace slowly dissolves into the solution until equilibrium is reached. Thus, dissolved oxygen (DO) can be maintained above 0.5 ppm over time when headspace is present. In the absence of headspace (gray circle), selenite cannot be stabilized due to the loss of dissolved oxygen (DO) over time.

[0208] Port tubes are another aspect that can contribute to dissolved oxygen (DO) loss, as they must be sealed between film layers, and it is difficult to make this sealed portion completely oxygen-resistant. Therefore, it is advantageous to improve the oxygen resistance of port tubes used in the settings described herein, or to remove port tubes completely where possible. In Figure 3, without headspace and without port tubes (white black circles), dissolved oxygen (DO) increases over time compared to when port tubes are present (gray circles), and it is clear that, for example, 5 ml of headspace cannot completely compensate for the loss due to port tubes (white black triangles). Preferably, where possible, headspace is present but port tubes are absent in order to stabilize the selenite-containing solution within the oxygen barrier bag. In such a setting, dissolved oxygen (DO) can be essentially maintained (gray triangles).

[0209] Figure 4 focuses on the volume of headspace. As can be seen, and further discussed above, headspace is required to maintain the required DO level in the composition. The oxygen present in the solution at filling is consumed by the components present in the solution (DO is consumed by redox reactions in the solution, see white black circle, dashed line), otherwise it is lost from the container. A headspace of 2 ml per 25 ml container / chamber volume or 2 ml per 15 ml solution is neither completely sufficient (black triangle). A headspace of 6 ml can nearly satisfy the threshold of 0.5 ppm even when a port tube is present (gray square, continuous line), and is completely sufficient when a port tube is absent (gray square, dashed line). The best results are obtained with a headspace of 10 ml per 15 ml solution in the chamber / container (gray circle, dashed line), even when a port tube is present (gray circle, dashed line).

[0210] These results demonstrate that headspace can be used as a reservoir for gaseous compositions, particularly in multi-chamber bags (MCBs) with various gas level settings, i.e., in combination with chambers and formulations requiring low oxygen levels. (Example 3) A flexible multi-chamber container filled with a liquid medium that should have a selective dissolved gas content to ensure the optimal stability of the contents (one or more liquids).

[0211] Flexible multi-chamber containers made from polymer films, used for storing and holding separate solutions, are widely used, particularly in the medical field, and more specifically in parenteral nutrition.

[0212] In most cases, these containers are made from polymer films with low or moderate gas barrier properties. For parenteral nutrition (PN) products or drug products related to many other nutrients, the gas in question is primarily oxygen. If, for stability reasons, one type of solution needs to be protected from oxygen, then all solutions will typically be prepared to have a low oxygen content. Even if only the sensitive solution is prepared to have a low oxygen content, the system will rapidly shift to equilibrium between the various chambers without the possibility of having a selective gas content in one chamber.

[0213] Furthermore, parenteral nutrition systems are typically packed in secondary top packaging flushed with inert gas or containing oxygen absorber sachets, both of which play a significant role in rapid movement toward equilibrium between the chamber and the annular space of the top packaging.

[0214] This invention describes how the use of high-barrier polymer film materials, the removal of any potential components with low-barrier properties, and the addition of gas headspace to the system can enable the maintenance of selectively dissolved gas content within a chamber over long-term storage.

[0215] The present invention describes a PN multi-compartment container having a chamber containing nutrients to be protected from oxygen (e.g., amino acids, lipids, vitamins), and a chamber containing trace elements alone or in mixtures with other non-oxygen-sensitive components, and which should contain a minimum amount of oxygen for the stability of selenium in selenite form.

[0216] For the purposes of this invention, the plastic film material used to manufacture the container has outstanding gas barrier properties. In the case of parenteral nutrition, the gas in question is oxygen. For this particular purpose, the oxygen permeability is preferably 0.5 cc / m³. 2The temperature should be lower than 30°C / 70%RH. This can be achieved with a co-extruded film containing a layer of ethylene vinyl alcohol copolymer (EVOH). However, PN products are typically sterilized by wet heat sterilization, and EVOH material partially loses its barrier properties during wet heat sterilization. Therefore, this material is not suitable.

[0217] A preferred option is to use a laminated structure in which a substrate polymer layer is incorporated by vapor deposition of silicon oxide or aluminum oxide. Additional barrier-containing layers may be added for better performance.

[0218] The experiments shown in Figures 5-9 used a laminated structure made of GL-RD material from TOPPAN. A three-chamber container was fabricated from this specific film. The chamber size was reduced by sealing it to accommodate approximately 25 mL.

[0219] In the first experiment, chambers A and B in Figure 5 were filled with 200 mL and 300 mL of water, respectively, with dissolved oxygen concentrations lower than 1 ppm. Chamber C in Figure 5 was filled with 25 mL of water and ambient air (dissolved oxygen approximately 8 ppm).

[0220] After filling, the tubes were capped, the bags were steam-sterilized, wrapped in oxygen absorbent sachets, and then stored at 40°C.

[0221] As shown in Figure 6, after 17 days at 40°C, the dissolved oxygen concentration in the small chamber was still very high (approximately 8 ppm), but after 48 days it had dropped to below 1 ppm.

[0222] In the second experiment, a 5 mL air headspace was added to chamber C in Figure 5. As shown in Figure 7, the decrease in dissolved oxygen was even slower, but remained very significant at values ​​between 2 ppm and 3 ppm after storage at 40°C for 3 months.

[0223] The container shown in Figure 5 is sealed with at least one filling port tube per compartment. These filling port tubes are manufactured by co-extrusion. Designing such tubes to present a high oxygen barrier is not easy. As discussed above, the use of a layer of EVOH polymer is not a good option because this polymer loses its barrier properties during wet heat sterilization. The addition of a PVDC layer is undesirable for sustainability reasons. The use of nylon only moderately improves the barrier.

[0224] This tube formulation does not exhibit any specific barrier properties; therefore, the decrease in dissolved oxygen in small compartments is assumed to be due to the permeation of oxygen toward the filled tube wall.

[0225] Figure 8 shows another exemplary multi-chamber container, similar to the one in Figure 5, but with a sealant added to isolate any filled tubes from chamber C.

[0226] The third experiment was performed in chamber C of the multi-chamber container shown in Figure 8, which was filled with 25 mL of water, had an additional 5 mL of air headspace, and had a sealant added to isolate the tube from chamber C.

[0227] Figure 9 shows the results of this third experiment, in which the dissolved oxygen level remained at approximately 8 ppm after 3 months of storage at 40°C and at approximately 6 ppm after 6 months of storage at 40°C.

[0228] The above results indicate that, despite low dissolved oxygen in other chambers and the upper packaging annular space, the use of particularly high-barrier polymer film materials, the removal of components with low-barrier properties (filling tubes), and the addition of gas headspace to the system enable the selective maintenance of high dissolved oxygen content within a single chamber over long-term storage.

[0229] While the 3-chamber bag is used as described above, the present invention may also be used for any multi-chamber container or bag, such as a 5-chamber bag, a 6-chamber bag, a 4-chamber bag, or a 2-chamber bag of "amino acids / dextrose," which may contain at least selenium in the form of trace elements or selenite within the dextrose chamber in an oxygen environment, whereas the amino acids are considered to remain within those chambers in an oxygen-free environment.

[0230] Alternatively, a primary film without specific barrier properties can be used, but chambers with different dissolved oxygen content should be protected afterward. A well-known method for doing so is to cover the chamber with a peelable foil strip that protects the chamber from gas transfer.

[0231] This technique is used in two-chamber bags "solid / diluent" (e.g., double containers made by BBrauun) to protect the compartment containing the solid drug from moisture. However, this process is technically more complex, especially with respect to products that must withstand wet heat sterilization. (Example 5) 6-month accelerated research

[0232] Figure 10 shows the dissolved oxygen level in a trace element chamber that should remain at a significant oxygen level, with a very high barrier primary film, a small headspace of air (5 ml), and removal of the port tube (sealing and cutting process). As shown in operation 5 of Figure 10, the dissolved oxygen level remains above 5 ppm after storage at 40°C for 6 months.

[0233] For comparison, Figure 11 shows the stability of low levels of dissolved oxygen in a chamber filled with a low-dissolved-oxygen medium. As shown in operation 5 of Figure 11, dissolved oxygen levels similar to those before sterilization are maintained after storage at 40°C for 6 months.

[0234] Table II shows the dissolved O2 (ppm) in the TE chamber, and Table III shows the dissolved O2 (ppm) in the AA chamber. In particular, Table II shows the generation of DO in the trace element chamber, and Table III shows the generation of DO in the amino acid chamber, demonstrating that this method can be used in MCBs and chambers with various oxygen requirements. In the AA chamber, the DO content is low at the time of filling because the chamber and solution are generally flushed with nitrogen to reduce the oxygen content. If a highly oxygen-impermeable film is used, this must be done, as the small amount of oxygen can be removed by passing it through the film, for example from the AA chamber, and then captured by an oxygen absorber / scavenger placed in the overpouch. In the TE chamber, the oxygen content is pushed up to about 8 ppm and is kept relatively high as soon as the headspace reservoir containing oxygen (e.g., ambient air) becomes available. [Table 2] [Table 3] (Example 6) Evaluation of various factors related to selenite stability

[0235] A fully factorial design (DoE) for the experiment was developed to evaluate the influence of five factors on the stability of selenite.

[0236] Container materials: The interaction between selenite and plastic bag materials has already been highlighted. To evaluate this factor, a neutral (gas-impermeable) material, namely a glass bottle, was used for comparison with the plastic bag.

[0237] Solution pH: All previous studies were performed at pH < 3.5 to ensure the stability of Fe. Comparison with the natural pH > 7 obtained by simple dilution of selenite in Milli-Q water allowed for evaluation of the effect of this parameter.

[0238] Sterilization: The final heat sterilization performed on the sample may initiate degrading chemical reactions due to thermal exposure. The effect of this process step was evaluated by comparing the selenite stability of unsterilized and sterilized samples.

[0239] Storage temperature: Accelerated stability studies were performed at 40°C, following established practice. However, selenite may be sensitive to this, so a comparison was performed with samples stored at 5°C.

[0240] Dissolved oxygen content: Oxygen is present in many oxidation-reduction reactions and is detrimental to macronutrients and micronutrients (especially vitamins) in most cases. To evaluate the effect of this parameter on the stability of selenite, selenite solutions were flushed with either oxygen (to a saturation level of approximately 8 ppm) or nitrogen (DO < 0.5 ppm).

[0241] All possible combinations of factors were generated and stored under appropriate conditions for six months. These were then subjected to several tests to evaluate the effect of each factor on several responses.

[0242] The following readings were performed to assess the impact of the factors listed above:

[0243] Se assay to evaluate selenium degradation.

[0244] Visual inspection of a sample to detect any precipitates, particles, or discoloration.

[0245] pH measurement to evaluate the evolution of sample pH after 6 months of storage.

[0246] Dissolved oxygen measurement to evaluate the evolution of dissolved oxygen after 6 months of storage.

[0247] This involves measuring the redox potential when selenite is involved with different Se redox pairs, and information about the redox potential of the solution can help understand the stability of this element.

[0248] For almost all of the responses studied, the same sample group exhibited different behavior from the rest. The observations are detailed in Table IV below. [Table 4]

[0249] These observations allowed us to conclude that the observed selenium decomposition in samples flushed with nitrogen and stored in oxygen-permeable plastic bags was likely due to the reduction of selenite SeO3 in H2Se / HSe-, i.e., due to a volatile form of Se known to emit a foul odor similar to sulfurous gas. The pH / redox diagram presented in Figure 12 shows the transformation of SeO3 in these volatile species in a completely oxygen-free medium. (Example 7) Effect of DO on selenium stability

[0250] The effect of oxygen appears to be primarily important in the stability of selenite. In fact, some amount of oxygen that permeates into the solution, which was initially flushed with nitrogen but stored in a glass bottle, certainly blocked the reduction reaction and maintained the stability of SeO3. To confirm this hypothesis, a regression test was performed between Se assay results and log(dissolved oxygen results). Only sterilized samples stored at 40°C were considered, as high-temperature sterilization and storage both appear to increase Se degradation. In fact, most reaction kinetics are accelerated by heat, which explains why samples kept at 5°C for 6 months without sterilization did not show degradation to the same extent as samples sterilized and stored at 40°C.

[0251] The fitted line plot presented in Figure 13 shows an 80% fit between Se dosage and log oxygen content. Considering the analytical variability of ±5% and the several samples used in this regression test, it can be regarded as a significant representative example. The dissolved oxygen content is therefore the most influential parameter and is a CQA (Critical Quality Attribute) for the stability of selenium. As shown in the figure, a low oxygen content of about 0.5 ppm can be sufficient to ensure the stability of selenite in the solution, and saturation may not be required.

[0252] The presence of oxygen promotes the stability of selenite. For comparison, the stability of a mixture of other trace elements (i.e., Zn, Cu, Cr, Mo, Mn, Fe, I, F & Se) was evaluated at pH 2.2 with 200 mM malic acid (to ensure the stability of iodide) and stored in glass bottles (thus containing about 3 ppm of dissolved oxygen). The solutions were autoclaved and stored for 6 months at 40°C or 5°C (T6M 40°C and T6M 5°C, respectively). After 6 months at the two temperatures, the recovered concentration of each trace element is summarized in Table V.

Table 5

[0253] For all TEs, the recovery is about 80~90% at both temperatures. Over-dilution may explain that this is lower than the expected recovery rate, but it is known that the samples should be stable at 5°C and can therefore be regarded as a reference. Comparison of the two samples shows that the TEs did not degrade significantly after 6 months of storage at 40°C. This confirms the hypothesis that selenite is stable in the presence of several ppm of dissolved oxygen. This presence of oxygen is not detrimental to the stability of other TEs.

[0254] It can be confirmed that oxygen introduction is no longer a problem in manufacturing. For example, instead of flushing the solution with nitrogen as has been done in the past, it can be kept under ambient air, thereby dissolving a sufficient amount of oxygen in the solution. However, to reproducibly adjust the dissolved oxygen content, the solution can also be flushed with nitrogen, and then flushed with an oxygen-containing gas for a predetermined time and amount. The oxygen content can be monitored at any time as an in-process control by methods known in the art. During the filling, sterilization, and storage steps, dissolved oxygen can be maintained in the solution by using oxygen-impermeable bag material. Such material prevents any oxygen from entering the bag or being removed from the bag (even in contact with an oxygen absorber). In this way, the oxygen remains trapped in the TE solution, preventing Se decomposition until the end of the product's shelf life. The present invention provides, for example, the following items: (Item 1) A flexible container having a selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product, (a) A solution comprising at least one compound having a selective dissolved gas requirement, (b) The headspace of the gas and A flexible container that includes [the specified element]. (Item 2) The flexible container according to item 1, wherein at least one of the compounds is a compound that requires a high level of oxygen, and the selectively dissolved gas is oxygen. (Item 3) The flexible container according to item 1, wherein the at least one compound is a compound that requires a high level of carbon dioxide, and the selectively dissolved gas is carbon dioxide. (Item 4) The flexible container according to item 1, wherein the container is a multi-chamber bag comprising at least one chamber, and the compound having the selective dissolved gas requirement is located within it. (Item 5) The flexible container according to item 1, wherein the volume of the headspace is approximately 5% to approximately 100% of the volume of the solution in the flexible container. (Item 6) The flexible container according to item 1, wherein the volume of the headspace is approximately 35% to approximately 45% of the volume of the solution in the flexible container. (Item 7) A flexible container as described in item 1, which will ultimately be heat-sterilized. (Item 8) The flexible container according to item 1, wherein at least one of the compounds is a selenium compound in the form of Se(IV). (Item 9) The flexible container according to item 8, wherein the at least one selenium compound is selected from the group consisting of sodium selenite, potassium selenite, lithium selenite, calcium selenite, magnesium selenite, selenite, and selenium dioxide. (Item 10) A flexible container according to item 2, wherein the solution contains dissolved oxygen (DO) equal to or greater than 0.5 ppm over the entire shelf life of the pharmaceutical product. (Item 11) A flexible container as described in item 2, wherein the solution contains approximately 0.5 ppm to approximately 8 ppm of dissolved oxygen (DO). (Item 12) A flexible container as described in item 2, wherein the solution contains dissolved oxygen (DO) equal to or greater than 1 ppm. (Item 13) A flexible container according to item 9, wherein the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm. (Item 14) The flexible container according to item 1, wherein the headspace of the gas stabilizes at least one compound for a time selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months when stored at a temperature between about 1°C and about 30°C. (Item 15) A flexible container as described in item 14, which is stored at a temperature between approximately 18°C ​​and 25°C. (Item 16) The flexible container according to item 8, wherein the solution has an acidic pH value in the range of about 1 to about 4, preferably about 2.5 to about 3.2. (Item 17) The flexible container according to item 4, wherein the multi-chamber container includes at least two chambers. (Item 18) The flexible container according to item 4, wherein the multi-chamber container is selected from the group consisting of a 2-chamber container, a 3-chamber container, a 4-chamber container, a 5-chamber container, a 6-chamber container, a 7-chamber container, and an 8-chamber container. (Item 19) The aforementioned multi-chamber container (a) A first chamber containing a carbohydrate preparation, (b) A second chamber containing an amino acid preparation, (c) A third chamber containing a lipid preparation, and (d) A fourth chamber containing a solution containing a compound having selective dissolved gas requirements. A flexible container as described in item 4, including the one specified in item 4. (Item 20) The flexible container according to item 19, wherein the solution contained in the fourth chamber comprises at least one selenium compound, and the headspace is filled with ambient air, oxygen-rich ambient air, or oxygen. (Item 21) 5cc / m 2 A flexible container as described in item 1, made of a material having an oxygen barrier of less than 1 day. (Item 22) The flexible container according to item 4, wherein the chamber in which a compound having selective dissolved gas requirements is located does not include a port tube. (Item 23) A multi-chamber container having a selective dissolved gas content for stabilizing at least one micronutrient in a pharmaceutical product, (a) A first chamber containing a carbohydrate preparation, an amino acid preparation, or a lipid preparation, (b) A second chamber containing a solution comprising the at least one micronutrient having selective dissolved gas requirements; and the headspace of the gas. A multi-chamber container, including one. (Item 24) The multi-chamber container according to item 23, wherein the at least one micronutrient is a compound of at least one micronutrient that is selenium in the form of Se(IV), and the dissolved gas is dissolved oxygen (DO). (Item 25) A multi-chamber container as described in item 23, comprising at least five chambers. (Item 26) The multi-chamber vessel according to item 23, wherein the at least one selenium compound is selected from the group consisting of sodium selenite, selenite, and selenium dioxide. (Item 27) The multi-chamber vessel according to item 23, wherein the at least one selenium compound is sodium selenite or selenium dioxide. (Item 28) The multi-chamber container according to item 23, wherein the solution in the second chamber contains dissolved oxygen (DO) equal to or greater than 0.5 ppm over the entire shelf life of the pharmaceutical product. (Item 29) The multi-chamber container according to item 23, wherein the solution in the second chamber contains approximately 0.5 ppm to approximately 8 ppm of dissolved oxygen (DO). (Item 30) The multi-chamber container according to item 23, wherein the solution in the second chamber contains dissolved oxygen (DO) equal to or greater than 1 ppm. (Item 31) A multi-chamber container, as described in item 23, which is ultimately heat-sterilized. (Item 32) The multi-chamber container according to item 32, wherein the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm. (Item 33) The multi-chamber container according to item 23, wherein the volume of the headspace is approximately 5% to approximately 100% of the volume of the solution in the multi-chamber container. (Item 34) The multi-chamber container according to item 23, wherein the volume of the oxygen headspace is approximately 35% to 45% of the volume of the solution in the flexible container. (Item 35) The multi-chamber container according to item 23, wherein the gas headspace stabilizes the at least one micronutrient when stored at a temperature between about 1°C and about 30°C for a period of time selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months. (Item 36) A multi-chamber container as described in item 36, stored at a temperature between approximately 18°C ​​and 25°C. (Item 37) A multi-chamber vessel as described in item 23, made of a material having an oxygen barrier of less than 0.5 cc / m2 / day. (Item 38) A flexible container as described in item 21, made of a material having an oxygen barrier of less than 2 cc / m2 / day. (Item 39) A flexible container as described in item 21, made of a material having an oxygen barrier of less than 1 cc / m2 / day.

Claims

1. A flexible container in the form of a multi-chamber bag having a selective dissolved gas for stabilizing at least one selenium compound of a pharmaceutical product, wherein the selective dissolved gas is oxygen, and the multi-chamber bag is (a) A first chamber containing a carbohydrate preparation, (b) A second chamber containing an amino acid preparation, (c) A third chamber containing a lipid preparation, and (d) A fourth chamber containing a solution comprising at least one selenium compound, wherein the fourth chamber comprises ambient air, oxygen-rich ambient air, or an oxygen-filled headspace. A flexible container that includes [the specified element].

2. The flexible container according to claim 1, wherein the volume of the headspace is about 5% to about 100% of the volume of the solution in the flexible container.

3. The flexible container according to claim 1, wherein the volume of the headspace is about 35% to about 45% of the volume of the solution in the flexible container.

4. The flexible container according to claim 1, wherein the flexible container is ultimately heat-sterilized.

5. The flexible container according to claim 1, wherein the at least one selenium compound is a selenium compound in the form of Se(IV).

6. The flexible container according to claim 5, wherein the at least one selenium compound is selected from the group consisting of sodium selenite, potassium selenite, lithium selenite, calcium selenite, magnesium selenite, selenite, and selenium dioxide.

7. The flexible container according to claim 1, wherein the solution contains dissolved oxygen (DO) equal to or greater than 0.5 ppm over the entire shelf life of the pharmaceutical product.

8. The flexible container according to claim 1, wherein the solution contains about 0.5 ppm to about 8 ppm of dissolved oxygen (DO).

9. The flexible container according to claim 1, wherein the solution contains dissolved oxygen (DO) equal to or greater than 1 ppm.

10. The flexible container according to claim 6, wherein the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm.

11. The flexible container according to claim 1, wherein ambient air, oxygen-rich ambient air, or an oxygen-filled headspace stabilizes the at least one selenium compound for a period of time selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months when stored at a temperature between about 1°C and about 30°C.

12. The flexible container according to claim 11, wherein the flexible container is stored at a temperature between approximately 18°C ​​and approximately 25°C.

13. The flexible container according to claim 5, wherein the solution has an acidic pH value in the range of about 1 to about 4.

14. The flexible container according to claim 1, wherein the multi-chamber bag is selected from the group consisting of a 4-chamber container, a 5-chamber container, a 6-chamber container, a 7-chamber container, and an 8-chamber container.

15. The aforementioned flexible container holds 5 cc / m³ ２ A flexible container according to claim 1, made of a material having an oxygen barrier of less than one day.

16. The flexible container according to claim 1, wherein the chamber in which the at least one selenium compound is located does not include a port tube.

17. A multi-chamber container having dissolved oxygen (DO) for stabilizing at least one selenium compound in the form of Se(IV) of a pharmaceutical product, wherein the multi-chamber container is (a) a first chamber containing a carbohydrate preparation, an amino acid preparation, or a lipid preparation; and (b) a solution containing the at least one Se(IV) form of selenium compound requiring the dissolved oxygen (DO) for stabilization; and a second chamber containing an oxygen-filled headspace. A multi-chamber container, including one.

18. The multi-chamber container according to claim 17, wherein the multi-chamber container includes at least five chambers.

19. The multi-chamber container according to claim 17, wherein the at least one selenium compound is selected from the group consisting of sodium selenite, selenite, and selenium dioxide.

20. The multi-chamber container according to claim 17, wherein the at least one selenium compound is sodium selenite or selenium dioxide.

21. The multi-chamber container according to claim 17, wherein the solution in the second chamber contains dissolved oxygen (DO) equal to or greater than 0.5 ppm over the entire shelf life of the pharmaceutical product.

22. The multi-chamber container according to claim 17, wherein the solution in the second chamber contains about 0.5 ppm to about 8 ppm of dissolved oxygen (DO).

23. The multi-chamber container according to claim 17, wherein the solution in the second chamber contains dissolved oxygen (DO) equal to or greater than 1 ppm.

24. The multi-chamber container according to claim 17, wherein the multi-chamber container is ultimately heat-sterilized.

25. The multi-chamber container according to claim 17, wherein the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm.

26. The multi-chamber container according to claim 17, wherein the volume of the headspace is about 5% to about 100% of the volume of the solution in the multi-chamber container.

27. The multi-chamber container according to claim 17, wherein the volume of the oxygen in the headspace is approximately 35% to 45% of the volume of the solution in the multi-chamber container.

28. The multi-chamber container according to claim 17, wherein the oxygen-filled headspace stabilizes the selenium compound in the form of at least one Se(IV) for a period of time selected from the group consisting of at least 3 months, at least 6 months, at least 12 months, at least 18 months, and at least 24 months when stored at a temperature between about 1°C and about 30°C.

29. The multi-chamber container according to claim 28, wherein the multi-chamber container is stored at a temperature between approximately 18°C ​​and approximately 25°C.

30. The multi-chamber container according to claim 17, wherein the multi-chamber container is made of a material having an oxygen barrier of less than 0.5 cc / m² / day.

31. The flexible container according to claim 15, wherein the flexible container is made of a material having an oxygen barrier of less than 2 cc / m² / day.

32. The flexible container according to claim 15, wherein the flexible container is made of a material having an oxygen barrier of less than 1 cc / m² / day.

33. The flexible container according to claim 13, wherein the solution has an acidic pH value in the range of about 2.5 to about 3.2.

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