Container containing selective 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 The present invention relates generally 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 pharmaceutical products preferably having multiple chambers, each chamber having a selective and controllable dissolved gas (eg, oxygen) content.

[0003] In certain embodiments, the present invention relates to a flexible or multi-chamber container in which a selective dissolved gas content is included in one or more compartments to stabilize at least one compound sensitive to the level of gas. In certain embodiments, such a compound can be a compound provided 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 or multi-chamber container in which a selective dissolved gas content is included in one or more compartments, and the head space of the compartment with a certain gas requirement is filled with the required gas (e.g., ambient air, oxygen-enriched 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, selenious acid, and selenium dioxide, and the head space of the compartment containing the solution containing selenium contains ambient air, oxygen-enriched ambient air, or oxygen as a part of the oxygen, thereby maintaining, for example, the level of dissolved oxygen (DO) in the solution at the intended level, such as, for example, 0.5 ppm to 8 ppm oxygen. Other compounds can be envisioned that have specific gas requirements.

[0004] In certain embodiments of the invention, the solution of the pharmaceutical product of the invention comprises at least one additional trace element, such as, for example, selenium. The expression "pharmaceutical product" as used herein encompasses IV solutions as well as parenteral and nutritional solutions. The expression "parenteral nutritional solution" refers to a solution for providing nutritional support given entirely intravenously via the bloodstream with an IV pump. The solution contains amino acids, carbohydrates, lipids, electrolytes, vitamins, and / or minerals. The pharmaceutical solution may be ready for use. The solution may be contained in one chamber of a multi-chamber container having at least 2, at least 3, at least 4, at least 5, at least 6, or more chambers. The solution may also be contained in a monobag. The solutions contained in the 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, which may for example require particularly low levels of oxygen. The invention further relates to a method for providing a pharmaceutical product in a multi-chamber container according to the invention, or possibly in a monobag according to the invention. [Background technology]

[0005] 2. Background of the Invention Solutions for intravenous administration, including parenteral nutrition (PN) products, are intended to supply certain compounds to patients by intravenous access. For example, parenteral nutrition products can 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 provided in flexible bags with different volumes. In particular, PN products are often provided in multi-chamber bags, since the different formulations, such as the lipid, carbohydrate, or amino acid formulations mentioned, must be kept separate from each other during production, filling, sterilization, and storage so as to remain stable. The 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 many pharma- ceutically active ingredients and render them inactive.

[0006] Moreover, although different formulations may be placed in different compartments of a multi-chamber bag, such as typically used in parenteral nutrition, different requirements regarding specific gases that must or must not be present in different formulations of the same MCB are difficult to realize. As can be easily understood, the multi-chamber bag is prepared from one film material. The different compartments are introduced by welded seals between the different compartments that are (partially) permanent or can be peeled off, for example, by hand pressure. Thus, if one or more of the formulations require the use of a certain film material, for example an oxygen semi-permeable 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 said formulation, it is also difficult to accommodate, for example, the compartments and formulations that require high oxygen levels, and as a result, 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 a compound has selective gas requirements for its stability, such as compounds that require high dissolved oxygen levels. Oxygen may be consumed by the components of the formulation and / or lost even when using high oxygen barrier materials by diffusion through the film. This is especially noticeable in the presence of oxygen absorbers, which can be placed in the overpouch of the MCB, which will slowly deplete the solution of dissolved oxygen even 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, using a film material for the container with a high oxygen barrier to reduce the loss of DO from the solution through the container may not be enough to address the problem of such compounds over the long term, i.e., typical shelf life requirements for ready-to-use pharmaceutical formulations, which should generally be at least 6, 12, 18, or at best 24 months at temperatures up to 25°C.

[0008] Parenteral nutrition solutions, such as in the form of one or more solutions, can also be provided in the form of a flexible bag, either in the form of a single flexible bag containing glucose, amino acids, or lipids, with or without electrolytes, or which may contain, for example, vitamins and / or trace elements, and any other solutions that can be mixed together before administration, or in the form of a multi-chamber flexible bag as described above that provides separate macronutrients and electrolytes in a ready-to-use format. Thus, the same problem of incompatible gas level requirements in various formulations can also arise with MCBs providing parenteral nutrition formulations.

[0009] Such headspace is known to be created when a liquid composition is introduced into a container, such as the containers discussed herein, meaning that air is trapped at the top of the container before it is sealed. In general, the goal of the industry is to reduce the headspace for various reasons. Methods have been developed to monitor the oxygen level in the headspace of prefilled containers, where the requirement arises to ensure the stability and efficacy of oxygen-sensitive products, and are used to test finished sterilized products, such as headspace oxygen analysis (HOA) or non-destructive laser-based headspace testing. As also described in WO2009021094A1, headspace can be reduced by various methods, including "topping off" the container with a sufficient amount of the composition to ensure that no air remains at the top of the container, or evacuating a container filled with liquid. Another technique is to provide an elaborate passageway in the closure, which allows gas to leave the system but minimizes liquid loss. Another system utilizes one or more small orifices in a rubber, metal, or plastic diaphragm that makes the material permeable to gas. If the headspace cannot be completely avoided, which is generally the case, the headspace is filled with an inert gas such as nitrogen.

[0010] In summary, the prior art headspace in containers for e.g. pharmaceutical solutions needs to be either reduced or avoided, or if possible controlled in such a way as to avoid the presence of any inert gases such as oxygen.

[0011] Typical medical solution containers, including those used for parenteral nutrition solutions, must meet several performance criteria including flexibility, transparency, gas barrier properties, drug compatibility, resistance to heat sterilization, resistance to drop impact, etc. Various types of medical solution containers are currently available, e.g., double-bagged having an inner bag and an outer bag, where the inner bag contains the functional medical solution and the outer bag (also called an "overpouch") covers the inner bag and provides a gas or oxygen barrier function.

[0012] The bag is typically made of a synthetic or plastic material, such as materials such as polypropylene (PP), polyethylene (PE), ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), and all possible copolymers, essentially any synthetic material suitable for containing the ingredient to be administered.

[0013] As stated above, in the current state of the art, micronutrients, but also certain drugs, are typically added directly to the nutrition bag before administration, since they cannot be stably incorporated into one of the compartments of the MCB. For this purpose, vitamins can be provided in glass vials in the form of lyophilisates or solutions that will be reconstituted and / or mixed into the nutrition / infusion bag. Trace elements are also provided in glass vials or polypropylene ampoules, which are meant to be mixed in the infusion bag before administration. The same is true for certain drugs that can or may typically be added to parenteral nutrition solutions for administration.

[0014] Prior to use, referring to the initiation of administration of the formulation to the patient, micronutrients or drugs are sometimes added to the mixture or macronutrients through an injection port in a container or bag (septum) or added to the infusion line through a Y-connector. This process takes time and several handling steps, increasing the risk of error or contamination.

[0015] To avoid these potential problems, products have been developed that already contain some trace elements in the nutrition 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, it has been reported that the trace element selenium, provided as selenium dioxide in the product, is absent in the finished product, possibly due to degradation, as published in July 2014 (http: / / www.pharmacovigilance-tours.fr / 490.html). Another product, Elneopa from Otsuka Pharmaceutical, contains certain trace elements in small dedicated chambers as part of the multi-chamber bag. However, this product does not contain selenium.

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

[0017] KR10-2019-0105737 relates to an infusion solution preparation containing fat-soluble vitamins and trace elements, more particularly to an infusion solution preparation containing multiple chambers therein, thus preserving reducing sugars, amino acids, lipids, and fat-soluble vitamins and trace elements separately. The publication describes preferred concentrations of 3 μg / mL to 7.0 μg / ml for selenium ions and selenium cations, among other trace elements, contained in the chambers of the multi-chamber nutritional product. It does not describe how to stabilize the specific ions or such selenium ions in the formulation. For example, selenium, iodine, and copper - especially in combination - are known in the art to be difficult to include in nutritional bags because they can undergo chemical reactions, especially because they must undergo extreme conditions such as heat sterilization and long shelf 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). Moreover, in various formulation studies, when attempting to introduce trace elements into nutritional multi-chamber bags, serious stability problems have been experienced, and in particular losses of selenium have been observed. This may be due to the fact that selenium in the form of Se(IV), especially in the form of sodium selenite, selenious acid, or selenium dioxide, tends to adsorb, for example, on plastic materials or iron oxides; can be reduced to metallic selenium in the presence of reducing agents such as ascorbic acid; can be reduced to hydrogen selenide, which is a volatile substance; and / or can be converted at low pH to selenium dioxide, which is also a volatile substance, under certain conditions. In short, the conditions for certain compounds, such as selenite, are not suitable in MCBs 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 provide in a stable manner a ready-to-use pharmaceutical product or a flexible container / multi-chamber container for a pharmaceutical product, including one intended for parenteral administration, including a solution for parenteral administration to a patient in need thereof, including a compound with selective gas requirements that may be even more contrasting with the requirements of other formulations in the same MCB. Selenium, for example in the form of Se(IV), can finally be provided stably over extended periods of time. The techniques disclosed herein can also be used with other compounds or combinations of compounds that have selective gas requirements, particularly in the context of multi-chamber bags containing formulations with conflicting requirements for 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 [Patent Document 3] Korean Patent Application Publication No. 10-2019-0105737 [Non-patent literature]

[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 Summary of the Invention [Problem to be solved by the invention]

[0020] Thus, there remains a need to provide a solution that accommodates sensitive compounds that require the presence of selective gases in the formulation, particularly in formulations that are part of an MCB that include additional formulations with different gas level requirements. [Means for solving the problem]

[0021] Summary of the Invention In one aspect, 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 to remain stable, the flexible container comprising: a solution containing at least one compound; a film material from which the container is made that provides a high gas barrier with respect to said gas; and a gas headspace.

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

[0023] According to another embodiment, the at least one compound is a compound that requires high levels of oxygen and the selective dissolved gas is oxygen.

[0024] According to another embodiment, the flexible container is a multi-chamber bag including at least one chamber in which a compound having a selective dissolved gas requirement is disposed.

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

[0026] According to another embodiment, the headspace volume is about 35% to 45% of the volume of the solution within the flexible container.

[0027] According to another embodiment, the container is terminally heat sterilized.

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

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

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

[0031] According to another embodiment, the solution comprises about 0.5 ppm to about 8 ppm of dissolved oxygen (DO).

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

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

[0034] According to another embodiment, the gaseous 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] According to another embodiment, the flexible container is stored at a temperature between about 18°C ​​and about 30°C.

[0036] According to another embodiment, the solution has an acidic pH value ranging from about 1 to about 4, preferably from about 2.5 to about 3.2.

[0037] According to another embodiment, the multi-chamber container comprises at least two chambers.

[0038] According to another embodiment, 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.

[0039] According to another aspect, the multi-chamber container comprises: (a) a first chamber containing a carbohydrate formulation; (b) a second chamber containing an amino acid formulation; (c) a third chamber containing the lipid formulation; and (d) a fourth chamber containing a solution containing a compound having a selective dissolved gas requirement; Includes.

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

[0041] According to another embodiment, the flexible container has a capacity of 1 cc / m 2 / day, preferably less than 0.5cc / m 2 It is made of materials with an oxygen barrier of less than 100 / day.

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

[0043] According to another aspect, 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, the multi-chamber container comprising: (a) a first chamber containing a carbohydrate formulation, an amino acid formulation, or a lipid formulation; (b) a second chamber containing a solution containing at least one micronutrient having a selective dissolved gas requirement; and a gas headspace. Includes.

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

[0045] According to another embodiment, the multi-chamber container comprises at least five chambers.

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

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

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

[0049] According to another embodiment, the solution in the second chamber comprises about 0.5 ppm to about 8 ppm of dissolved oxygen (DO).

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

[0051] According to another embodiment, the container is terminally heat sterilized.

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

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

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

[0055] According to another embodiment, the gas headspace stabilizes the at least one micronutrient for a time 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 30° C.

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

[0057] According to another embodiment, the multi-chamber container has a capacity of 1 cc / m 2 / day, preferably less than 0.5cc / m 2 It is made of materials with an oxygen barrier of less than 100 / day.

[0058] The present invention is further described by the following figures, which do not limit the scope of the invention but represent preferred embodiments of aspects of the invention provided for greater illustration of the invention described herein. [Brief description of the drawings]

[0059] [Figure 1] FIG. 1 is a set of graphs showing the variation of dissolved oxygen (DO) over time at 40° C. for samples of EU-2S batch (semi-permeable) and EU2-F bag (oxygen impermeable).

[0060] [Figure 2A] FIG. 2 (FIGS. 2A and 2B) are a pair of graphs showing selenite recovery levels for selenite batch EU2-S (semi-permeable film) (FIG. 2A) and selenite batch EU2-F (oxygen impermeable film) (FIG. 2B). [Figure 2B] FIG. 2 (FIGS. 2A and 2B) are a pair of graphs showing selenite recovery levels for selenite batch EU2-S (semi-permeable film) (FIG. 2A) and selenite batch EU2-F (oxygen impermeable film) (FIG. 2B).

[0061] [Diagram 3] FIG. 3 is a set of graphs showing an analysis of the effect of headspace and the presence of a port tube in combination with an oxygen impermeable bag.

[0062] [Figure 4] FIG. 4 is a set of graphs showing the effect of headspace volume on the variation of dissolved oxygen (DO) over time.

[0063] [Diagram 5] FIG. 5 illustrates an exemplary multi-chamber vessel.

[0064] [Figure 6] FIG. 6 is a graph showing the variation of dissolved oxygen (DO) over time at 40° C. for chamber C of the multi-chamber vessel of FIG.

[0065] [Figure 7]FIG. 7 is a graph showing the variation of dissolved oxygen (DO) over time at 40° C. for chamber C of the multi-chamber vessel of FIG. 5 after a headspace of 5 mL of air was added to chamber C.

[0066] [Figure 8] FIG. 8 shows another exemplary multi-chamber container similar to that of FIG. 5 but with the addition of a seal to isolate any fill tube from chamber C.

[0067] [Figure 9] FIG. 9 is a graph showing the variation of dissolved oxygen (DO) over time at 40° C. for chamber C of the multi-chamber container of FIG. 8 , showing that the dissolved oxygen levels are still around 5 to 6 ppm after 6 months of storage at 40° C.

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

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

[0070] [Figure 12] FIG. 12 is a pH / redox diagram showing the conversion of SeO3 in these volatile species in a totally oxygen-free medium.

[0071] [Figure 13] Figure 13 is a graph showing a fitted line plot between Se dose and log oxygen content. Figure 13 shows an approximately 80% fit between Se dose and log oxygen content. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[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. As used herein, the following terms have the following meanings:

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

[0074] The term "about" when used before numerical designations, such as temperature, time, amounts, and concentrations, including ranges, indicates approximations that 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 synonymously. The terms "solution" and "formulation" are also used synonymously in the context of the present invention.

[0076] The term "micronutrient" as used herein refers to any essential element required by an organism in varying amounts throughout the life span to regulate a range of physiological functions to maintain health. Important micronutrients include iodine, iron, zinc, calcium, selenium, fluorine, copper, chromium, molybdenum, manganese, as well as vitamins A, B, and C. 6 , B 12 , B 1 , B 2 , B 3 , B 8 , B 9 These include Calcium, K, D, E, and C. With respect to human nutrition, micronutrient requirements may generally be in amounts less than 100 milligrams per day, whereas macronutrients may be required in daily gram amounts. Calcium is sometimes also referred to as an electrolyte.

[0077] The term "macronutrients" as used herein refers to the class of compounds that humans consume in relatively large amounts 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" disclosed herein relates to any product intended to be used for medical purposes, preferably for clinical nutritional purposes. The pharmaceutical product of the present invention is intended and designed for medical purposes to prevent or correct selenium deficiency in patients.

[0079] The term "dissolved oxygen" (DO) as disclosed herein refers to the level of free, non-compound oxygen present in water or other liquids or solutions, such as solutions for parenteral nutrients. Oxygen saturation (symbol SO 2 ) is a relative measure of the concentration of oxygen dissolved or retained in a given medium as a percentage of the maximum concentration that can be dissolved in that medium. In liquid media, usually water, it can be measured with an oxygen sensor or dissolved oxygen probe such as an optode.

[0080] Dissolved oxygen is usually reported in milligrams per liter (mg / L) or as a percent of air saturation. However, studies also report DO in parts per million (ppm) or in micromoles (μmol). 1 mg / L is equal to 1 ppm. The relationship between mg / L and % air saturation varies with the temperature, pressure, and salinity of the water. One micromole of oxygen is equal to 0.022391 milligrams. Therefore, 100 μmol / L of DO is 0.022391 milligrams. 2 2.2 mg / L O 2is equal to. To calculate the dissolved oxygen concentration from the air saturation, it is necessary to know the temperature and salinity of the sample. The atmospheric pressure is already taken into account as the partial pressure of oxygen which contributes to the percent air saturation. The salinity and temperature can then be used in Henry's Law 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 salinities. This value can then be multiplied by the measured percent air saturation to calculate the dissolved oxygen concentration [Fondriest Environmental, Inc. "Dissolved Oxygen." Fundamentals of Environmental Measurements. 19 Nov. 2013.].

[0081] Oxygenation of a liquid can occur, for example, through exposure of the liquid to a gas containing oxygen. For example, about 21% O 2 Exposure of a liquid sample to an atmosphere containing oxygen 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 similar techniques known to those skilled in the art.

[0082] There are several methods available in the art for measuring dissolved oxygen concentration. Modern techniques include either electrochemical or optical sensors, where the dissolved oxygen sensor is attached to a meter for spot sampling and laboratory applications, or to a data logger, process monitor, or transmitter for deployed measurement and process control. Examples include gaseous and dissolved O 2The fiber optic oxygen meter Microx TX3 from PreSens Precision Sensing GmbH (Germany) for use in water purification plants. The colorimetric method provides a basic approximation of the dissolved oxygen concentration in the sample. There are two methods designed for high and low range dissolved oxygen concentrations. These methods are quick and cheap for basic projects, but are limited in range and subject to errors due to other redox agents that may be present in the water. The traditional method is the Winkler titration.

[0083] The term "shelf life" as used herein relates 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 the defined storage conditions after sealing and sterilization. Depending on the storage conditions, the shelf life may vary.

[0084] The terms "stable", "stably" or "stable" as used herein mean that at least 50%, at least 60%, at least 70%, or at least 80% of the amount of components, particularly compounds with selective gas requirements, provided in the product when produced are still available, preferably after terminal heat sterilization, for at least 6 months, preferably at least 12 months, more preferably at least 18 months, even more preferably at least 24 months, at a temperature of 1° C. to 40° C., such as at a temperature of 1° C. to 30° C. Preferably, at least 80%, at least 85%, at least 90%, and at least 95% of the components, when produced, are still available, preferably after terminal heat sterilization, for at least 6 months, preferably at least 12 months, at a temperature of 1° C. to 40° C., and / or for at least 18 months, preferably at least 24 months, at a temperature of 1° C. to 30° C. The term "when produced" refers to the time immediately prior to terminal heat sterilization.

[0085] In light of the prior art, the technical problem underlying the present invention is to provide a flexible container / multi-chamber container containing at least one solution with selective dissolved gas content for stabilizing at least one compound with such selective gas requirement (e.g., the aforementioned selenium compound in the form of Se(IV)). In particular, the problem concerns providing a multi-chamber bag containing at least two formulations with different dissolved gas requirements, for example, one with the requirement to maintain a very low level of gas for a long time, and another with the requirement to maintain a high or higher level of the same gas for a long time, for the respective stability of the formulations or compounds contained therein. As mentioned above, MCBs are generally prepared from one film material that cannot individually accommodate said diverse gas requirements. Therefore, in certain cases, the film material will be selected to allow the gas to diffuse out of the formulation and be captured by a scavenger located outside the primary container, such as an oxygen scavenger that will consume the oxygen still present to some extent in the formulation where oxygen is not desired. However, this is contrasted with the need to retain the same gas in the second compartment, perhaps oxygen, which must remain over a certain concentration threshold to ensure that at least one compound contained within said compartment remains stable.

[0086] This problem of different selective gas requirements of formulations contained in one multi-chamber bag has not been previously addressed or solved in the prior art. Thus, compounds that require selective dissolved gas content in the formulation as opposed to the requirement of another formulation are not provided in one MCB, but are generally added to the MCB after reconstitution and prior to administration to the patient, or are provided in a second pharmaceutical solution.

[0087] This problem is solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0088] It has been found that there is a relatively simple yet highly effective method of stabilizing compounds with certain selective gas requirements in the above-mentioned containers. The method can be used for monobags made from rigid, semi-rigid or flexible containers, and is particularly suitable for multi-chamber containers in which formulations with very different requirements for such selective gases are stored.

[0089] The present invention therefore relates to a flexible container / multi-chamber container with selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product contained in its compartment(s) or one of the container / multi-chamber container, said container being prepared from a gas barrier film material for the selective dissolved gas in question and a headspace containing said gas, said gas headspace acting as a reservoir for the gas required by at least one compound to be stabilized in the container.

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

[0091] Prior art headspace, for example in containers for pharmaceutical solutions, is sought to be reduced and avoided and, where possible, controlled in a manner that avoids the presence of any non-inert gases, such as oxygen.

[0092] Thus, it is a very different and unobvious approach to stabilize compounds that require certain dissolved gas levels for stability by providing them in a solution contained in a container or container compartment that has an intentionally created headspace, e.g., filled with a reservoir gas that can replenish said dissolved gas lost through the film material, especially when a gas scavenger, e.g., an oxygen absorber, is used to serve the needs of other formulations that can be placed in the same MCB.

[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 gases in question. According to one embodiment, the flexible container / multi-chamber container has a capacity of 5 cc / m 2 / day, less than 2cc / m 2 / day, less than 1cc / m 2 / day, preferably less than 0.5cc / m 2 / day, e.g., 0.2cc / m 2 / day, less than 0.3cc / m 2 / day or less than 0.4cc / m 2 The film is made of an oxygen-impermeable material with an oxygen or carbon dioxide barrier of less than 1000 / day. If the film material has a somewhat lower oxygen or carbon dioxide barrier, the corresponding head space and / or concentration of the selective gas can be increased to preserve more of the selective gas and keep the dissolved gas level above the desired threshold for a long period of time. By using a film material with a higher oxygen barrier, the head space and / or concentration of the selective gas in the head space can be reduced.

[0094] In particular, within a container, such as a multi-chamber container having at least two compartments, it is possible to accommodate one or more formulations with selective gas requirements by deliberate use of the headspace to act as a reservoir of the required gas or gas mixture that can replenish the dissolved gas used up in the solution containing the compound that requires gas for stability, while at the same time a film is used to generate a container with low permeability with respect to said gas, especially when the container contains further compartments and formulations that require low or at least lower levels of the same gas, and therefore gas scavengers are often included inside the package, for example in an overpouch that envelops the primary container containing said various formulations.

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

[0096] According to one embodiment, the selective dissolved gas is oxygen, which is usually avoided as a dissolved gas in pharmaceutical solutions, since it may cause oxidation and decomposition of the active ingredients contained therein.However, the present invention can be equally well applied to other selective gases that are required to maintain the stability of the compounds provided in the pharmaceutical solutions.The present invention expressly does not refer to and / or encompass dissolved gases such as nitrogen or other inert gases that are used to replace any non-inert gas.Therefore, the present invention expressly denies nitrogen.In a preferred embodiment, the selective dissolved gas is oxygen.

[0097] Those skilled in the art will be aware 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 in ppm as a function of temperature (760 mmHg, salinity = 0.0 ppt). Thus, a DO concentration of about 8 ppm corresponds to a solution that is saturated with oxygen at approximately room temperature (about 21°C).

[0098] According to one embodiment of the invention, the DO in the pharmaceutical solution is above 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 a particular embodiment, the compound to be stabilized by the present invention is selenium in its Se(IV) form.Selenium in its Se(IV) form in particular can be provided in pharmaceutical solutions for parenteral nutrition.It is known in the art that, for example, selenium, iodine, and copper are difficult to include in nutrition bags, as they may undergo chemical reactions, especially under extreme conditions such as heat sterilization steps, and during 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. Thus, in one embodiment, the at least one compound is selenium in the form of Se(IV), preferably selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, and the oxygen headspace maintains the solution at a level of 0.5 ppm to 8 ppm dissolved oxygen (DO).

[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 a patient comprising a solution provided in an oxygen-impermeable flexible container for parenteral administration, comprising at least one selenium compound, preferably in the form of Se(IV) selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, characterized in that the solution contains dissolved oxygen (DO), preferably between 0.5 ppm and 8 ppm DO.

[0101] In certain embodiments of the 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 invention, it may be 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 may be preferable to stably formulate the composition according to the invention.

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

[0103] In a preferred embodiment, the solution of the pharmaceutical product of the present invention comprises sodium selenite with selective gas requirements to remain stable in such solution for extended periods of time.Surprisingly, it has been found that the presence of oxygen headspace above 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 at about 0.5 ppm to about 8 ppm results in the stabilization of sodium selenite, selenious acid, and / or selenium dioxide in a solution that would otherwise be protected from exchange of gas with its surroundings, since oxygen is generally expected to participate in redox reactions and is often detrimental to the stability of macro- and micronutrients in the solution.In particular, it has been reported that certain trace elements and vitamins are 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 discovery that the presence of a controlled concentration of dissolved oxygen in a solution, e.g., maintained by a headspace of oxygen above a solution containing sodium selenite, selenious acid, and / or selenium dioxide, either alone or in combination with other sensitive trace elements, e.g., iodine and / or copper, results in the stabilization of these selenium-containing compounds, which are known to be unstable when present in solution, especially in sealed pharmaceutical and nutritional products, which are generally provided in oxygen-impermeable containers to avoid the above-mentioned redox reactions.

[0105] As mentioned above, oxygen-permeable containers are known and used, for example, in Peditrace™, allowing gas exchange between the interior of the container and the ambient air, but most parenteral products are provided in oxygen-impermeable containers due to the redox sensitivity of the nutritional components contained. On the other hand, oxygen-permeable containers no longer provide a defined and stable oxygen concentration, which has been found to be a prerequisite for providing long-term stability, especially for sensitive compositions of various trace elements. In contrast, oxygen levels are subject to changes, for example based on temperature or height (pressure), and unfavorable conditions, for example during sterilization, transportation or storage, can result in the decomposition and loss of sensitive compounds, such as selenium in its Se(IV) form, even if the container is then stored again under suitable conditions that better result in the replenishment of the dissolved gas lost in the container, such as oxygen, through the oxygen-permeable film.

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

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

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

[0109] In the context of the present invention, the phrase "stable" or "controlled" concentration of a dissolved gas means that the concentration of the dissolved gas does not drop below a given threshold value over the complete shelf life of a product containing a pharmaceutical solution that includes an ingredient with a selective gas requirement. It does not mean that the concentration of the selective dissolved gas is the same at any time from production to the end of the shelf life, but rather that its loss or consumption can be controlled in a manner that maintains a certain minimum concentration throughout the entire shelf life.

[0110] For example, "a controlled concentration of dissolved oxygen in the solution of 0.5 ppm to 8 ppm" refers to a dissolved oxygen (DO) concentration that remains within the range of 0.5 ppm to 8 ppm throughout the shelf life of the pharmaceutical product of the present invention, with 8 ppm being approximately the oxygen saturation of the solution of the present invention. In other words, it is not necessary that the exact oxygen concentration of the solution in the pharmaceutical product remains stable, but it is required that the concentration does not fall below this range, i.e., below 0.5 ppm, throughout the shelf life. Thus, 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 of the present invention, a controlled concentration of dissolved oxygen in solution of 0.5 ppm to 8 ppm is maintained by an oxygen headspace above the solution in one chamber of a flexible / multi-chamber container. In one embodiment, the chamber contains a stable (and controlled) concentration of dissolved oxygen in solution of 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 during the shelf-life. In certain embodiments, the dissolved oxygen (DO) in the Se(IV)-containing solution does not fall below 0.5 ppm throughout the shelf-life of the pharmaceutical product.

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

[0114] In one embodiment, the solution is a sterile solution, such as, for example, a terminal heat sterilization solution.

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

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

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

[0118] As already mentioned, headspace may generally be avoided or minimized to the extent that it is possibly considered to be an undesirable interaction between the gas contained therein (ambient air) and the liquid (or solid) content within the container (see, e.g., US20030110736A1).

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

[0120] In some embodiments, the selective gas is oxygen. In such a case, the gas composition in the headspace containing oxygen may be ambient air containing about 78% nitrogen, 21% oxygen, and about 1% other gases. However, in certain embodiments, the gas composition in the headspace containing oxygen may be an oxygen-rich gas composition, which may be composed almost exclusively of oxygen, especially when the headspace volume is to be reduced. In certain embodiments, the gas composition of the headspace may comprise about 10 to about 100% oxygen, e.g., 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 known to those skilled in the art, higher oxygen levels are not recommended due to the risk of fire or explosion, especially during production.

[0121] In the case of ambient air, the volume of the headspace may be the same as or higher than the normal headspace remaining in the container or compartment providing 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 / multi-chamber container of the present invention.

[0122] For example, for a 25 ml selenium(IV) solution containing about 70 μg 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 greater than about 10%, 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% of the volume of the selenium solution.

[0123] In general, the volume of the selective gas headspace according to the present invention may range from about 5% to 100% of the volume of the pharmaceutical solution containing the compound having the selective gas requirement, for example within the range of 10% to 60%, for example 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 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 54, about 55, about 56, about 57, about 58, about 59, about 60, about 61, about 62, about 63, about 64, about 65, about 66, about 67, about 68, about 69, about 70, about 71, about 72, about 73, about 74, about 75, about 76, about 77, about 78, about 79, about 80, about 81, about 82, about 83, about 84, about 85, about 86, about 87, about 88, about 89, about 90, about 91, about 92, about 93, about 94, about 95, about 96, about 97, about 98, about 99, about 10 It may be 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 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, about 50, about 51, about 52, about 53, about 55, about 56, about 57, about 58, about 59, or about 60%.

[0124] For example, for 25 ml of selenium solution sealed in a chamber of a flexible / 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, e.g., about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11 ml, or about 12 ml. For other volumes of selenium solution, one skilled in the art can calculate the corresponding volume of headspace based on the present disclosure.

[0125] As disclosed herein, the volume of the head space of the gas can be adjusted accordingly when different gas compositions are used.For example, in the case of gas with abundant oxygen content, smaller head space can be used as is clear to those skilled in the art, and can be calculated based on the above ratio shown for ambient air, and / or can be calculated by routine experimentation according to the compound that is stable in pharmaceutical solution.

[0126] In certain embodiments of the flexible container / multi-chamber container of the present invention, the headspace of ambient air or oxygen and the dissolved oxygen (DO) in the solution stabilize at least one selenium compound in the form of Se(IV), such as sodium selenite, selenious acid, and / or selenium dioxide, alone or in combination with other trace elements, for at least three months in solution when stored at a wide range of temperatures ranging between about 1° C. and about 50° C. Instead of sodium selenite, other salt forms such as potassium selenite, lithium selenite, calcium selenite, or magnesium selenite may be used as well. Thus, when sodium selenite is mentioned, it should be understood as merely a preferred example of such alternatives. It was surprising and unexpected that comparative experiments could demonstrate that the listed selenium-containing compositions were stabilized in solution during various temperatures tested ranging from about 1° C. to about 50° C. over extended 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 solutions according to the present invention stabilizes sodium selenite, selenious acid, and / or selenium dioxide, alone or in the presence of other trace elements, in solution for at least 3 months when stored at up to about 40° C. Further, in certain embodiments, the ambient air or oxygen headspace and dissolved oxygen (DO) in solutions stabilizes sodium selenite, selenious acid, and / or selenium dioxide, alone or in the presence of other trace elements, in solution for at least 6 months when stored at up to about 40° C.

[0128] In a further embodiment of the invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solutions of the present invention stabilize sodium selenite, selenious acid, 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 invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solutions of the present invention stabilize sodium selenite, selenious acid, 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 temperatures up to about 30° C.

[0130] In yet other embodiments of the invention, the ambient air or oxygen headspace and dissolved oxygen (DO) in the solutions of the invention stabilize sodium selenite, selenious acid, 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, at temperatures of about 18° C. to about 25° C.

[0131] In yet other embodiments of the present invention, the dissolved oxygen (DO) in the ambient air or oxygen headspace and solutions of the present invention is stabilized in solution with sodium selenite, selenious acid, 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, and most preferably at least 24 months at normal storage temperatures, including but not limited to room temperature, temperatures ranging from about 15° C. to about 30° C., more preferably from about 18° C. to about 25° C., or storage under refrigerated conditions, including for example from about 1° C. to about 10° C., preferably from about 2° C. to about 8° C., or from about 3° C. to about 7° C.

[0132] According to another embodiment of the 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 may be placed in an MCB where different compartments have different requirements for carbon dioxide. Thus, the disclosure made herein regarding oxygen is equally applicable and valid for carbon dioxide.

[0133] According to one embodiment of the present invention, the selective gas is carbon dioxide (CO 2 According to yet another embodiment, the compound with the selective gas requirement is a bicarbonate, e.g., sodium bicarbonate. Bicarbonate and carbon dioxide in an aqueous solution are connected via the following formula: [ka]

[0134] Loss or permeation of carbon dioxide, for example from the sodium bicarbonate solution, results in an increase in the sodium carbonate content and thus an increased pH level. Furthermore, loss of carbon dioxide results in a decrease in the desired content and / or availability of bicarbonate ions in the final mixed composition of the sodium bicarbonate component solutions. However, bicarbonate is required in such pharmaceutical solutions. Carbonate, in turn, tends 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, a large amount of dissolved carbon dioxide is considered undesirable in another compartment of the MCB, as it may lower the pH to values ​​that are not beneficial to the compounds located therein. Loss of carbon dioxide is therefore to be avoided or controlled as best as possible. CO2 from and between the bicarbonate and other solutions, particularly in the MCB, is a major problem. 2 It is also important to have proper control over the extent of the transition. 2 Improved control and limitation of the amount of gas may also provide the opportunity to eliminate the need for overwrap.

[0135] Known methods of obtaining some control include the use of a gas impermeable primary film and / or overwrap. The volume occupied by the overwrap is necessarily greater than the volume of the flexible bag container containing the bicarbonate and other solutions, so that there is no CO2 within the overwrap that escapes from the bicarbonate solution itself. 2There is always a volume that can accommodate the gas. As with oxygen, a carbon dioxide barrier material can be used to limit the loss of carbon dioxide in the primary bag material as well as any loss through the overpouch. The primary bag can therefore be designed to contain a nylon layer. The overpouch can also be made from or include nylon. For example, the overpouch can be made of various layers: Al, with adhesive layers between them, and supported by a polypropylene copolymer. 2 O 3 The film may be a laminated film composed of PVDC and nylon.

[0136] For example, U.S. Patent No. 7,491,411 (B2) describes a multiple compartment flexible bag assembly including a first predetermined volume of an aqueous sodium bicarbonate solution contained in at least one of the multiple compartments and a second predetermined volume of an aqueous acid component solution contained in at least another of the multiple compartments, where the aqueous acid component solution includes a quantity of dissolved carbon dioxide, and mixing of the bicarbonate component solution with the acid component solution causes the bicarbonate solution to dissolve in CO 2 CO2-free solution 2 Exposure to the environment of the containing solution then allows carbon dioxide to migrate across the packaging material from the acid component solution into the gas impermeable overwrap flexible bag, thereby limiting the amount of carbon dioxide that can migrate from the sodium bicarbonate component solution into said overwrap flexible bag. However, in this case, both compartments are tolerated, thereby utilizing the presence of carbon dioxide.

[0137] According to the present invention, similar to that described for MCBs where one compartment contains a compound that requires higher dissolved oxygen levels (e.g., sodium selenite or selenium dioxide), the headspace can be used to provide a reservoir of carbon dioxide, particularly when the second compartment cannot tolerate higher dissolved carbon dioxide levels and approaches described in the prior art cannot be used.

[0138] In particular, when contained in one compartment of an MCB that would otherwise contain formulations with different requirements, it is an important advantage that a pharmaceutical solution containing a compound with selective gas requirements can be prepared and sterilized after packaging in a flexible bag prepared from an oxygen-impermeable material that can be sealed air-tight and liquid-tight without significant loss of the compounds provided therein, in particular sodium selenite, selenious acid, and / or selenium dioxide, alone or in the presence of other components, such as further trace elements, vitamins, or macronutrients, such as glucose. For example, the present invention stabilizes sodium selenite, selenious acid, and / or selenium dioxide in a separate dedicated chamber of the MCB, but also in, for example, the glucose chamber of a multi-chamber bag for parenteral nutrition, in a self-contained glucose solution for parenteral nutrition, or in a self-contained pharmaceutical solution, for example, containing certain vitamins and / or trace elements.

[0139] In certain embodiments, the solutions of the invention are subjected to terminal heat sterilization after preparation of the solutions and filling into flexible containers. Sterilization may occur before or after filling of the solutions into flexible bags of pharmaceutical products of the invention, with terminal sterilization, especially heat sterilization, of the filled and sealed flexible container being preferred.

[0140] It is highly preferred that the flexible container / multi-chamber container or the chamber of the flexible container / multi-chamber container containing the compound requiring gas is impermeable to said gas. For example, if the gas is oxygen or carbon dioxide, an oxygen or carbon dioxide impermeable material should be used. For example, the flexible container / multi-chamber container or the chamber of the flexible container / multi-chamber container containing the solution containing selenium should be impermeable to 5 cc / m 2 / day, less than 4cc / m 2 / day, less than 3cc / m 2 / day, less than 2cc / m 2 / day, less than 1cc / m 2 / day, preferably less than 0.5cc / m 2 The device may be made of a material that has an oxygen barrier of less than 100 MPa / day.

[0141] As previously stated, a lower gas barrier should accompany a larger headspace and / or a higher concentration of the selective gas. A higher gas barrier of the film material may reduce the headspace volume and / or the concentration of the selective gas.

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

[0143] The sterilization of the present invention may be performed by a terminal heat sterilization process, but also by using a terminal filtration, gamma irradiation, or any other sterilization technique. The solution of the flexible container / multi-chamber container of the present invention may also be filled into the flexible container / multi-chamber container by an aseptic filling process that ensures that no contamination of the essentially sterile solution occurs during filling and before sealing of the flexible bag. In some embodiments, the solution may be sterile, but is not necessarily sterile. 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 concentration of dissolved oxygen (DO) in the solution is greater than 0.8 ppm and less than or equal to 2 ppm.

[0145] In certain embodiments of the 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 about 1 to about 2 ppm, or about 0.5, about 0.75, about 1, or about 2 to about 8 ppm, such as 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 ranges indicated include the stated end values. Ranges including any combination of the disclosed values ​​are considered embodiments of the invention.

[0146] In some embodiments, the concentration of dissolved oxygen (DO) in the solution maintained by the 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 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 the 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 the ambient air or oxygen headspace may decrease during 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, and preferably sealed.

[0149] In certain embodiments, it is believed that the dissolved oxygen (DO) concentration in the solution can decrease in the pharmaceutical product after filling, sealing, and sterilization, and during the shelf life of the product, 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 in the chamber over time, and thus the oxygen concentration may decrease. Therefore, it is preferred that the dissolved oxygen (DO) concentration is at least 6 ppm, for example in the range of 6 ppm to 8 ppm, when filling and sealing the pharmaceutical solution according to the present invention in the chamber of the flexible container / multi-chamber container. Such a high dissolved oxygen (DO) concentration at the time of filling and sealing ensures that the dissolved oxygen (DO) concentration remains stable above 0.5 ppm during the shelf life of the product, meaning that the DO concentration does not fall below 0.5 ppm even if oxygen consumption and / or loss occurs through the film material in the chamber.

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

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

[0152] In a preferred embodiment, the flexible / multi-chamber container or chambers thereof containing a solution containing at least one selenium compound in the form of Se(IV) further comprises a headspace of a gaseous composition comprising oxygen, the sealed chamber being oxygen impermeable, and the dissolved oxygen (DO) in the solution upon filling, preferably sealing, of the chamber is at least 6 ppm. In such an embodiment, the dissolved oxygen (DO) in the solution has been shown to be equal to or greater than, or remain equal to or above, 0.5 ppm throughout the 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 adequate to stabilize selenium-containing compounds alone and especially in combination with other sensitive trace elements is of great advantage in the context of the pharmaceutical products of the present invention, since the dissolved oxygen (DO) concentration can be easily established without complex technical measurements or manipulation of the solution.

[0154] It will also be readily apparent to those skilled in the art that other parameters may have to be adjusted to further improve the stability of compounds with selective gas requirements, such as selenium in the form of Se(IV), to remain stable in pharmaceutical solutions over extended periods of time. For example, the pH may have to be adjusted and / or incompatibilities with other possible compounds in the formulation will have to be taken into account.

[0155] For example, solutions 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, more preferably about 2.5 to about 3.2. However, for long-term stability, the dissolved oxygen content becomes crucial. Furthermore, the solutions of the present invention are particularly advantageous in that the sodium selenite, selenious acid, and / or selenium dioxide are stable 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, at about neutral pH in the range of about 7 to about 7.5, as well as at acidic pH. Selenium in solution in the flexible / multi-chamber containers according to the invention is particularly stable at acidic pH, such as pH values ​​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 are inclusive of the stated end values. Ranges including any combination of the disclosed end values ​​are considered embodiments of the invention.

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

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

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

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

[0160] In the context of the present invention, oxygen impermeable materials (e.g., 2 cc / m 2 / day, less than 1cc / m 2 / day, preferably less than 0.5cc / m 2 The solution in the multi-chamber container, preferably made from a selenium-containing aqueous solution (e.g., any material with an oxygen barrier of less than 1000 ppm / day), comprises at least one compound selected from the group consisting of selenite, e.g., sodium selenite, selenious acid, and selenium dioxide, and is characterized in that the solution comprises about 1 ppm to about 8 ppm of dissolved oxygen (DO).

[0161] Sodium selenite has the formula Na 2 SeO 3 The salt is a colorless solid. 2 SeO 3 (H 2 O) 5 is the most common water-soluble selenium compound. Selenous acid (or selenious acid) has the formula H 2 SeO 3 Structurally, it is a compound having the structure H 2 SeO 3 This is the principal oxoacid of selenium; the others are selenoic acids. Selenium dioxide has the formula SeO 2 It is a colorless solid. It is one of the most frequently encountered compounds of selenium.

[0162] In some embodiments, the 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, the at least one selenium compound is selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide.

[0164] In some embodiments, the 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 2, at least 3, at least 4, at least 5, or at least 6 chambers. In some embodiments, the headspace settings of the multi-chamber container may be applicable to certain existing multi-chamber containers having at least 2, at least 3, at least 4, at least 5, or at least 6 chambers.

[0166] For example, US Patent Publication No. 2009 / 0166363(A1) (Baxter) discloses a multi-chamber bag (MCB) with at least a fourth chamber (see claim 20). EP 790051 A1 (B. Braun) shows a four-chamber bag that also includes a smaller chamber. EP 2568947 A1 (B. Braun) shows a three-chamber bag with a port tube for filling from one side. US Patent No. 8,343,128(B2) (Otsuka) shows a configuration with a small chamber. US Patent No. 5,267,646 A (Otsuka) contains another example for including a small chamber that may contain a special compound (i.e., a drug, TE) that has certain requirements regarding gas levels / presence.

[0167] In some embodiments, the multi-chamber container of the present invention comprises at least 5 chambers.

[0168] In certain embodiments, the multi-chamber container of the present invention comprises either five chambers or six chambers.

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

[0170] In certain embodiments, the solution in the fourth chamber of the multi-chamber container comprises about 0.5 ppm to about 8 ppm of dissolved oxygen (DO) maintained by a headspace of ambient air or oxygen.

[0171] In certain embodiments, the solution in the fourth chamber of the multi-chamber container comprises dissolved oxygen (DO) equal to or greater than 1 ppm maintained by a headspace of ambient air or oxygen.

[0172] In an embodiment of the 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 process of sterilization. Sterilization refers to any process that eliminates, removes, kills, or inactivates all forms of life (particularly referring to microorganisms such as fungi, bacteria, viruses, spores, single-cell eukaryotes, e.g. Plasmodium) and other biological agents, such as prions, present on a particular surface, object, or fluid, e.g. food or biological media. 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, the object is said to be sterile or aseptic.

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

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

[0175] Exposure to radiation is another sterilization method used throughout industry. Gamma radiation is the most common, but other options include infrared and ultraviolet radiation and high-speed electrons. Radiation is typically used to sterilize single-use components / systems, but can be used on packaged drug products.

[0176] Treatment with gases 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 via filtration is the only option when other processes are not appropriate for a particular product or ingredient. In filtration, the final drug product solution is produced under aseptic manufacturing conditions and passed through a filter designed with the appropriate pore size / surface chemistry to remove bacteria via size exclusion, entrapment, electrostatic attraction, and other modes.

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

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

[0179] In certain embodiments, the volume of the multi-chamber container is about 35% to 45% of the volume of the solution in the fourth chamber of the multi-chamber container.

[0180] In certain embodiments, the ambient air or oxygen headspace of the fourth chamber of the multi-chamber container stabilizes the at least one selenium compound for a time 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 30° C.

[0181] In certain embodiments, the multi-chamber container is stored at a temperature between about 18°C ​​and about 25°C.

[0182] In the context of the present invention, the pharmaceutical solution is provided in one sealed chamber of a multi-chamber container with a headspace of ambient air or an optional gas such as oxygen. In certain embodiments of the present invention, the solution is contained and sealed in one chamber of a multi-chamber container having at least 2, at least 3, at least 4, at least 5, or at least 6 chambers with a headspace of ambient air or oxygen.

[0183] Preferably, the seal around the compartment containing the medical solution and headspace according to the present invention should be airtight. The filling port may form a potential gas leak through which the necessary gas according to the present invention may be lost from the medical solution. Therefore, care should be taken in the use of airtight ports or their removal after filling if not required later, for example as a medical or injection port according to an embodiment of the present invention.

[0184] As used herein, the term "flexible container" or "multi-chamber container" refers to a container or bag made of a flexible material, such as a bag made from a plastic film. This term does not encompass polymeric rigid or semi-rigid containers.

[0185] The flexible container or bag of the present invention can be made of 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 elastomeric copolymers, essentially any synthetic material suitable for containing the ingredient to be administered, including laminate materials.

[0186] Oxygen-impermeable flexible containers are known in the art and are made with gas barrier films that block the migration of oxygen to the outside of the container. Various techniques have been developed to provide an oxygen barrier to transparent films, such as polyolefin or polyethylene terephthalate films. The main techniques are: (1) high-barrier materials, generally inorganic oxide layers (e.g., SiOx or Al 2 O 3 (2) multilayer films, in which the inner layer is a barrier material, such as EVOH, polyamide, aluminum, halogenated polyvinylidene, such as PVDC, amorphous or crystalline nylon or a combination of both, a copolymer of ethylene vinyl alcohol copolymer layer (EVOH), polyolefin, including a combination of two or more of the above layers, and the outer layer is made of a structural polymer, such as PE, PP, or PET. For example, EVOH has one of the lowest reported oxygen transmission rates among the polymers commonly used in packaging. By chemical structure, EVOH is a semi-crystalline copolymer of ethylene and vinyl alcohol monomer units.

[0187] In one embodiment, the flexible or multi-chamber container has a capacity of 5 cc / m 2 / day, less than 2cc / m 2 / day, preferably less than 1cc / m 2 / day, preferably less than 0.5cc / m 2 It may be made of materials with a high oxygen barrier of less than 1000 psi / day (30°C / 70% RH).

[0188] "Oxygen transmission rate", also called "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 one-day period; cc / m 2 It is expressed as per day (or 24 hours) and is measured at a standard temperature of 23°C and 0% relative humidity (RH).

[0189] Therefore, the present disclosure also provides a flexible container, preferably a multi-chamber container for parenteral or nutritional preparations, which can be prepared from any of the flexible films described above.Generally, a person skilled in the art can select a suitable film that has a sufficiently low gas barrier according to the present invention, such as a low oxygen or carbon dioxide barrier.For example, the container can be in the form of a bag with one or many compartments or chambers.The container, such as a bag, can include at least two chambers, but can also contain three, four, five, or six or more chambers, in one preferred embodiment two or three chambers, or in another preferred embodiment 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 nutrition products for adults, children, and newborns, and can provide a carbohydrate formulation disclosed herein in a first chamber, an amino acid formulation disclosed herein in a second chamber, and a lipid formulation disclosed herein in a third chamber of the container.

[0191] The multi-chamber container may include a vertical chamber as disclosed in US Patent Application Publication No. 2007 / 0092579. For example, the multi-chamber container may be configured as a bag containing 2, 3, 4, 5, or 6 adjacent chambers or compartments. If desired, a frangible barrier or releasable seal (e.g., peel seal or frangible seal) is used to separate the chambers of the multi-chamber container. The multi-chamber container may include three chambers containing a lipid emulsion, a carbohydrate formulation, and an amino acid formulation, and may further include at least one, and in certain embodiments, two or three smaller chambers containing, for example, a vitamin formulation and / or a trace element formulation. In certain embodiments, 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 formulation, a third chamber containing a carbohydrate formulation, a fourth chamber containing a vitamin formulation, and a fifth chamber containing a trace element formulation.

[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 contents after mixing of the formulations contained in each chamber. Such MCBs may have 2, 3, 4, 5, 6 or more chambers. The chambers of said MCBs may have the same size or may have different sizes to accommodate different compositions and volumes. The chambers may be designed to contain volumes of, 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, about 1000 to about 1500 ml. The MCB may be designed to have chambers arranged adjacent to each other. The chambers may have various shapes. The chambers may be oriented horizontally and / or vertically relative to each other. Certain smaller chambers can be designed to be positioned within another larger chamber, for example a smaller chamber disposed within another larger chamber can be received and secured within the larger chamber by welding at least one edge of the smaller chamber between the weld seams of the surrounding larger chamber.

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

[0194] The multi-chamber container may include instructions explaining the desired sequence of which peel seals to open so that the component fluids are mixed in the desired sequence. The opening strengths of the two or more peel seals may be varied to facilitate opening of the seals in the desired sequence. For example, the opening strength of the peel seal to be opened first may be 1 / 3 to 1 / 2 the opening strength required to open the peel seal to be opened second.

[0195] In some embodiments, the multi-chamber container comprises at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, and optionally a third chamber containing a lipid formulation, 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, selenious acid, and / or selenium dioxide further comprises a headspace of ambient air or oxygen.

[0196] Carbohydrate preparations provide a supply of calories, typically in the form of glucose, and in particular provide a sufficient amount of carbohydrate to avoid adverse effects such as hyperglycemia observed in patients receiving parenteral nutrition. EXAMPLES

[0197] The present invention is further described by the following examples, which do not limit the scope of the invention but rather represent preferred embodiments of aspects of the invention, provided to further illustrate the invention described herein. Example 1 Tests performed with oxygen semi-permeable and oxygen impermeable barrier films

[0198] Tests were performed on two different films, an oxygen semi-permeable film and an oxygen impermeable film.

[0199] The semi-permeable film is a coextruded film with the following structure: PP|Tie|PA|Tie|PP / SEBS / LLDPE, in which 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 polar and non-polar repeating units and functional reactive groups or without functional reactive groups, which is used to improve adhesion between the main layers of a multi-layer film. The oxygen barrier of the film is the polyamide layer (about 50 cc / m 2 / day). Such films are described, for example, in US Patent Application Publication No. 2010 / 0247935(A1). Semi-permeable films allow some oxygen to pass through.

[0200] The oxygen impermeable film is made from a co-extruded polyolefin material laminated to polyester by vapor deposition of silicon oxide coated with a barrier layer to provide an oxygen barrier; i.e., the oxygen barrier provided by this particular PET-SiOx is <0.5 cc / m 2 / day. In the studies shown in Figures 1 and 2 (Figures 2A and 2B), 1 dd / 25 ml of sodium selenite was present at pH 3.0 ± 0.2. 100 mM malic acid was also present in a 50 ml monobag with a one-port tube, made of either the semi-permeable or oxygen-impermeable materials mentioned above.

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

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

[0203] As shown in Figure 1, DO dropped quickly from saturation to essentially 0 ppm DO within about 3 months in both cases, but even faster in the EU2S semi-permeable condition due to the effect of the oxygen absorber. After that, DO was essentially 0 ppm in both samples.

[0204] Thus, the dissolved oxygen (DO) was reduced even when an oxygen barrier film was used. It was found that the components in the solution, including other components (trace elements, malic acid), consumed the dissolved oxygen (DO) even though they were no longer lost by permeation through the film. In the presence of malic acid, this was more pronounced. Without wishing to be bound by theory, it is assumed that the redox potential in the solution favors the consumption of oxygen (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 more than 80% over a period of 5 months. This was achieved by having a dissolved oxygen (DO) of more than 6 ppm at the time of loading, preferably 6-8 ppm (essentially to saturation).

[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 the dissolved oxygen (DO) rapidly dropped below the threshold of 0.5 ppm even when an oxygen impermeable film was used without a headspace (as opposed to the above setup with a headspace included).

[0207] It could therefore be shown that the headspace filled with ambient air provides a certain "oxygen stock" to replace the oxygen lost from the container. Oxygen from the headspace slowly becomes dissolved in the solution until equilibrium is reached. Thus, the dissolved oxygen (DO) can be maintained above 0.5 ppm over time when headspace is present. In the absence of headspace (grey filled circle), selenite cannot stabilize due to the loss of dissolved oxygen (DO) over time.

[0208] The port tube is another aspect that may contribute to dissolved oxygen (DO) loss, since it must be sealed between the film layers and it is difficult to make this seal completely oxygen-tight. Therefore, it is advantageous to improve the oxygen-tightness of the port tube used in the setup described herein, or to completely remove the port tube when possible. In FIG. 3, it becomes clear that without headspace and without port tube (open black circle), the dissolved oxygen (DO) is higher over time compared to the port tube present (grey filled circle), and a headspace of e.g. 5 ml cannot fully compensate for the loss of the port tube (open black triangle). Preferably, when possible, there is a headspace and no port tube, in order to stabilize the solution containing selenite in the oxygen barrier bag. In such a setup, the dissolved oxygen (DO) can essentially be maintained (grey filled triangle).

[0209] FIG. 4 focuses on the volume of the headspace. As can be seen, and as discussed above, headspace is required to maintain the required DO level in the composition, and the oxygen present in the solution at the time of filling is consumed by the components present in the solution (DO is consumed by redox reactions in the solution, see open black circle, dashed line) and would otherwise be lost from the container. Neither 25 ml container / chamber volume nor 2 ml headspace per 15 ml solution is completely sufficient (black triangles). With 6 ml headspace, the threshold of 0.5 ppm can be almost met even in the presence of a port tube (grey square, continuous line), and is completely sufficient in the absence of a port tube (grey square, dashed line). The best results are obtained with 10 ml headspace per 15 ml solution of the chamber / container (grey square, continuous line), even in the presence of a port tube (grey filled circle, dashed line).

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

[0211] Flexible multi-chamber containers made from polymeric films for storing and holding separate solutions have become widespread, especially in the medical field, and more particularly in parenteral nutrition.

[0212] In most cases, these containers are made from polymeric films with low or moderate gas barrier properties. For many other nutritional parenteral nutrition (PN) or drug products, the gas of concern is primarily oxygen. If one of the solutions is to be protected from oxygen for stability reasons, all solutions will usually be formulated with low oxygen content. Even if only the sensitive solution is formulated with low oxygen, the system will move quickly to equilibrium between the various chambers without the possibility of having selective gas contents in the chambers.

[0213] Furthermore, parenteral nutrition systems are usually packed in a secondary overwrap that is flushed with an inert gas or contains an oxygen absorbing sachet, both of which play a significant role in the rapid movement towards equilibrium between the chamber and the overwrap annular space.

[0214] The present invention describes how the use of specifically high barrier polymeric film materials, the elimination of any potential components with low barrier properties, and the addition of a gas headspace to the system allows selective dissolved gas contents to be maintained within the chamber over long term storage.

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

[0216] For purposes of the present invention, the plastic film material used to make the container is one that has outstanding gas barrier properties. In the case of parenteral nutrition, the gas of interest is oxygen. For this particular purpose, the oxygen permeability is preferably less than 0.5 cc / m 2 / day (30°C / 70% RH). This can be achieved with a coextruded film containing a layer of ethylene vinyl alcohol copolymer (EVOH). However, PN products are usually moist heat sterilized, and the EVOH material loses part of its barrier upon moist heat sterilization. Therefore, this material is not suitable.

[0217] A preferred option is to use a laminate structure incorporating a base polymer layer with a vapor deposition of silicon oxide or aluminum oxide. Additional barrier-containing layers may be added for better performance.

[0218] In the experiments shown in Figures 5-9, a structure laminated with GL-RD material from TOPPAN was used. A three-chamber container was fabricated with this particular film. The size of the chambers was reduced by sealing to fit 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 a dissolved oxygen concentration below 1 ppm. Chamber C in Figure 5 was filled with 25 mL of water with ambient air (dissolved oxygen approximately 8 ppm).

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

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

[0222] In a second experiment, 5 mL of air headspace was added to chamber C of Figure 5. As shown in Figure 7, the drop in dissolved oxygen during is slower but remains highly significant with values ​​between 2 ppm and 3 ppm after 3 months of storage at 40°C.

[0223] The container shown in FIG. 5 is sealed with at least one fill port tube per compartment. These fill port tubes are manufactured by coextrusion. It is not easy to design such tubes so that they can present a high oxygen barrier. As discussed above, the use of a layer of EVOH polymer is not a good option since this polymer loses its barrier properties during moist heat sterilization. The addition of a PVDC layer is not desirable for sustainability reasons. The use of nylon improves the barrier only moderately.

[0224] This tube formulation does not exhibit any particular barrier properties and therefore it is assumed that the drop in dissolved oxygen in the small compartment results from permeation of oxygen towards the filled tube wall.

[0225] FIG. 8 shows another exemplary multi-chamber container similar to that of FIG. 5, but with a seal added to isolate any fill tube from chamber C.

[0226] A third experiment was performed in chamber C of the multi-chamber vessel of FIG. 8, filled with 25 mL of water, with 5 mL of additional air headspace, and with a seal added to isolate the tubing from chamber C.

[0227] FIG. 9 shows the results of this third experiment, where the dissolved oxygen levels are still about 8 ppm after 3 months storage at 40° C., and about 6 ppm after 6 months storage at 40° C.

[0228] The above results indicate that the use of a specifically high barrier polymeric film material, removal of a component with low barrier properties (fill tube), and addition of a gas headspace to the system allows for the maintenance of high dissolved oxygen content selectively in one chamber over extended storage, despite low dissolved oxygen in the other chambers and overwrap annular space.

[0229] Although a three-chamber bag is used as described above, the present invention may also be used with any multi-chamber container or bag, e.g., a five-chamber bag, a six-chamber bag, a four-chamber bag, or a two-chamber bag of "amino acid / dextrose" in which at least selenium, in the form of trace elements or selenite, is contained in the dextrose chamber in an oxygen environment, whereas the amino acids would remain in those chambers in an oxygen-free environment.

[0230] Alternatively, a primary film without specific barrier properties can be used, but a chamber that is supposed to have a different dissolved oxygen content should then be protected. A known way to proceed is to cover this particular chamber with a peelable piece of foil that protects that chamber from gas transfer.

[0231] This technology is used in two-chamber bags "solid / diluent" to protect the compartment containing the solid drug from moisture (e.g. double container from BBraun). However, this process is technically more complicated, especially for products that must withstand moist heat sterilization. Example 5 6-Month Accelerated Study

[0232] Figure 10 shows the dissolved oxygen levels in the trace element chamber with a very high barrier primary film, a small headspace of air (5ml), and removal of the port tube (seal & cut process) which should remain at significant oxygen levels. As shown in run 5 of Figure 10, the dissolved oxygen levels remain above 5 ppm after 6 months storage at 40°C.

[0233] In comparison, Figure 11 shows the stability of low levels of dissolved oxygen in a chamber filled with low dissolved oxygen media. As shown in run 5 of Figure 11, similar dissolved oxygen levels to those before sterilization remain after 6 months of storage at 40°C.

[0234] Table II shows the dissolved O in the TE chamber. 2(ppm), and Table III shows the dissolved O in the AA chamber. 2 Tables 1 and 2 show the DO evolution in the trace element chamber and 2 show the DO evolution in the amino acid chamber, respectively, to demonstrate that this approach can be used in MCBs and chambers with different oxygen requirements. In the AA chamber, the DO content is low at the time of filling because the chamber and solutions are typically flushed with nitrogen to lower the oxygen content. This must be done if a highly oxygen impermeable film is used, since low oxygen can be removed, for example, by passing the film from the AA chamber and being captured by an oxygen absorber / scavenger placed in the overpouch. In the TE chamber, the oxygen content is boosted to about 8 ppm and kept relatively high as soon as a headspace reservoir containing oxygen (e.g., ambient air) is available. [Table 2] [Table 3] Example 6 Evaluation of various factors related to the stability of selenite

[0235] A full factorial design of experiments (DoE) was developed to evaluate the effect of five factors on the stability of selenite.

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

[0237] Solution pH: All previous studies were carried out at pH < 3.5 to ensure the stability of Fe. Comparison with the natural pH > 7 obtained by simple dilution of selenite in MilliQ water allowed the assessment of the impact of this parameter.

[0238] Sterilization: A terminal heat sterilization was performed on the samples which may initiate degradative chemical reactions due to heat exposure. Non-sterilized vs. sterilized samples were compared with respect to selenite stability to assess the impact of this process step.

[0239] Storage temperature: Accelerated stability studies are routinely performed at 40° C. However, selenite may be sensitive to it, so a comparison with samples stored at 5° C. was performed.

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

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

[0242] The following readings were taken to assess the influence of the factors listed above:

[0243] Se assay to assess selenium degradation.

[0244] Visually inspect the sample to detect any precipitates, particles, or discoloration.

[0245] pH measurements to assess the evolution of sample pH after 6 months of storage.

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

[0247] Redox potential measurements when selenite is involved in different Se redox couples. Information on the redox potential of the solution can help understand the stability of this element.

[0248] For almost all 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 suggest that in samples flushed with nitrogen and stored in oxygen-permeable plastic bags, the observed decomposition of selenium is probably due to the 2 Selenite SeO in Se / HSe- 3 This allowed the conclusion that the reduction of SeO2 was responsible for the volatile forms of Se known to emit a foul odor similar to that of sulfurous gases. The pH / redox diagram presented in Figure 12 shows that the reduction of SeO2 in these volatile species in a completely oxygen-free medium is 3 The conversion of is shown below. Example 7 Effect of DO on selenium stability

[0250] The effect of oxygen appears to be of major importance in the stability of selenite. In fact, some amount of oxygen penetrating into a solution initially flushed with nitrogen but stored in a glass bottle certainly blocks the reduction reaction and reduces the amount of SeO 3 The stability of Se was maintained at 40°C. To confirm this assumption, regression tests were performed between the Se assay results and log(dissolved oxygen results). Only sterilized samples stored at 40°C were considered, since both sterilization and storage at higher temperatures appear to increase Se degradation. In fact, most reaction kinetics are accelerated by heat, explaining why samples kept unsterilized at 5°C for 6 months do not show degradation as significant 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 few samples used in this regression study, it can be considered as a significant representative. Dissolved oxygen content is therefore the most influential parameter and a CQA (Critical Quality Attribute) in selenium stability. As shown in the figure, a low oxygen amount of about 0.5 ppm can be sufficient to ensure the stability of selenite in solution, and saturation may not be required.

[0252] The presence of oxygen promotes the stability of selenite. For comparison, the stability of mixtures 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 iodide stability) and stored in glass bottles (thus containing approximately 3 ppm dissolved oxygen). The solutions were heat sterilized and stored at 40°C or 5°C for 6 months (T6M 40°C and T6M 5°C, respectively). The recovered concentrations of each trace element after 6 months at the two temperatures are summarized in Table V. [Table 5]

[0253] For all TEs, the recovery is around 80-90% at both temperatures. Overdilution could explain this being lower than expected recovery, but it is known that at 5°C the samples should be stable and can therefore be considered 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 a few ppm of dissolved oxygen. The presence of this oxygen is not detrimental to the stability of the other TEs.

[0254] It can be proved that oxygen introduction is no longer a problem in the production. 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 control the dissolved oxygen content, the solution can also be flushed with nitrogen and then with a defined time and amount of oxygen-containing gas. 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, the dissolved oxygen can be maintained in the solution by using a bag material that is impermeable to oxygen. Such a material does not allow any oxygen to enter or be removed out of the bag (even in contact with an oxygen absorber). In this way, the oxygen remains trapped in the TE solution, avoiding Se decomposition until the end of the product's shelf life.

Claims

1. A flexible container of a multi-chamber bag having a selective dissolved gas content for stabilizing at least one compound of a pharmaceutical product, wherein the multi-chamber bag is (a) a first chamber containing a carbohydrate formulation, (b) a second chamber containing an amino acid formulation, (c) a third chamber containing a lipid formulation, and (d) a fourth chamber containing a solution comprising at least one compound requiring the selective dissolved gas for stabilization, wherein the fourth chamber includes a headspace of the selective dissolved gas, the solution is contained in the fourth chamber comprising at least one selenium compound, and the headspace is filled with ambient air, oxygen-rich ambient air, or oxygen, a fourth chamber comprising a flexible container.

2. The flexible container according to claim 1, wherein the at least one compound is a compound requiring at least about 0.5 ppm of oxygen for stabilization, and the selective dissolved gas is oxygen.

3. The flexible container according to claim 1, wherein the at least one compound is a compound requiring at least about 1 ppm of carbon dioxide for stabilization, and the selective dissolved gas is carbon dioxide.

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

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

6. The flexible container according to claim 1, wherein the flexible container is finally heat sterilized.

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

8. The flexible container according to claim 7, wherein the at least one selenium compound is selected from the group consisting of sodium selenite, potassium selenite, lithium selenite, calcium selenite, magnesium selenite, selenous acid, and selenium dioxide.

9. The flexible container according to claim 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.

10. The flexible container according to claim 2, wherein the solution contains dissolved oxygen (DO) of from about 0.5 ppm to about 8 ppm.

11. The flexible container according to claim 2, wherein the solution contains dissolved oxygen (DO) equal to or more than 1 ppm.

12. The flexible container according to claim 8, wherein the selected dissolved gas is oxygen and the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm.

13. The flexible container according to claim 1, wherein the headspace of the selected dissolved gas stabilizes 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 storing at least one compound at a temperature between about 1 °C and about 30 °C.

14. The flexible container according to claim 13, wherein the flexible container is stored at a temperature between about 18 °C and about 25 °C.

15. The flexible container according to claim 7, wherein the solution has an acidic pH value in the range of about 1 to about 4.

16. 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.

17. The flexible container according to claim 1, wherein the flexible container is made of a material having an oxygen barrier of less than 5 cc / m ２ / day.

18. The chamber in which the at least one compound that requires the selected dissolved gas for stabilization is located does not include a port tube, the flexible container according to claim 1.

19. A multi-chamber container having a dissolved oxygen (DO) content for stabilizing at least one selenium compound in the form of Se(IV) of a pharmaceutical product, the multi-chamber container comprising (a) a first chamber containing a carbohydrate formulation, an amino acid formulation, or a lipid formulation, and (b) a solution containing the at least one selenium compound in the form of Se(IV) that requires the dissolved oxygen (DO) for stabilization; and a second chamber containing the headspace of the dissolved oxygen (DO) A multi-chamber container.

20. The multi-chamber container according to claim 19, wherein the multi-chamber container includes at least 5 chambers.

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

22. The multi-chamber container according to claim 19, wherein the at least one selenium compound is sodium selenite or selenium dioxide.

23. The multi-chamber container according to claim 19, wherein the solution in the second chamber contains dissolved oxygen (DO) equal to or more than 0.5 ppm over the entire shelf life of the pharmaceutical product.

24. The multi-chamber container according to claim 19, wherein the solution in the second chamber contains from about 0.5 ppm to about 8 ppm of dissolved oxygen (DO).

25. The multi-chamber container according to claim 19, wherein the solution in the second chamber contains dissolved oxygen (DO) equal to or more than 1 ppm.

26. The multi-chamber container according to claim 19, wherein the multi-chamber container is finally heat sterilized.

27. The multi-chamber container according to claim 19, wherein the concentration of dissolved oxygen (DO) in the solution during sterilization is at least 6 ppm.

28. The multi-chamber container according to claim 19, wherein the volume of the headspace is from about 5% to about 100% of the volume of the solution in the multi-chamber container.

29. The multi-chamber container according to claim 19, wherein the volume of the headspace of the selective dissolved gas is from about 35% to 45% of the volume of the solution in the multi-chamber container.

30. The headspace of the dissolved oxygen (DO) stabilizes the at least one selenium compound in the form of Se(IV) 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. The multi-chamber container according to claim 19.

31. The multi-chamber container according to claim 30, wherein the multi-chamber container is stored at a temperature between about 18°C and about 25°C.

32. The multi-chamber container according to claim 19, wherein the multi-chamber container is made of a material having an oxygen barrier of less than 0.5 cc / m2 / day.

33. The flexible container according to claim 17, wherein the flexible container is made of a material having an oxygen barrier of less than 2 cc / m2 / day.

34. The flexible container according to claim 17, wherein the flexible container is made of a material having an oxygen barrier of less than 1 cc / m2 / day.

35. The flexible container according to claim 15, wherein the solution has an acidic pH value in the range of about 2.5 to about 3.2.

Images