Stabilization of selenate in nutrient solutions by dissolved oxygen

Abstract

To provide stabilization of selenate in a nutrient solution by dissolved oxygen.SOLUTION: The present invention relates to a medicament for preventing or correcting a selenium deficiency in a patient comprising a solution provided in a flexible container comprising at least one selenium compound in the form of Se (IV), preferably selected from the group consisting of sodium selenite, selenous acid and selenium dioxide, characterized in that the solution comprises dissolved oxygen (DO), preferably from 0.5 ppm to 8 ppm DO.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of clinical nutrition and corresponding pharmaceuticals and nutritional solutions.

[0002] The present invention relates to a pharmaceutical product for preventing or correcting selenium deficiency in a patient, comprising a solution provided in an oxygen-impermeable flexible container comprising selenium as Se(IV), the solution comprising dissolved oxygen (DO), preferably between 0.5 ppm and 8 ppm DO.

[0003] In one embodiment of the present invention, the pharmaceutical solution of the present invention contains at least one additional trace element. The solution is ready to use and can be contained in one chamber of a multi-chamber container having at least two, at least three, at least four, at least five, or at least six chambers. Furthermore, the present invention relates to a method for producing the pharmaceutical of the present invention. [Background technology]

[0004] Parenteral nutrition aims to provide nutrition to a patient through intravenous access. The nutrients consist of macronutrients (lipids, amino acids or proteins, and dextrose or carbohydrates), micronutrients (vitamins and trace elements), and electrolytes.

[0005] Parenteral nutrition, such as in the form of one or more solutions, can be provided in the form of a flexible bag, such as a single flexible bag containing glucose, amino acids, or lipids, with or without electrolytes, which can be mixed together before administration, or a multi-chamber flexible bag providing separated macronutrients and electrolytes in a ready-to-use form. The bag is typically made from a synthetic or plastic material, such as polypropylene (PP), polyethylene (PE), ethylene vinyl alcohol (EVOH), ethylene-vinyl acetate, and all possible copolymers, essentially any synthetic material suitable for containing the components to be administered.

[0006] In the current state of the art, micronutrients are typically added to nutritional bags immediately prior to administration. For this purpose, vitamins can be provided in glass vials in the form of lyophilized tablets or in the form of a solution that is reconstituted and / or mixed into the nutritional / infusion bag. Trace elements are also provided in glass vials or polypropylene ampoules intended for mixing into the infusion bag prior to administration.

[0007] Prior to use, with reference to initiating administration of the formulation to a patient, micronutrients may be added to the mixture or macronutrients through an inlet on a container or bag (septum) or added to an infusion line through a Y-connector. This process is time-consuming, requires several processing steps, and increases the risk of error or contamination.

[0008] To avoid these potential problems, products containing trace elements in nutritional multi-chamber bags have already been developed, such as Pediaven, a binary parenteral nutrition solution for infants, children, and adolescents containing trace elements in glucose chambers. However, as published in July 2014, it was reported that the trace element selenium, supplied as selenium dioxide in the product, is not present in the final product due to potential degradation (http: / / www.pharmacovigilance-tours.fr / 490.html). Another product, Elneopa (Otsuka Pharmaceuticals), contains trace elements in small, dedicated chambers as part of a multi-chamber bag. However, this product does not contain selenium. A flexible multi-chamber container for preparing medical mixed solutions is also described in WO 2006 / 010410 A1.

[0009] Patent Publication KR10-2019-0105737 relates to an infusion solution preparation containing fat-soluble vitamins and trace elements, and more particularly to an infusion solution preparation containing multiple chambers therein, thus separately storing reducing sugars, amino acids, lipids and fat-soluble vitamins, and trace elements. This publication also mentions preferred concentrations of 3 μg / mL to 7.0 μg / mL based on selenium ions and selenium cations, among other trace elements, contained in the chambers of the multi-chamber nutritional product. No specific ions or methods for stabilizing such selenium ions in the formulation are described. Furthermore, in WO2010 / 067251A1, Bahr K et al. (Laboratoriumsmedizin (DE), vol. 23, no. 11, 1999, pp. 594-599) and Baptista RJ et al. (The American Journal of Clinical Nutrition, vol. 39, no. 5, May 1984, pp. 816-820) describe selenium-containing compositions for nutritional supplementation. Furthermore, Slavik P et al. (Reproduction In Domestic Animals, vol. 43, no. Suppl. 5, November 2008, pp. 102-103) describe the use of sodium selenite to compensate for selenium deficiency.

[0010] It is known in the art that selenium, iodine and copper can be chemically reactive and difficult to include in nutritional bags, especially since they must undergo extreme conditions such as heat sterilization and long-term storage (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).

[0011] Furthermore, various formulation studies have observed significant stability problems, particularly losses of selenium, when attempting to introduce trace elements into nutrient multi-chamber bags. This may be due to the fact that selenium in the form of Se(IV), particularly in the form of sodium selenite, selenious acid, or selenium dioxide, is prone to adsorption, 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.

[0012] In addition to selenium, iodine, fluoride, and copper also exhibited stability issues during formulation testing. Copper is a reactive substance and can catalyze various chemical reactions, which are known to precipitate. Iodide is reduced to iodine and can be volatile. Additionally, fluoride exhibited a decrease in concentration over time.

[0013] Thus, while it is possible to stabilize selenium under certain conditions, such as with Peditrace, Nutryelt or Addaven, with certain other trace elements in plastic ampoules or glass vials specially adapted for addition to such parenteral nutrition products, it has proven difficult to stabilize selenium in standard parenteral nutrition products, which contain a variety of different compounds in flexible bags, where the containers and conditions cannot be easily adapted for selenium alone or in combination with other trace elements, such as iodine and / or copper, and which generally must be subjected to special terminal heat sterilization in the presence of a lipid emulsion.

[0014] As a result of the above, to date, there are no ready-to-use pharmaceutical products available for parenteral administration, including solutions for parenteral administration to patients in need thereof, that contain selenium and are stable over long periods of time. Selenium, and potentially other trace elements, must be added manually to the prepared solution immediately prior to administration. This process is associated with a significant risk of medication errors, e.g., regarding the amount of trace elements, or the introduction of contamination into the sterile product. Contamination can include potential infectious agents, which pose a significant risk to hospital patients, especially those receiving nutritional solutions, such as parenteral administration.

[0015] In light of the prior art, there remains a significant need to develop pharmaceutical products for preventing or correcting selenium deficiency in patients that are simple, have a reasonable shelf life, and are easy to use, including avoiding additional mixing steps. Due to the instability of selenium in solution, especially when combined with additional trace elements, such products are not readily available. Summary of the Invention

[0016] In light of the prior art, the technical problem underlying the present invention is to provide a pre-prepared, sterile medicinal product for preventing or correcting selenium deficiency in a patient, comprising a ready-to-use formulation for parenteral administration containing selenium, provided in a flexible container, preferably made from an oxygen-impermeable material.

[0017] This problem is solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0018] The present invention therefore relates to a pharmaceutical product for preventing or correcting selenium deficiency in a patient, comprising a solution provided in an oxygen-impermeable flexible container for parenteral administration, the solution comprising at least one selenium compound, preferably in the form of Se(IV), selected from the group consisting of sodium selenate, selenious acid and selenium dioxide, the solution being characterized in that it contains dissolved oxygen (DO), preferably a DO of 0.5 ppm to 8 ppm.

[0019] Preferably, in some embodiments of the present invention, when other oxygen-sensitive compounds, such as trace elements or vitamins, are present in the same compartment as the selenium compound of the present invention, it may be preferable to target an oxygen range of 0.5 to 2.0 ppm. In some embodiments, an oxygen range of 1.0 ppm to 2.0 ppm may be preferred for stable formulation of the compositions according to the present invention.

[0020] In certain embodiments of the present invention, the pharmaceutical solution of the present invention comprises sodium selenite. In some embodiments, the pharmaceutical solution of the present invention comprises selenious acid. In some embodiments, the pharmaceutical solution of the present invention comprises selenium dioxide.

[0021] In particular, it is surprising that the presence of dissolved oxygen at the indicated stability concentrations of 0.5 ppm to 8 ppm results in stabilization of sodium selenite, selenious acid, and / or selenium dioxide in solutions otherwise protected from inter-exchange of gases with their surroundings. This is because oxygen is generally expected to participate in redox reactions, which are often detrimental to the stability of macro- and micronutrients in solution. In particular, certain trace elements and vitamins have been reported to be sensitive to the presence or absence of oxygen when stored in sealed containers, such as sealed flexible bags.

[0022] However, the present invention is based on the discovery that the presence of a stable and controlled concentration of dissolved oxygen in a solution containing sodium selenite, selenious acid, and / or selenium dioxide, alone or in combination with additional sensitive trace elements such as iodine and / or copper, stabilizes these selenium-containing compounds, which are known to be unstable in solution, particularly when present in sealed medical nutritional products, which are generally provided in oxygen-impermeable containers to avoid the above-mentioned redox reactions. Specifically, while oxygen-permeable containers, such as Peditrace™, are known and allow gas exchange between the interior of the container and the surrounding air, most parenteral products are provided in oxygen-impermeable containers due to the redox sensitivity of the nutritional ingredients contained therein. On the other hand, oxygen-permeable containers do not provide a defined, stable oxygen concentration, which has been found to be a necessary condition for providing long-term stability, especially for compositions sensitive to various trace elements.

[0023] As used herein, a pharmaceutical solution of the present invention comprising providing at least one selenium compound in the form of Se(IV), preferably selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, may also be referred to as a "selenium solution," a "solution comprising / containing selenium," or a "solution comprising / containing Se(IV)."

[0024] In the context of the present invention, the phrase "a stable (and controlled) concentration of dissolved oxygen in the solution of 0.5 ppm to 8 ppm" refers to a DO concentration that remains in the range of 0.5 ppm and 8 ppm throughout the shelf life of the pharmaceutical product of the present invention, where 8 ppm corresponds to the oxygen saturation of the solution of the present invention. In other words, the exact oxygen concentration of the solution in the pharmaceutical product does not need to remain stable, but it does need to not fall below this concentration range, i.e., 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.

[0025] In embodiments, the DO in the Se(IV)-containing solution is at least 0.5 ppm during storage. In embodiments, the DO in the Se(IV)-containing solution does not fall below 0.5 ppm throughout the shelf life of the pharmaceutical product.

[0026] In a preferred embodiment, the DO in the Se(IV)-containing solution is at least 6 ppm when the solution is filled (and optionally sealed) in the flexible container and before sterilization. In an embodiment, the DO concentration in the solution when filled and before sterilization is 6 ppm to 8 ppm (where 8 ppm corresponds approximately to the oxygen saturation level of the solution).

[0027] In a preferred embodiment, the oxygen-tightly sealed chamber of the flexible container containing the selenium solution includes a headspace of a gaseous composition containing oxygen. In other words, in such an embodiment, the chamber of the flexible container containing the selenium solution further includes a volume of a gaseous composition containing oxygen. Such additional gas volume or "headspace" is understood to be the space or volume within the sealed chamber that is not filled with the solution, i.e., the volume filled with air / gas remaining at the top of the filled container before sealing. Generally, headspace is avoided or minimized as much as possible in terms of potentially undesirable interactions between the gas contained therein (ambient air) and the liquid (or solid) content of the container (see, e.g., US2003 / 0110736A1). In contrast, in the context of the present invention, such headspace may be intentionally used and designed to be sufficient to conserve oxygen, e.g., via ambient air, so that consumed oxygen is replaced and the DO in the solution is maintained at 0.5 ppm or higher throughout its intended shelf life. The use of headspace according to the present invention, i.e., providing a sufficient gas reservoir containing, for example, ambient air and / or other gases or gas mixtures that may be consumed by the solution in the gas or oxygen impermeable bag or its chamber, is a general principle that can also be used with other compounds that require a certain level of gas, e.g., oxygen, for long-term stability, e.g., where the gas is consumed by one or more components of the solution stored in the bag or chamber of the MCB, or where there is a risk of loss of such gas, e.g., via the primary container or any port tubing.

[0028] In a preferred embodiment, the oxygen-containing gas composition is ambient air, which contains about 78% nitrogen, 21% oxygen, and about 1% other gases. However, in embodiments, the oxygen-containing gas composition may also be an oxygen-enriched gas composition, which may consist essentially of oxygen, particularly where headspace volume is to be reduced. In embodiments, the gas composition of the headspace may comprise 10-100% oxygen, for example, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 44, 46, 48, 50, 54, 58, 62, 66, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% oxygen.

[0029] In the case of ambient air, the volume of the headspace is preferably within about 40% of the volume of the selenium solution contained in the chamber. For example, for a 25 ml selenium solution containing preferably about 70 μg of selenium, the headspace can be 10 ml. However, in embodiments, the volume of the headspace can be within the range of 10-80% of the volume of the selenium solution, e.g., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 42, 44, 46, 48, 49, 50, 55, 60, 65, 70, 75, or 80% of the volume of the selenium solution. For example, for a 25 ml volume of selenium solution sealed in a chamber of a flexible container, the headspace can range from 2.5 ml to 12.5 ml, preferably about 3 to 12 ml, e.g., 3, 4, 5, 6, 7, 8, 9, 10, or 11 ml. For other volumes of selenium solution, one skilled in the art can calculate the corresponding volume of headspace based on this disclosure.

[0030] As mentioned above, if a different gas composition is used, the headspace volume can be adjusted accordingly. For example, for gases rich in oxygen content, a smaller headspace can be used, as will be apparent to those skilled in the art, and can be calculated based on the above ratios given for ambient air.

[0031] In pharmaceutical embodiments of the present invention, the DO of the present invention stabilizes sodium selenite, selenious acid, and / or selenium dioxide in solution, alone or in combination with other trace elements, for at least three months when stored over a wide temperature range of 1-50° C. Comparative experiments unexpectedly demonstrated that the listed selenium-containing compositions are stabilized in solution in oxygen-impermeable flexible containers at various temperatures tested, ranging from 1-50° C., for extended periods of time, such as at least three months.

[0032] In embodiments, DO according to 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 3 months when stored at up to 40° C. Furthermore, in embodiments, DO 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 when stored at up to 40° C.

[0033] In a further embodiment of the invention, the DO stabilizes sodium selenite, selenious acid and / or selenium dioxide in solution, 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.

[0034] In a further embodiment of the invention, the DO is stabilized in solution with sodium selenite, selenious acid and / or selenium dioxide, alone or in the presence of other trace elements, at a temperature of up to 30°C for at least 6 months, preferably 12 months, more preferably 18 months and most preferably 24 months.

[0035] In yet another embodiment of the present invention, the DO is stabilized in solution with sodium selenite, selenious acid and / or selenium dioxide, alone or in the presence of other trace elements, at a temperature of about 18°C ​​to 25°C for at least 6 months, preferably at least 12 months, more preferably at least 18 months, and most preferably at least 24 months.

[0036] In yet another embodiment of the present invention, the DO according to the present invention is stable 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, when stored at normal storage temperatures, for example, room temperature varying from, but not limited to, 15-30°C, more preferably 18-25°C, or under refrigerated conditions such as 1-10°C, preferably 2-8°C, or 3-7°C.

[0037] In embodiments of the invention, the pharmaceutical solution is a sterile solution. In some embodiments, the pharmaceutical solution of the invention may be sterile.

[0038] An important advantage of the solutions of the present invention is that they can be sterilized after preparation and packaging in flexible bags made of oxygen-impermeable materials that can be sealed airtight and liquid-tight, without significant loss of trace elements provided therein, particularly sodium selenite, selenious acid, and / or selenium dioxide, either alone or in the presence of other trace elements. In certain embodiments, the solutions of the present invention are subjected to terminal heat sterilization after the solutions are prepared and filled into flexible containers. Sterilization can be carried out before or after filling the solutions into flexible bags of pharmaceutical products of the present invention, where terminal sterilization, specifically heat sterilization of filled and sealed flexible containers, is preferred.

[0039] It is highly preferred that the container or chamber of the container containing the selenium-containing solution be able to stabilize its DO content between 0.5 and 8 ppm. According to the present invention, this can be achieved in different ways, for example, by using an oxygen-impermeable membrane material in which an oxygen adsorbent is added to the primary pouch, for example, if other formulations contained in the product, e.g., an MCB product, require the absence of oxygen. If an oxygen adsorbent is not required, it is also possible to use a semi-permeable membrane material in conjunction with oxygen-impermeable secondary packaging or an outer package. Both approaches can be used and are applicable to flexible container embodiments in which a medical port or fill port is used. Such a port should preferably be attached to or sealed on the container in a manner that ensures that the chamber containing the Se(IV)-containing solution is sealed in an oxygen-tight manner to the greatest extent possible. The inevitable loss of oxygen, for example, through a port seal in which an oxygen absorber is used, can be addressed according to the present invention by, for example, using an appropriate headspace used as an oxygen reservoir to ensure the stability of Se(IV) for the intended shelf life. In an embodiment, the chamber containing the selenium-containing solution includes an essentially oxygen-impermeable port.

[0040] Sterilization can be achieved by a terminal heat sterilization process, but can also be achieved by using terminal filtration, gamma irradiation, or any other sterilization technique. Alternatively, the pharmaceutical solution of the present invention can be filled into a flexible bag by an aseptic filling process that ensures that no contamination of the essentially sterile solution occurs during filling and before sealing the flexible bag. In some embodiments, the solution may be sterile, but need not be. For example, a sterilization process may be performed, but absolute sterility may not be achieved and / or required.

[0041] In the context of the present invention, the terms "flexible bag" and "flexible container" can be used interchangeably. The terms "solution" and "formulation" can also be used interchangeably in the context of the present invention.

[0042] In further embodiments, the DO concentration in the solution is greater than or equal to 0.5 ppm, more preferably greater than or equal to 1.0 ppm. In embodiments, the DO concentration is not greater than 4 ppm. In embodiments, the DO is greater than 0.8 ppm and not greater than 2 ppm.

[0043] In embodiments of the invention, the concentration of DO in the solution can be 0.5, 0.75, or 1-2 ppm, or any value in the range of 0.5, 0.75, 1, or 2-8 ppm, for example, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, or 8 ppm. The indicated ranges include the stated end values. Ranges including any combination of the disclosed values ​​are considered embodiments of the invention.

[0044] In embodiments, the DO concentration in the solution is greater than or equal to 0.5 ppm, more preferably greater than or equal to 1.0 ppm, throughout the shelf life of the pharmaceutical product.

[0045] In an embodiment of the present invention, the DO in the Se(IV)-containing solution is at least 0.5 ppm throughout the shelf life of the pharmaceutical product of the present invention. In an embodiment, the DO concentration in the solution can decrease during the shelf life, but remains above 0.5 ppm. For example, the 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 DO concentration can decrease over time, but will not fall below 0.5 ppm throughout the shelf life.

[0046] In an embodiment of the pharmaceutical product of the present invention, the DO concentration in the solution when the chamber of the flexible container containing the solution is filled and preferably sealed is at least 6 ppm.

[0047] In embodiments, the oxygen concentration in the selenium-containing solution can decrease within the pharmaceutical product after filling, sealing, and sterilization, and throughout the product's shelf life, even if the chamber containing the solution is completely oxygen-impermeable. In embodiments, oxygen in the solution can be consumed by compounds that may be present in the Se(IV)-containing solution during the shelf life, potentially resulting in a decrease in the oxygen concentration in the Se(IV)-containing formulation. While such oxygen consumption is generally not a problem or may even be intentional, it is preferred for Se(IV)-containing formulations that the oxygen concentration is at least 6 ppm, e.g., in the range of 6 ppm to 8 ppm, when the selenium solution is filled and sealed within the pharmaceutical product's chamber. Such a high oxygen concentration at the time of filling and sealing ensures that the oxygen concentration will not fall below 0.5 ppm throughout the product's shelf life, meaning that even if oxygen consumption occurs within the chamber, the DO concentration will not fall below 0.5 ppm and the Se(IV) will remain stable.

[0048] In embodiments, the sealed chamber of the flexible container containing the solution comprising at least one selenium compound in the form of Se(IV) further comprises a headspace of a gas composition comprising oxygen.

[0049] In a preferred embodiment, the flexible container or chamber thereof further comprising a solution containing at least one selenium compound in the form of Se(IV) contains a headspace of a gaseous composition comprising oxygen, the sealed chamber is oxygen impermeable, and the DO in the solution is at least 6 ppm when the chamber is filled and preferably sealed. In such an embodiment, the DO in the solution has been shown to be equal to or greater than, or remain equal to or greater than, 0.5 ppm throughout the shelf life of the pharmaceutical product.

[0050] As used herein, the term "shelf life" refers to the time during which the pharmaceutical product of the present invention can be stored under specified storage conditions after sealing and sterilization. The shelf life may vary depending on the storage conditions.

[0051] The fact that the content of DO according to the invention is suitable for stabilizing selenium-containing compounds alone, especially in combination with other sensitive trace elements in the context of the pharmaceutical preparations of the invention, is highly advantageous since such DO concentrations can be easily established without complex technical equipment or manipulation of solutions.

[0052] In some embodiments, the pharmaceutical solution comprises sodium selenite. The use of sodium selenite in the context of the present invention is particularly advantageous because this compound has been found to be stable in products of the present invention containing stable, predetermined DO concentrations of greater than 0.5 ppm, particularly 0.5 ppm to 8 ppm, whereas in the absence of a stable amount of DO in said range, sodium selenite has been observed to be unstable and only undetectable or undetectable at significantly lower concentrations after storage for more than 1 to 3 months.

[0053] In a further embodiment, the pharmaceutical preparation according to the invention has an acidic pH, preferably in the range of 1 to 4, more preferably 2 to 3.5, and more preferably about 2.5 to 3.2. It is a particular advantage of the solutions of the invention that sodium selenite, selenious acid, and / or selenium dioxide are stable in the presence of 0.5 to 8 ppm DO, particularly also in the presence of 0.8 ppm to 4 ppm DO, or 1 ppm to 2 ppm DO, at neutral pHs in the range of 7 to 7.5, as well as at acidic pHs. Selenium in the products according to the invention is particularly stable at acidic pHs, e.g., in the ranges of 1 to 4, 1.5 to 3.5, 1.8 to 3.2, 2 to 3.2, 2.1 to 2.9, 2.2 to 2.8, 2.3 to 2.7, 2.4 to 2.6, and about 2.5. The indicated ranges include the stated endpoints. Ranges incorporating any combination of the disclosed endpoints are considered embodiments of the invention.

[0054] Stability under such acidic pH conditions is particularly important when the solution contains other trace elements that are not stable at neutral pH but are stable only under acidic conditions. This is particularly the case for iodide (I), which has been reported to be more stable in acidic pH solutions. However, this is also true for nutrient solutions containing some of the trace elements copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), chromium (Cr), fluoride (F), and molybdenum (Mo), some of which are also sensitive to oxygen.

[0055] In an embodiment of the invention, the solution comprises an acid, preferably an organic acid selected from the group comprising malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, more preferably malic acid, and the concentration of the organic acid is preferably in the range of 100 mM to 400 mM, preferably 190 mM to 220 mM, more preferably in the range of about 200 mM.

[0056] In another embodiment, the solution comprises an acid, preferably an organic acid, selected from the group consisting of malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, and more preferably malic acid, and the concentration of the organic acid is preferably in the range of 50 mM to 400 mM, preferably 100 mM to 200 mM.

[0057] In another embodiment, the solution comprises malic acid. In an embodiment, the solution comprises malic acid at a concentration ranging from 100 mM to 400 mM, preferably from 190 mM to 220 mM, for example, from 140 mM to 180 mM or from 160 mM to 200 mM. The use of malic acid in the context of a nutritional pharmaceutical is particularly advantageous because it is an organic acid naturally occurring in fruits such as apples, apricots, blackberries, blueberries, cherries, grapes, and peaches, and is particularly well tolerated by human subjects when administered in the context of a nutritional product.

[0058] The acid concentration in the pharmaceutical solution of the present invention can be any range that results in a pH value suitable for the desired application. Depending on the acid, slightly different concentrations may be required to achieve an acidic pH value, for example, in the range of 1 to 4. Those skilled in the art can select and appropriately adjust the appropriate acid concentration for a preferred embodiment, including a solution of a given pH and specific acid.

[0059] In an embodiment of the pharmaceutical product of the present invention, the solution does not contain macronutrients, preferably such macronutrients are selected from the group comprising carbohydrates, proteins and lipids, and preferably the solution does not contain other nutrients.

[0060] In a further embodiment, the solution is carbohydrate-free.

[0061] In further embodiments, the solution does not contain proteins or amino acids, optionally in addition to selenium. In embodiments, the solution does not contain lipids. In embodiments, the solution does not contain electrolytes. In embodiments, the solution does not contain vitamins. In embodiments, the solution does not contain trace elements other than selenium. In embodiments, the solution contains only trace elements. In embodiments, the solution contains selenium as the only trace element. In embodiments, the solution contains selenium as the only nutrient. In embodiments, the solution contains selenium as the only nutrient, in addition to water (if water is considered a nutrient).

[0062] In an embodiment, the pharmaceutical solution of the present invention comprises at least one additional trace element, preferably selected from the group comprising zinc, iron, copper, manganese, chromium, iodine, fluoride and molybdenum.

[0063] In an embodiment, the pharmaceutical solution of the present invention comprises at least one additional trace element, preferably selected from the group comprising zinc, iron, manganese and / or copper.

[0064] In an embodiment, the pharmaceutical solution of the present invention comprises at least one additional trace element, preferably selected from the group consisting of zinc, iron, copper, manganese, chromium, iodine, fluoride and molybdenum. In an embodiment, the pharmaceutical solution of the present invention comprises at least one additional trace element, preferably selected from the group consisting of zinc, iron, manganese and / or copper.

[0065] In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, and copper as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, iodine, fluoride, and molybdenum as additional trace elements.

[0066] In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, and chromium as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, and iodine as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, and fluoride as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, and molybdenum as additional trace elements.

[0067] In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, and iodine as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, and fluoride as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, and molybdenum as additional trace elements.

[0068] In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, iodine and fluoride as additional trace elements.In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, iodine and molybdenum as additional trace elements.

[0069] In an embodiment, the pharmaceutical solutions of the present invention contain at least zinc, iron, manganese, copper, fluoride and molybdenum as additional trace elements.

[0070] In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, iodine, and fluoride as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, iodine, and molybdenum as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, chromium, fluoride, and molybdenum as additional trace elements. In an embodiment, the pharmaceutical solution of the present invention comprises at least zinc, iron, manganese, copper, iodine, fluoride, and molybdenum as additional trace elements.

[0071] In the context of the present invention, zinc can be provided as any suitable compound, preferably as a salt such as gluconate, chloride, or sulfate. In the context of the present invention, iron can be provided as any suitable compound, preferably as a salt such as gluconate, chloride, or sulfate. In the context of the present invention, copper can be provided as any suitable compound, preferably as a salt such as gluconate, chloride, or sulfate. In the context of the present invention, manganese can be provided as any suitable compound, preferably as a salt such as gluconate, chloride, or sulfate. In the context of the present invention, chromium can be provided as any suitable compound, preferably as a salt such as gluconate, chloride, or sulfate. In the context of the present invention, iodine can be provided as any suitable compound, preferably as a salt such as potassium iodide or sodium iodide. In the context of the present invention, fluoride can be provided as any suitable compound, preferably as a salt such as potassium fluoride or sodium fluoride. In the context of the present invention, molybdenum can be provided as any suitable compound, preferably as a salt such as gluconate, chloride, or sulfate.

[0072] Additionally, embodiments of the present invention relate to pharmaceutical solutions in which the solution is administered parenterally. In further embodiments, pharmaceutical solutions of the present invention are administered or consumed orally. In embodiments, the solution can be administered enterally.

[0073] In the context of the present invention, the claimed pharmaceutical solutions may contain sodium selenite, selenious acid and / or selenium dioxide in an amount corresponding to 10-200 μg, preferably 40-100 μg, more preferably about 70 μg of selenium.

[0074] In embodiments, the amount of selenium in the solution of the pharmaceutical corresponds to the recommended daily dose (dd) of selenium, where the daily dose may be quantified as the mass of selenium administered to a patient per day, e.g., μg selenium per patient per day (μg / patient / day). In embodiments, the amount of selenium in the product solution can be in the range of 1-500, 2-450, 4-400, 6-350, 7-300, 8-270, 9-235, 10-200, 15-190, 20-180, 25-170, 30-160, 35-150, 40-140, 45-130, 50-120, 52-115, 54-110, 56-105, 58-100, 60-95, 62-90, 64-88, 66-86, 68-84, 70-82, 72-80, 74-78, or 76 μg selenium. The indicated ranges are inclusive of the recited endpoints. Ranges incorporating any combination of the disclosed endpoints are considered embodiments of the invention.

[0075] In the context of the solutions of the present invention, selenium is provided as sodium selenite, selenious acid, and / or selenium dioxide. Thus, for example, if 70 μg of selenium is provided in the form of sodium selenite (Na2O3Se), the molar mass is 172.95 g / mol, and selenium has a molar mass of 78.97 g / mol, which corresponds to approximately 153.2 μg of sodium selenite.

[0076] Thus, if 70 μg of selenium is provided in the form of selenious acid (HSeO, or more accurately described as (HO)SeO), the molar mass is 128.97 g / mol, and selenium has a molar mass of 78.97 g / mol, which corresponds to approximately 114.32 μg of selenious acid.

[0077] Furthermore, if 70 μg of selenium is provided in the form of selenium dioxide (SeO 2 ), the molar mass is 110.96 g / mol, and selenium has a molar mass of 78.97 g / mol, which corresponds to approximately 98.36 μg of selenium dioxide.

[0078] As is clear from these examples, a person skilled in the art can calculate the amount of a selenium-containing compound in the solution of the pharmaceutical preparation of the present invention based on the molar mass of the compound and the amount of selenium present in the solution. Similarly, the amount of a compound containing other trace elements can be calculated based on the molar mass of each trace element and the compound containing said trace element.

[0079] In an embodiment, the pharmaceutical product of the present invention represents a daily nutritional dose for a patient.Therefore, the amount of the component of the product, such as selenium, in the solution of the product is calculated and provided to cover the daily dose of the compound in the patient.Depending on the volume of the solution of the product and the amount of selenium, the concentration of selenium in the solution can be calculated.

[0080] In a pharmaceutical embodiment of the present invention, the solution in the oxygen-impermeable flexible container has a volume of approximately 25 ml. In such an embodiment, the amount of selenium in the solution may be 70 μg, resulting in a selenium concentration of 2.8 μg / ml (or 2.8 mg / L). The Se concentration range can be calculated based on the Se amounts disclosed herein. A preferred Se concentration for the present invention is in the range of 0.28 to 28 mg / L. However, the Se concentration may also be in the range of 0.1-100 mg / l, 0.2-90, 0.3-85, 0.4-80, 0.5-75, 0.6-70, 0.7-65, 0.8-60, 0.9-55, 1-50, 1.2-48, 1.4-46, 1.6-44, 1.8-42, 2-40, 2.2-38, 2.4-36, 2.6-34, 2.8-32, 3-30, 3.5-29, 4-28, 4.5-27, 5-26, 5.5-25, 6-24, 6.5-23, 7-22, 7.5-21, 8-20, 9-19, 10-18, 11-17, 12-16, 13-15 or 14 mg / ml. The stated ranges are inclusive of the recited endpoints, and ranges incorporating any combination of the disclosed endpoints are considered embodiments of the invention.

[0081] Table 1 below shows the appropriate ranges and preferred amounts for adults of trace elements that may be included in pharmaceutical preparations, particularly solutions of pharmaceutical preparations of the present invention. Ranges and amounts for children may differ and may be adapted according to applicable recommendations. Such appropriate ranges may be updated from time to time, so that the preferred amounts of any trace elements that may be included in pharmaceutical preparations of the present invention may be adapted according to currently valid recommendations.

[0082] Table 1. Suitable amounts and amount ranges of trace elements that can be used in the context of the present invention. The ranges indicated are based on different ranges recommended in the art. The amounts refer to pharmaceuticals of the present invention that provide a daily dose for one patient. The indicated ranges include the stated end values. Ranges including any combination of the disclosed end values ​​are considered embodiments of the invention.

[0083] [Table 1]

[0084] Table 2 shows the range of concentrations of trace elements suitable for adults that can be included in the solution of the pharmaceutical preparation of the present invention. The ranges for pediatric use may differ and can be adapted according to applicable recommendations. Such suitable ranges can be updated from time to time, so that any preferred amount of trace elements that can be included in the pharmaceutical preparation of the present invention can be adapted according to currently valid recommendations.

[0085] Table 2. Suitable concentrations and concentration ranges of trace elements (TEs) that can be used in the context of the pharmaceutical solutions of the present invention. The indicated ranges refer to the preferred daily doses for patients listed in Table 1 and solution volumes of 2.5 to 250 ml. Se(IV) listed in this table encompasses sodium selenite, selenious acid, and / or selenium dioxide.

[0086] [Table 2]

[0087] In the context of the pharmaceutical preparation of the present invention, the volume of the solution containing sodium selenite, selenious acid and / or selenium dioxide may be from 1 to 1000 ml, 1.5 to 980, 2 to 960, 2.5 to 940, 3 to 920, 3.5 to 900, 4 to 880, 4.5 to 860, 5 to 840, 6 to 820, 7 to 800, 8 to 780, 9 to 760, 10 to 740, 12 to 720, 14 to 700, 16 to 680, 18 to 660, 20 to 640, 22 to 620, 24 to 600, 26 to 580, 28 to 560, 30 to 540, 32 to 520, 34 to 500, The ranges may be 36-480, 34-460, 36-440, 38-420, 40-400, 45-490, 50-480, 55-470, 60-460, 65-450, 70-440, 85-430, 90-420, 95-410, 100-400, 110-390, 120-380, 130-370, 140-360, 150-350, 160-340, 170-330, 180-320, 190-310, 200-300, 210-290, 220-280, 230-270, 240-260, or 250 ml. The indicated ranges include the stated end values. Ranges incorporating any combination of the disclosed end values ​​are considered embodiments of the invention.

[0088] In embodiments of the invention, the solution is contained in one chamber of a multi-chamber container having at least two, at least three, at least four, at least five, or at least six chambers.

[0089] In embodiments, the container comprises at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, a third chamber containing a lipid formulation, and optionally electrolytes and / or vitamins in at least the first, second and / or third chambers, and at least one chamber containing sodium selenite, selenious acid and / or selenium dioxide in the presence of 0.5 ppm to 8 ppm oxygen.

[0090] In embodiments, the container comprises at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, and a third chamber containing a lipid formulation, with electrolytes and / or vitamins in at least the first, second and / or third chambers, and at least one chamber containing sodium selenite, selenious acid and / or selenium dioxide in the presence of 0.5 ppm to 8 ppm oxygen.

[0091] In embodiments, the container comprises at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, a third chamber containing a lipid formulation, electrolytes and / or vitamins in a fourth and / or fifth chamber, and sodium selenite, selenious acid and / or selenium dioxide in the presence of 0.5 ppm to 8 ppm oxygen in a further chamber, optionally together with other trace elements.

[0092] In embodiments, the container comprises at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, a third chamber containing a lipid formulation, and a solution comprising sodium selenite, selenious acid and / or selenium dioxide in the presence of 0.5 ppm to 8 ppm dissolved oxygen (DO) is present in a fourth chamber.

[0093] In an embodiment of the present invention, the solution is contained in one chamber of a multi-chamber container having at least two, at least three, at least four, at least five, or at least six chambers, and the solution comprises sodium selenite. In an embodiment of the present invention, the container is made from an oxygen-impermeable flexible material. In a further embodiment, the sodium selenite-containing solution further comprises trace elements and 0.5 to 3 ppm DO.

[0094] In certain embodiments, including a container having at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, and a third chamber containing a lipid formulation, the solution comprises sodium selenite. In embodiments of the invention, the container is made from an oxygen-impermeable flexible material.

[0095] In an embodiment of the present invention, the solution is prepared by dissolving sodium selenite, selenious acid, and / or selenium dioxide in a liquid medium. In a preferred embodiment, the liquid medium is water, preferably ultrapure water (UPW; also known as deionized water (DI)) or water for injection. UPW water has been purified to remove organic particles and dissolved gases. Water for injection is ultra-high quality water that is free of significant contamination.

[0096] Furthermore, the present invention relates to a method for producing a medicament for preventing or correcting selenium deficiency in a patient according to any one of the above claims, wherein said solution is prepared by the following steps: a. Dissolving sodium selenite, selenious acid and / or selenium dioxide in a liquid medium, preferably water for injection, to produce a solution with a selenium concentration of 0.28 to 28 mg / L; b. optionally further dissolving an acid, preferably an organic acid selected from the group comprising malic acid, tartaric acid, citric acid, maleic acid and fumaric acid, and / or at least one additional trace element selected from the group comprising zinc, iron, copper, manganese, chromium, iodine, fluoride and molybdenum, alone or together with sodium selenite, selenious acid and / or selenium dioxide; c. adjusting the solution to a dissolved oxygen concentration of 0.5 ppm to 8 ppm; d. The solution is sterilized, preferably by heat sterilization.

[0097] Sterilization of the solution can be carried out before or after the solution is filled into the flexible container of the present invention.

[0098] Preferably, sterilization of the solution occurs after filling the solution into a flexible container or a chamber of a flexible multi-chamber container and sealing the solution within the container.

[0099] In a preferred embodiment of the method of the present invention, the DO concentration in the solution is adjusted to at least 6 ppm, for example 6 to 8 ppm, when the solution is filled into the flexible bag.

[0100] Any method step that dissolves an acid can be used to adjust the pH of the solution to an acidic pH.

[0101] Furthermore, in an embodiment of the method of the present invention, at least one additional trace element, preferably selected from the group consisting of zinc, iron, copper, manganese, chromium, iodine, fluoride and molybdenum, is added to the solution.

[0102] The present invention further relates to a sterile or sterilized solution for parenteral administration comprising at least one compound selected from the group comprising sodium selenite, selenious acid and selenium dioxide for use in preventing or correcting selenium deficiency in a patient, characterized in that the solution contains dissolved oxygen (DO).

[0103] The present invention further provides a method for preventing or correcting selenium deficiency in a patient, the method comprising administering to the patient a solution comprising at least one compound selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, wherein the solution comprises dissolved oxygen (DO).

[0104] In an embodiment of a method for preventing or correcting selenium deficiency in a patient according to the invention, the method comprises administering a solution to maintain plasma selenium levels and prevent depletion of endogenous stores in a patient receiving total parenteral nutrition.

[0105] In the context of methods of preventing or correcting selenium deficiency in a patient, the patient is an adult patient. In embodiments, the patient is a pediatric patient, such as a neonate, infant, child, or adolescent.

[0106] As used herein, the term "adult" refers to a person aged 20 years or older. The term "child" refers to newborns, e.g., preterm (earlier than expected) babies up to 1 month, full-term and postterm babies, infants aged 1 month to 1 year, infants aged 1-12 years, and adolescents aged 13-19 years.

[0107] All features disclosed in relation to the medicaments for preventing or correcting selenium deficiency in a patient of the present invention also relate to, and are disclosed herein in relation to, methods of making such medicaments, and other methods. The same is true for the sterile or sterilized solutions of the present invention and the methods of preventing or correcting selenium deficiency in a patient of the present invention. [Brief explanation of the drawings]

[0108] [Figure 1] FIG. 1 is a pH / redox diagram showing the conversion / reduction of SeO3 to volatile species in an oxygen-free medium. [Figure 2] Figure 2 shows a fitted line plot showing an 80% fit of Se dose versus log oxygen content (ppm). [Figure 3] Figure 3 shows the change in DO over time in bags made with oxygen semi-permeable (EU2-S) and oxygen impermeable (EU2-F) membranes. [Figure 4] FIG. 4 shows an analysis of the effect of (A) oxygen semi-permeable bag material and (B) oxygen impermeable bag material on selenite stability. [Figure 5] FIG. 5 shows an analysis of the effect of headspace and port tubing on DO in combination with an oxygen-impermeable bag. DETAILED DESCRIPTION OF THE INVENTION

[0109] All cited references, both patent and non-patent, are incorporated herein by reference in their entirety.

[0110] The present invention provides a sterile pharmaceutical product for preventing or correcting selenium deficiency in a patient, comprising a solution provided in an oxygen-impermeable flexible container containing at least one compound selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, wherein the solution contains 0.5 ppm to 8 ppm of dissolved oxygen (DO) at 20°C to 25°C.

[0111] As disclosed herein, the term "medicament" relates to any product intended to be used for medical purposes, preferably for clinical nutrition. The pharmaceutical of the present invention is intended and designed for the medical purpose of preventing or correcting selenium deficiency in a patient.

[0112] Selenium deficiency refers to a condition in which selenium is insufficient in the body, which can lead to several health problems. The patient group of the present invention includes all patients or patient groups at risk of developing selenium deficiency or who already have selenium deficiency. In particular, the pharmaceutical agent of the present invention is intended to correct or treat selenium deficiency that has already occurred in patients. Furthermore, the present invention can be used to prevent the development of selenium deficiency in patients who are at risk of developing or suspected of developing selenium deficiency, for example, due to severe intestinal dysfunction, total or partial parenteral nutrition, gastrointestinal bypass surgery, or advanced age. In the present context of the present invention, prevention is considered to include both absolute prevention, i.e., stopping the disease from developing altogether, and / or preventative measures that reduce the risk or likelihood that a patient will develop an undesirable medical condition or delay the onset, initial occurrence, and / or progression of a disease.

[0113] Selenium is a chemical element with the symbol Se and atomic number 34. It is a nonmetal (more rarely considered a metalloid), intermediate in the periodic table between sulfur and tellurium, and has properties similar to arsenic. Selenium itself exists in various chemical forms, including selenite and selenate, as well as elemental selenium, which is often found in association with sulfur-containing compounds. Selenium is a component of the amino acids selenocysteine ​​and selenomethionine. Very small amounts of selenium are required to maintain proper health in both animals and humans, and this selenium must be obtained from the diet. Humans have approximately 25 selenoproteins, many of which are enzymes that protect the body from oxidative damage. Without selenium, the function of selenium-requiring proteins is impaired, resulting in signs and symptoms of deficiency. Because the aging process, as well as certain diseases, including cancer and cardiovascular disease, are associated with increased oxidative damage, maintaining adequate selenium intake may provide some protection against these processes.

[0114] In humans, selenium is a trace element nutrient that functions as a cofactor for glutathione peroxidase and certain forms of thioredoxin reductase. Selenium-containing proteins are converted to selenium phosphate (PSeO3 3- ) is produced from inorganic selenium via the intermediate

[0115] Selenium deficiency can occur in patients with severely impaired intestinal function, such as those receiving total parenteral nutrition, CRRT, cancer patients, premature infants, patients staying in the ICU for extended periods, patients who have undergone gastrointestinal bypass surgery, and elderly patients (over 90 years of age). These patients are at risk of developing selenium deficiency. Also at risk are people who rely on foods grown in selenium-deficient soils. Even if an individual lacks optimal amounts of selenium but not enough to be classified as deficient, they may be at increased risk for developing various diseases.

[0116] The pharmaceutical preparations of the present invention can be used to treat patients who have, develop, or are at risk of developing a selenium deficiency, and the treatment can be aimed at preventing or correcting the selenium deficiency in this patient population.

[0117] Selenium deficiency, defined by low (<60% of normal) selenoenzyme activity levels in the brain and endocrine tissues, occurs when low selenium levels are associated with additional stressors, such as increased oxidative stress due to high mercury exposure or vitamin E deficiency. As used herein, selenium deficiency can occur even in healthy, well-nourished individuals. Selenium deficiency in combination with coxsackievirus infection can be fatal and can cause Keshan disease, which represents a specific form of selenium deficiency within the meaning of the present invention. Selenium deficiency is also involved (along with iodine deficiency) in Kashin-Beck disease, another selenium deficiency within the meaning of the present invention. The primary symptom of Keshan disease is myocardial necrosis, weakening the heart. Kashin-Beck disease causes atrophy, degeneration, and necrosis of cartilage tissue. Keshan disease also predisposes the body to other nutritional, biochemical, or infectious diseases. Selenium is also required for the conversion of the thyroid hormone thyroxine (T4) to its more active counterpart triiodothyronine (T3). Therefore, selenium deficiency can lead to symptoms of hypothyroidism, such as extreme fatigue, mental retardation, goiter, cretinism, and recurrent miscarriage.

[0118] The Institute of Medicine (IOM) updated the Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for selenium in 2000. When there is insufficient information to set the EAR and RDA, estimates designated as Adequate Intakes (AI) are used instead. The current EAR for selenium for people aged 14 years and older is 45 μg / day. The RDA is 55 μg / day. The RDA is higher than the EAR and identifies amounts that cover people with higher-than-average requirements. The RDA for pregnancy is 60 μg / day. The RDA for breastfeeding is 70 μg / day. For children aged 1 to 13 years, the RDA increases with age from 20 to 40 μg / day. Regarding safety, the IOM sets tolerable upper intake levels (ULs) for vitamins and minerals when evidence is sufficient. For selenium, the UL is 400 μg / day. Collectively, the EAR, RDA, AI, and UL are referred to as the Dietary Reference Intakes (DRI) [Institute of Medicine (2000). "Selenium." Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press. pp. 284-324]. The European Food Safety Authority (EFSA) calls this collective set of information the Dietary Reference Values, substituting the Population Reference Intake (PRI) for the RDA and the Average Requirement (AR) for the EAR. The AI ​​and UL are defined as in the United States. For men and women aged 15 years and older, the AI ​​is set at 70 μg / day. The AI ​​for pregnancy is 70 μg / day, and for lactation, it is 85 μg / day. For children aged 1 to 14 years, the AI ​​increases with age from 15 to 55 μg / day. These AIs are higher than the US RDA [EFSA, Overview on Dietary Reference Values ​​for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), September 2017].The European Food Safety Authority (EFSA) considered the same safety issue and set its UL at 300 μg / day, which is lower than the US value [EFSA, “Tolerable Upper Intake Levels For Vitamins And Minerals”, February 2006].

[0119] In the context of the present invention, the pharmaceutical product comprises a flexible container or bag, preferably made from an oxygen-impermeable material, containing at least one compound selected from the group consisting of sodium selenite, selenious acid and selenium dioxide, the solution being characterized in that it contains 1 ppm to 8 ppm of dissolved oxygen (DO).

[0120] Sodium selenite is an inorganic compound with the formula Na2SeO3. This salt is a colorless solid. The pentahydrate Na2SeO3(H2O)5 is the most common water-soluble selenium compound. Selenous acid (or selenious acid) is a compound with the formula H2SeO3. Structurally, it is more accurately described by H2SeO3. It is the primary oxoacid of selenium; the others are selenic acids. Selenium dioxide, a compound with the formula SeO2, is a colorless solid. It is one of the most frequently encountered compounds of selenium.

[0121] The term "dissolved oxygen" (DO) refers to the level of free, non-compound oxygen present in water or other liquids or solutions, such as solutions for parenteral nutrition. Oxygen saturation (symbol SO2) is a relative measure of the concentration of oxygen dissolved or carried in a medium as a percentage of the maximum concentration that can be dissolved in that medium. It can be measured with a dissolved oxygen probe, such as an oxygen sensor or optode, in a liquid medium, usually water.

[0122] Dissolved oxygen is usually reported in milligrams per liter (mg / L) or percent air saturation. However, studies also report DO in parts per million (ppm) or micromoles (μmol). 1 mg / L is equal to 1 ppm. The relationship between mg / L and percent air saturation varies with water temperature, pressure, and salinity. 1 micromole of oxygen equals 0.022391 milligrams. Therefore, 100 μmol / L of O2 equals 2.2 mg / L of O2. To calculate dissolved oxygen concentration from air saturation, the sample's temperature and salinity must be known. Since oxygen partial pressure contributes to air saturation, atmospheric pressure is already taken into account. Then, using Henry's law and salinity and temperature, the DO concentration at 100% air saturation can be calculated. However, it is easier to use oxygen solubility charts. These charts show the dissolved oxygen concentration at 100% air saturation as temperature and salinity change. This value is then multiplied by the measured air saturation to calculate the dissolved oxygen concentration [Fondriest Environmental, Inc. “Dissolved Oxygen.” Fundamentals of Environmental Measurements. 19 November 2013.]

[0123] Oxygenation of a liquid can occur, for example, by exposing the liquid to an oxygen-containing gas. For example, exposing a liquid sample to an atmosphere containing approximately 21% O2 causes oxygenation by diffusing gaseous oxygen into the liquid. This process can be accelerated, for example, by agitation, sparging the liquid with an oxygen-containing gas, or similar techniques known to those skilled in the art.

[0124] Several methods for measuring dissolved oxygen concentration are available in the art. Modern technologies include either electrochemical or optical sensors, where the dissolved oxygen sensor is attached to a data logger, process monitor, or transmitter for spot sampling and laboratory applications, or for deployed measurement and process control. For example, the Microx TX3 fiber optic oxygen meter for gaseous and dissolved O2 from Precens Precision Sensing GmbH (Germany) provides a basic approximation of the dissolved oxygen concentration in a sample. Two methods are designed for high- and low-range dissolved oxygen concentration. While these methods are quick and inexpensive for basic projects, they have a limited range and are subject to errors due to other reoxidants that may be present in the water. The traditional method is Winkler titration.

[0125] In an embodiment of the present invention, the pharmaceutical solution is a sterilized solution. In the context of the present invention, the term "sterilized" refers to a solution that has undergone a sterilization step. Sterilization refers to a process that eliminates, removes, kills, or inactivates all forms of life (especially microorganisms, e.g., fungi, bacteria, viruses, spores, and unicellular eukaryotes such as Plasmodium) as well as other biological agents, such as prions, present on certain surfaces, objects, or liquids, such as food and biological culture media. Sterilization can be achieved by various means, including heat, chemicals, irradiation, high pressure, and filtration. Sterilization differs from disinfection, sanitization, and pasteurization, as these methods reduce rather than eliminate all forms of biological agents present. After sterilization, the object is said to be sterile or aseptic.

[0126] According to one embodiment of the present invention, sterilization is performed by heating. According to another embodiment of the present invention, sterilization involves heating under pressure in the presence of water to generate steam, which is recommended by various pharmacological authorities. Generally, the steam sterilization is performed in an autoclave and can be used for pharmaceuticals, medical devices, plastic bags and other single-use devices, glass containers, surgical dressings, etc.

[0127] Other methods include sterilization by moist heat. As used herein, the term "moist heat" includes the use of saturated steam, steam air, and hot water cascade or water spray sterilization. According to one embodiment of the present invention, sterilization by moist heat is preferred.

[0128] Sterilization can also be achieved by dry heat, which requires much higher temperatures (180-200°C). Dry heat is commonly used to sterilize glassware, metals, and other surfaces.

[0129] Exposure to radiation is another sterilization method used throughout industry. Gamma radiation is the most common, but other options include infrared, ultraviolet, and high-speed electrons. Radiation is typically used to sterilize single-use components / systems, but can be used on packaged drug products.

[0130] Gas treatment is also an alternative method of sterilization. Such gases include ethylene oxide, formaldehyde, glutaraldehyde, propylene oxide, hydrogen peroxide, and chlorine dioxide. This method is often used to sterilize clean room suites. Sterilization by filtration is the only option when other steps are not suitable for a particular product or component. In filtration, the final formulation solution is produced under aseptic manufacturing conditions and passed through filters designed with the appropriate pore size / surface chemistry to remove bacteria via size exclusion, entrapment, electrostatic attraction, and other modalities.

[0131] In an embodiment of the invention, the solution comprises an acid, preferably an organic acid, selected from the group comprising malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, more preferably malic acid.

[0132] As used herein, nutrients are substances used by organisms, such as humans, for survival, growth, and reproduction. Nutrients can be taken up by cells for metabolic purposes or excreted by cells to create non-cellular structures such as hair, scales, feathers, or exoskeletons. Some nutrients are metabolically converted into smaller molecules, producing end products of water and carbon dioxide, in the process releasing energy, such as carbohydrates, lipids, proteins / amino acids, and fermentation products (ethanol or vinegar). All living organisms require water. Essential nutrients for animals and humans are energy sources, and some amino acids combine to create proteins, fatty acids, vitamins, and a subset of certain minerals / trace elements.

[0133] The classification primarily used to describe the nutritional requirements of animals divides nutrients into macronutrients and micronutrients. Macronutrients (carbohydrates, lipids / fats, proteins / amino acids, water) are consumed in relatively large amounts and are used primarily to generate energy or to be incorporated into tissues for growth and repair. Micronutrients are required in smaller amounts and play subtle biochemical and physiological roles in cellular processes such as blood vessel function and nerve conduction. Insufficient amounts of essential nutrients, or diseases that prevent absorption, result in deficiencies that impair growth, survival, and reproduction.

[0134] Macronutrients include carbohydrates, proteins, lipids, and water. Macronutrients are defined as the group of compounds consumed in the largest quantities by humans and that provide the majority of energy to humans. Water accounts for the majority of the total amount consumed as part of a normal diet, but has no nutritional value. Carbohydrates include glucose, sucrose, ribose, amylose (the main component of starch), amylopectin, maltose, galactose, fructose, and lactose. Proteins are composed of amino acids, including the standard amino acids alanine, arginine, aspartic acid (aspartic acid), asparagine, cysteine, glutamic acid (glutamic acid), glutamine, glycine, histidine, isoleucine (branched-chain amino acid), leucine (branched-chain amino acid), lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine (branched-chain amino acids). Lipids (or fats) include saturated fats, such as butyric acid (C4), caproic acid (C6), caprylic acid (C8), capric acid (C10), lauric acid (C12), myristic acid (C14), pentadecanoic acid (C15), palmitic acid (C16), margaric acid (C17), stearic acid (C18), arachidic acid (C20), behenic acid (C22), lignoceric acid (C24), and cerotic acid (C26); monounsaturated fats, such as myristyl, pentadecanoic, palmitoyl, and heptadecanoic. Oleic acid, eicosene, erucic acid, nervonic acid; polyunsaturated fats such as linoleic acid (LA) - essential fatty acid, alpha-linolenic acid (ALA) - essential fatty acid, stearidonic acid (SDA), arachidonic acid (ETA), thymnodonic acid (EPA), clupanodonic acid (DPA), cervonic acid (DHA); essential fatty acids such as alpha-linolenic acid ALA (18:3) omega-3 fatty acid and linoleic acid LA (18:2) omega-6 fatty acid, which are the starting point for other important omega acids (DHA, EPA).

[0135] Micronutrients are essential elements required by humans in small amounts throughout life to regulate a range of physiological functions to maintain health, particularly vitamins and dietary minerals / trace elements, including boron, cobalt (as a component of vitamin B12), fluoride, chromium, copper, iodine, iron, manganese, molybdenum, selenium, and zinc.

[0136] For the pharmaceutical preparations of the present invention, trace elements are provided as chloride or sodium salts such as zinc chloride, iron chloride, copper chloride, sodium selenite, manganese chloride, sodium fluoride, potassium iodide, chromium chloride, sodium molybdate, and the like.

[0137] Vitamins include B complex vitamins, vitamin B1 (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin), vitamin B5 (pantothenic acid), vitamin B6 complex (pyridoxine, pyridoxal-5-phosphate, pyridoxamine), vitamin B7 (biotin), vitamin B9 (folate), vitamin B12 (cobalamin), choline, vitamin A (e.g., retinol (see also provitamin A carotenoids)), vitamin C (ascorbic acid), vitamin D (vitamin D2 (ergocalciferol), vitamin D3 (cholecalciferol)), vitamin E (tocopherols and tocotrienols), and vitamin K (vitamin K1 (phylloquinone), vitamin K2 (menaquinone)).

[0138] Electrolytes such as sodium, potassium, chloride, calcium, magnesium, phosphate and bicarbonate may also be classified as nutrients.

[0139] The pharmaceutical product of the present invention includes a solution provided in a flexible container containing at least one compound selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, the solution being characterized by having a dissolved oxygen (DO) of 1 ppm to 8 ppm. The pharmaceutical product may further include a solution containing nutrients, such as macronutrients and micronutrients. The pharmaceutical product solution can be reconstituted prior to administration to a patient. Administration of one or more solutions of the product can be via various administration routes, such as parenteral, oral, or enteral, potentially after reconstitution of the one or more solutions.

[0140] As used herein, "reconstituted solution" refers to a solution for parenteral administration, which is produced by mixing the contents of the chambers of a multi-chamber container prior to use.

[0141] Parenteral administration is preferred in the context of the present invention. Parenteral nutrition (PN) is the intravenous administration of specialized nutritional products, following the normal process of eating and digestion. When no significant nutrition is available through other routes, it is called total parenteral nutrition (TPN) or total nutrient mixture (TNA), and when some enteral nutrition is also provided, it is called partial parenteral nutrition (PPN). When administered via venous access in the limbs rather than via a central vein as in total parenteral nutrition (CVN), it is sometimes called peripheral parenteral nutrition (PPN). Enteral food administration occurs via the human digestive tract, as opposed to parenteral administration.

[0142] In the context of the pharmaceutical product of the present invention, the solution is provided in a flexible container. In an embodiment of the present invention, the solution is contained in one chamber of a multi-chamber container having at least two, at least three, at least four, at least five, or at least six chambers.

[0143] As used herein, the term "flexible container" refers to a vessel or bag made from a flexible material, such as a bag made from a plastic film. The term does not encompass polymeric rigid or semi-rigid containers.

[0144] The flexible container or bag of the present invention can be made from materials including, but not limited to, polyvinyl chloride (PVC), polypropylene (PP), polyethylene (PE), ethylene vinyl alcohol (EVOH), ethylene vinyl acetate (EVA), and essentially any synthetic material suitable for containing the ingredient to be administered.

[0145] Oxygen-impermeable flexible containers are made with gas barrier films that block oxygen from migrating out of the container. Various technologies have been developed to provide an oxygen barrier to transparent films, such as PE or polyethylene terephthalate films. The main technologies are: (1) coating with a high-barrier material, typically an inorganic oxide layer (e.g., SiOx or Al2O3); and (2) multilayer films, in which the inner layer is made of 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 (EVOH), or a polyolefin (including a combination of two or more of the above layers), and the outer layer is made of a structural polymer (e.g., PE, PP, or PET).

[0146] Therefore, the present disclosure also provides a flexible container, preferably a multi-chamber container, for parenteral or nutritional formulations that can be prepared from any of the flexible membranes described above. For example, the container can be in the form of a bag having one or more compartments or chambers. The bag-like container can contain at least two chambers, but can also contain three, four, five, six or more chambers, and in one preferred embodiment, can contain two or three chambers.

[0147] 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, or neonates, and can provide a carbohydrate formulation as disclosed herein in a first chamber, an amino acid formulation as disclosed herein in a second chamber, and a lipid formulation as disclosed herein in a third chamber of the container.

[0148] The multi-chamber container may include vertical chambers, such as those disclosed in U.S. Patent Publication No. 2007 / 0092579. For example, the multi-chamber container may be configured as a bag containing two, three, four, five, or six adjacent chambers or compartments. If desired, frangible barriers or releasable seals (e.g., peel seals or frangible seals) are used to separate the chambers of the multi-chamber container. The multi-chamber container may also include three chambers for containing the lipid emulsion, carbohydrate formulation, and amino acid formulation, and in certain embodiments, may further include at least two or three smaller chambers containing, for example, a vitamin formulation and / or a trace element formulation. In one specific embodiment, the multi-chamber container of the present invention has a first chamber containing the lipid emulsion of 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.

[0149] The multi-chamber container or multi-chamber bag used in connection with the present invention can be designed to mix formulations contained in each chamber and then parenterally administer the reconstituted contents. Such an MCB can have two, three, four, five, six, or more chambers. The chambers of the MCB can be the same size or can have different sizes to accommodate various compositions and volumes. The chambers can be designed to contain volumes of, for example, 1-5 ml, 5-10 ml, 10-50 ml, 50-100 ml, 100-250 ml, 250-500 ml, 500-1000 ml, or 1000-1500 ml. The MCB can be designed with chambers positioned adjacent to one another. The chambers can have various shapes. The chambers can be oriented horizontally and / or vertically relative to one another. Certain small chambers can be designed to be placed within another larger chamber; for example, a small chamber placed within another larger chamber can be received and secured within the larger chamber by welding at least one edge of the small chamber between the weld seams of the surrounding larger chamber.

[0150] The releasable seals of the multi-chamber container allow formulations to be stored separately and mixed / reconstituted immediately prior to administration, thereby allowing formulations that should not be stored as a mixture for long periods to be stored in a single container. Opening the seal allows communication between the chambers and mixing of the contents of each chamber. The outer seal of the multi-chamber container is a strong seal that will not open under the applied fluid pressure, opening weaker peel seals or fragile seals between the chambers. In some embodiments, the releasable seals of the multi-chamber container can be designed to allow mixing or reconstitution of only selected chambers of the multi-chamber container, for example, mixing a lipid emulsion with the vitamin chamber and the amino acid chamber as needed.

[0151] The multi-chamber container can be provided with instructions describing the desired order for opening the peel seals so that the constituent fluids are mixed in the desired order. The tear strength of two or more peel seals can be varied to facilitate opening the seals in the desired order. For example, the tear strength of the first peel seal can be 1 / 3 to 1 / 2 of the tear strength required to open the second peel seal.

[0152] In embodiments, the container comprises at least a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, and a third chamber containing a lipid formulation, and optionally electrolytes and / or vitamins in at least the first, second, and / or third chambers, and at least one chamber containing sodium selenite, selenious acid, and / or selenium dioxide in the presence of 1 ppm to 8 ppm oxygen.

[0153] As used herein, an amino acid preparation includes a sterile aqueous solution of one or more amino acids and one or more electrolytes. Typically, an amino acid preparation contains about 2 g to about 10 g of amino acids per 100 mL of amino acid preparation, for example, about 3 g to about 9 g and / or about 5 g to about 7 g per 100 mL of amino acid preparation. Typical amino acids contained in amino acid preparations include isoleucine, leucine, valine, lysine, methionine, phenylalanine, threonine, tryptophan, arginine, histidine, alanine, aspartic acid, cysteine, glutamic acid, glycine, proline, serine, tyrosine, ornithine, and taurine. Furthermore, the tyrosine content can be increased by adding, for example, glycyl-tyrosine dipeptide or acetyl-tyrosine (Ac-Tyr). However, glycyl-tyrosine dipeptide typically has improved pharmacokinetics compared to Ac-Tyr, which is excreted more rapidly by the kidney, resulting in reduced tyrosine release into the blood.

[0154] The amino acid formulation may further comprise electrolytes. As used herein, electrolytes include sodium, potassium, calcium, magnesium, and / or phosphate ions. For example, the amino acid preparation may contain, per 100 mL of the amino acid preparation, about 0.1 mmol to about 10 mmol of sodium (e.g., about 3.75 mmol to about 10 mmol of sodium), about 0.1 mmol to about 10 mmol of potassium (e.g., about 3.75 mmol to about 6.90 mmol of potassium), about 0.05 mmol to about 1.0 mmol of magnesium (e.g., about 0.05 mmol to about 0.11 mmol and / or about 0.38 mmol to about 0.65 mmol of magnesium), about 0.1 mmol to about 10 mmol of calcium (e.g., about 1.13 mmol to about 5.10 mmol of calcium), about 0.1 mmol to about 10 mmol of phosphate (e.g., about 0.94 mmol to about 5.10 mmol of phosphate), and 10 mmol or less of chloride (e.g., 5.6 mmol or less of chloride). The coexistence of calcium and phosphorus in the same heat sterilization solution can result in the precipitation of insoluble calcium phosphate. The use of organic salts of phosphorus, such as sodium glycerophosphate 5H2O or calcium glycerophosphate, can increase the calcium and phosphate content without solubility issues or the provision of excess sodium or chloride. In amino acid formulations, sodium can be provided in the form of sodium chloride, calcium in the form of calcium chloride 2H2O or calcium gluconate, magnesium in the form of magnesium acetate 4H2O or magnesium chloride, and potassium in the form of potassium acetate.

[0155] Carbohydrate preparations typically provide calories in the form of glucose. Specifically, carbohydrate preparations provide a sufficient amount of carbohydrate to avoid adverse effects such as hyperglycemia observed in patients receiving parenteral nutrition. Typically, carbohydrate preparations contain approximately 20 to 50 grams of glucose per 100 mL of carbohydrate preparation.

[0156] The lipid formulation referred to in the context of the present invention is an emulsion of an oil phase, an aqueous phase, and an emulsifier that makes the two phases miscible. For lipid emulsions used as injectable emulsions for parenteral nutrition, the emulsion must be an oil-in-water (o / w) emulsion. This means that the oil must be in the internal (or dispersed) phase, while water is in the external (or continuous) phase, since the emulsion must be miscible with blood. Therefore, the lipid emulsions disclosed herein must be substantially free of suspended solids. Of course, lipid emulsions can contain additional ingredients, including, but not limited to, antioxidants, pH adjusters, isotonicity agents, vitamins, trace elements, and various combinations thereof. A summary of lipid emulsions, their composition, and uses is provided, for example, in Driscoll, Journal of Parenteral and Enteral Nutrition 2017, 41, 125-134. Further information regarding the use of lipid emulsions in parenteral nutrition of intensive care patients is provided, for example, in Calder et al., Intensive Care Medicine, 2010, 36(5), 735-749.

[0157] The oil phase of the lipid emulsion may contain polyunsaturated fatty acids, such as long-chain polyunsaturated fatty acids, which may exist as free acids, as ionized or salt forms of free acids, and / or in ester form. Suitable esters of polyunsaturated fatty acids / long-chain polyunsaturated fatty acids include, but are not limited to, alkyl esters (e.g., methyl esters, ethyl esters, propyl esters, or combinations thereof) and triglyceride esters. In some cases, the long-chain polyunsaturated fatty acid has the structure R(C=O)OR', where R is at least 17 carbon atoms, at least 19 carbon atoms, at least 21 carbon atoms, or at least 23 carbon atoms, and R' is absent, H, a counterion, an alkyl group (e.g., methyl, ethyl, or propyl), or a glyceryl group (e.g., R(C=O)OR' is a monoglyceride, diglyceride, or triglyceride). The polyunsaturated fatty acids for use in the lipid formulations disclosed herein include, but are not limited to, linoleic acid (LA), arachidonic acid (ARA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), stearidonic acid (SDA), γ-linolenic acid (GLA), dihomo-γ-linolenic acid (DPA) and docosapentaenoic acid (DPA), particularly DHA, ARA and EPA, each of which can exist in free acid form, ionized or salt form, alkyl ester form, and / or triglyceride form.In some cases, polyunsaturated fatty acids and / or long-chain fatty acids exist in triglyceride form.

[0158] Typically, the lipid formulation comprises about 5% to about 35% by weight of the oil phase, based on the total weight of the lipid emulsion. For example, the oil phase of the lipid emulsion is present in an amount of about 8-12%, about 10-20%, about 10-15%, about 15-20%, about 12-17%, about 18-22%, and / or about 20% by weight, based on the total weight of the lipid formulation. The oil phase typically preferably contains various amounts of omega-3 fatty acids, depending on the source of the oil. Three types of omega-3 fatty acids involved in human metabolism are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), both of which are commonly found in marine fish oils, and alpha-linolenic acid (ALA), which is commonly found in vegetable oils.

[0159] The oil phase and its components can be derived from a single source or from different sources (see, for example, Fell et al., Advances in Nutrition, 2015, 6(5), 600-610). Currently used vegetable oils include, but are not limited to, soybean oil and olive oil, as well as coconut oil or palm kernel oil (medium-chain triglycerides (MCT)). Another source is algae, including microalgae such as Crypthecodinium cohnii and Schizochytrium sp., which in some cases serve as the sole source of the long-chain polyunsaturated fatty acid docosahexaenoic acid (DHA). Marine oils used in parenteral lipid emulsions are processed from oily fish found primarily in cold waters, including, but not limited to, herring, shad, and sardines. However, other marine organisms, such as Antarctic yrill (Euphausia superba Dana), can also be used as oil sources. For example, krill oil provides both EPA and DHA in amounts up to 35 w / w of fatty acids. Krill oil as a component of lipid emulsions is thought to have anti-inflammatory properties due to the presence of DHA and EPA, which are hypothesized to bind endotoxins (Bonaterra et al.: Krill oil-in-water emulsions protects against lipopolysaccharides-induced proinflammatory activation of macrophages in vitro. Marine Drugs (2017), 15:74).

[0160] The lipid emulsion referred to herein can further comprise additional components such as surfactants (also called emulsifiers), co-surfactants, isotonicity agents, pH adjusters, and antioxidants.Generally, surfactants are added to stabilize emulsions by reducing the interfacial tension between the oil phase and the aqueous phase.Surfactants typically comprise a hydrophobic portion and a hydrophilic portion, and the amount of surfactant / emulsifier contained in the formulation is determined based on the amount required to achieve the desired level of emulsion stabilization. Typically, the amount of surfactant in the lipid formulation is about 0.01% to about 3% by weight, e.g., about 0.01% to about 2.5%, about 0.01% to about 2.3%, about 0.02% to about 2.2%, about 0.02% to about 2.1%, about 0.02% to about 2%, about 0.05% to about 1.8%, about 0.1% to about 1.6%, about 0.5% to about 1.5%, about 0.8% to about 1.4% by weight, about 0.9% to about 1.3% by weight, about 1% to about 1.2% by weight, and / or about 1.2% by weight, based on the total weight of the lipid formulation. Suitable surfactants and co-surfactants include surfactants approved for parenteral use, including, but not limited to, phospholipids (e.g., phosphate and soy lecithin), oleates, and combinations thereof. Krill oil can also be used as an emulsifier in lipid emulsions, where the lipid emulsion contains about 0.5 to 2.2 wt. % krill oil based on the total weight of the emulsion, and the emulsion does not contain egg yolk lecithin (US2018 / 0000732A1). Another exemplary surfactant is lecithin, including both natural and synthetic lecithins, such as lecithin derived from egg, corn, or soybean, or mixtures thereof. In some cases, lecithin is present in an amount of about 1.2% based on the total weight of the lipid formulation.

[0161] In some cases, the lipid emulsion formulation contains a co-surfactant. Typically, the amount of co-surfactant in the lipid formulation is less than the amount of surfactant, and typically the amount of co-surfactant in the formulation is about 0.001% to about 0.6% by weight, based on the total weight of the lipid formulation, for example, about 0.001% to about 0.55%, about 0.001% to about 0.525%, about 0.001% to about 0.5%, about 0.005% to about 0.5%, about 0.01% to about 0.4%, about 0.02% to about 0.3%, about 0.03% to about 0.2%, about 0.04% to about 0.1%, and / or about 0.05% to about 0.08%. An exemplary co-surfactant is an oleate, such as sodium oleate. In some cases, the lipid formulation contains lecithin and oleate as surfactants, and a co-surfactant, for example, 1.2% lecithin and 0.03% oleate. Optionally, sodium oleate is present in an amount of about 0.03% by weight based on the total weight of the lipid formulation.

[0162] An isotonicity agent can be added to the lipid emulsion to adjust the osmolarity of the lipid emulsion to a desired level, e.g., a physiologically acceptable level. Suitable isotonicity agents include, but are not limited to, glycerol. Typically, the lipid emulsion has an osmolarity of about 180 to about 300 mOsmol / L, e.g., about 190 to about 280 mOsmol / L, and / or about 200 to about 250 mOsmol / L. In some cases, the lipid emulsion contains about 1 to about 10% by weight, e.g., about 1 to about 5%, about 1 to about 4%, and / or about 2 to about 3% of the isotonicity agent based on the total weight of the lipid formulation. In some cases, the lipid emulsion formulation contains about 2% to about 3% by weight of glycerol.

[0163] A pH modifier can be added to the lipid emulsion to adjust the pH to a desired level, such as a physiologically acceptable pH for parenteral use. Suitable pH modifiers include, but are not limited to, sodium hydroxide and hydrochloric acid. Typically, the lipid emulsion formulation has a pH of about 6 to about 9, e.g., about 6.1 to about 8.9, about 6.2 to about 8.8, about 6.3 to about 8.7, about 6.4 to about 8.6, about 6.5 to about 8.5, about 6.6 to about 8.4, about 6.7 to about 8.3, about 6.8 to about 8.2, about 6.9 to about 8.1, about 7 to about 8, about 7.1 to about 7.9, about 7.2 to about 7.8, about 7.3 to about 7.7, about 7.4 to about 7.6, about 7, about 7.5, and / or about 8.

[0164] The lipid formulation can further include an antioxidant. Suitable antioxidants can be pharmaceutically acceptable antioxidants, including, but not limited to, tocopherols (e.g., gamma tocopherol, delta tocopherol, alpha tocopherol), ascorbyl palmitate, or combinations thereof. In some cases, the lipid emulsion formulation contains an antioxidant in an amount of about 0 to about 200 mg / L, e.g., about 10 to about 200 mg / L, about 40 to about 150 mg / L, about 50 to about 120 mg / L, or about 75 to about 100 mg / L of antioxidant (e.g., vitamin E).

[0165] The aqueous phase (or phases) of all intravenous lipid emulsions must conform to the requirements of the pharmacopoeia suitable for injection, ie, water for injection must be sterile water for injection.

[0166] Lipid emulsions can be prepared according to generally known methods (see, for example, Hippalgaonkar et al., AAPS PharmSciTech 2010, 11(4), 1526-1540 or WO2019 / 197198A1). Generally, water-soluble and oil-soluble components are dissolved in an aqueous phase and an oil phase, respectively.

[0167] Unless otherwise defined herein, all terms used in the context of the present invention should be interpreted according to the understanding of those skilled in the art.

[0168] drawing The present invention is further illustrated by the accompanying drawings, which are not intended to limit the scope of the invention, but rather represent preferred embodiments of aspects of the invention provided for a more detailed explanation of the invention described herein. [Example]

[0169] The present invention is further illustrated by the following examples, which are not intended to limit the scope of the invention but rather represent preferred embodiments of the invention provided for a more detailed description of the invention described herein.

[0170] Example 1: Lab-scale production of selenium-containing solutions for parenteral nutrition or administration To prepare a selenium-containing solution according to the present invention, the required amount of organic acid is dissolved in water for injection, and the pH of the solution is adjusted to a target pH of ±0.5 with NaOH or HCl, as needed. In a next step, selenium, as sodium selenite, selenium dioxide, or selenic acid, is introduced into the solution and stirred or agitated until completely dissolved. The pH is then adjusted again, and if necessary, finally adjusted to a target pH of ±0.2 with NaOH or HCl. Next, the solution is exposed to the atmosphere while stirring or agitating. If the DO is too high and needs to be adjusted lower, oxygen can be introduced by measuring the DO and flushing the solution with nitrogen, stopping the nitrogen flush once the target oxygen concentration is reached.

[0171] Alternatively, the solution can be first flushed with nitrogen to remove essentially all of the dissolved oxygen, and then oxygen can be added, for example, by stirring the solution or by bubbling oxygen through the solution in a measured manner until the desired amount of oxygen is dissolved. Once the desired DO is achieved, the solution is filled into a container under controlled DO and then closed / sealed. The solution can then undergo terminal heat sterilization. Additionally, any remaining gas headspace present in the bag after filling can be completely removed, partially removed, or replaced with oxygen or nitrogen in an amount that defines the amount required to reach the target DO level.

[0172] Example 2: Lab-scale production of a multi-trace element solution for parenteral nutrition or administration containing selenium To prepare a multi-trace element selenium-containing solution for parenteral nutrition / administration, the required amount of organic acid is dissolved in water for injection, and the pH of the solution is adjusted to a target pH of ±0.5 with NaOH or HCl, if necessary. In the next step, the required amount of trace element is weighed and added to the solution with constant stirring or agitation until completely dissolved. If the required amount of a particular trace element is too small to weigh, an intermediate concentrate can be prepared in advance. A predetermined amount of this intermediate solution is then added to the final solution to reach the target concentration. The pH is then again controlled, and if necessary, finally adjusted to a target pH of ±0.2 with NaOH or HCl. The solution is then exposed to the atmosphere with stirring or agitation. If the DO is too high and needs to be adjusted lower, oxygen can be introduced by measuring the DO and flushing the solution with nitrogen, stopping the nitrogen flush once the target oxygen concentration is reached.

[0173] Alternatively, the solution can be first flushed with nitrogen to remove essentially all of the dissolved oxygen, and then oxygen can be added, for example, by stirring the solution or by bubbling oxygen through the solution in a measured manner until the desired amount of oxygen is dissolved. Once the desired DO is achieved, the solution is filled into a container under controlled DO and then closed / sealed. The solution can then undergo terminal heat sterilization. Additionally, any remaining gas headspace present in the bag after filling can be completely removed, partially removed, or replaced with oxygen or nitrogen in an amount that defines the amount required to reach the target DO level.

[0174] Example 3: Method for measuring DO concentration As described in the present description, various methods can be used to determine the DO content of a given solution. Generally, electrochemical or optical sensors are used to determine DO concentrations according to the present invention. A preferred method involves using a fiber optic oxygen meter such as the MICROX TX3, a single-channel temperature-compensated oxygen meter equipped with a fiber optic tracing oxygen microsensor based on glass fiber (e.g., 140 μm). Optical oxygen microsensors (also called optodes) do not consume oxygen, their signal is independent of sample flow rate, the microsensor tip diameter is, for example, <50 μm, they measure oxygen in both the liquid and gas phases, and they have online temperature compensation of the oxygen content. For data visualization during measurement, the oximeter is connected to an LCD & Data-Logger Unit.

[0175] Oxygen measurement and regulation is based on a balance between exposure to nitrogen and oxygen-containing gases during the mixing and filling stages of the process. By acutely and periodically monitoring the solution DO throughout these process steps, the oxygen level in the final container can be controlled. Additionally, the bag headspace can be filled with specific amounts of nitrogen or oxygen to reach a final target level of DO.

[0176] Example 4: Evaluation of various factors on selenite stability A full-factorial DoE was designed to evaluate the influence of five factors on selenate stability.

[0177] Container material: The interaction between selenate and plastic bag materials has been highlighted previously. To assess this factor, a neutral material, a glass bottle, was used as a comparison to the plastic bag.

[0178] Solution pH: All previous studies were carried out at pH < 3.5 to ensure Fe stability. The impact of this parameter was assessed by comparing the pH with the natural pH > 7 obtained by simple dilution of selenite in MilliQ water.

[0179] Sterilization: Final heat sterilization performed on samples may initiate degradative chemical reactions due to heat exposure. To assess the impact of this step, we compared unsterilized vs. sterilized samples with respect to selenate stability.

[0180] Storage temperature: Accelerated testing is traditionally performed at 40°C, but selenite may be more sensitive, so a comparison was made with samples stored at 5°C.

[0181] Dissolved oxygen content: Oxygen is involved in many redox reactions that are detrimental to macro- and micronutrients (especially vitamins). To assess the influence of this parameter on selenate stability, selenate solutions were flushed with oxygen (up to saturation at approximately 8 ppm) or nitrogen (DO<0.5 ppm).

[0182] All combinations of factors were manufactured and stored under appropriate conditions for 6 months and then submitted to several studies to evaluate the effect of each factor on several responses.

[0183] To assess the impact of the above factors, the following readouts were performed:

[0184] Se assay to assess selenium degradation.

[0185] Visual inspection of the sample to detect precipitates, particles, or discoloration.

[0186] pH measurements to assess changes in sample pH after 6 months of storage.

[0187] Dissolved oxygen measurements to assess dissolved oxygen evolution after 6 months of storage.

[0188] Since selenite is involved in different Se redox reactions, redox potential measurements may be useful for understanding the stability of this element, as information on the redox potential of the solution may be useful.

[0189] For nearly every reaction studied, the same sample group behaved differently from other sample groups, observations detailed in Table 3 below.

[0190] Table 3. Evaluation of different readouts visual inspection, pH, dissolved oxygen, delta redox potential, and Se assay for samples flushed with nitrogen and stored in plastic bags versus other samples (i.e., all samples flushed with oxygen, flushed with nitrogen, and stored in glass bottles).

[0191] [Table 3]

[0192] These observations allowed us to conclude that the decomposition of selenium observed in samples flushed with nitrogen and stored in oxygen-permeable plastic bags was probably due to the reduction of selenite SeO3 in H2Se / HSe-, a volatile form of selenium known to exhibit a foul odor similar to that of sulfuric acid gas. The pH / redox diagram shown in Figure 1 illustrates the transformation of these volatile species of SeO3 in a completely oxygen-free medium.

[0193] Example 5: Effect of DO on selenium stability The effect of oxygen appears to be important in the stability of selenite. Indeed, the penetration of small amounts of oxygen into the solution, initially flushed with nitrogen but stored in a glass bottle, certainly prevented the reduction reaction and maintained the stability of SeO3. To confirm this hypothesis, a regression test was performed between the Se assay results and log(dissolved oxygen results). Only the sterilized samples stored at 40°C showed significant Se degradation, suggesting that both sterilization and high-temperature storage increase Se degradation. In fact, most reaction rates are accelerated by heating, explaining why samples that were not sterilized and stored at 5°C for 6 months did not show as significant degradation as samples sterilized and stored at 40°C.

[0194] The fitted line plot shown in Figure 2 shows an 80% fit between Se dose and log oxygen content. Considering the analytical variability of ±5% and the small number of samples used in this regression test, it can be considered significantly representative. Dissolved oxygen content is the most influential parameter and CQA in selenium stability. As shown in Figure 2, a low oxygen content of approximately 0.5 ppm is sufficient to ensure the stability of selenate in solution, and saturation is not required.

[0195] The presence of oxygen promotes the stability of selenite. To ensure that it is not detrimental to other TEs, the stability of a mixture of nine TEs of interest (i.e., Zn, Cu, Cr, Mo, Mn, Fe, I, F, and Se) was evaluated in 200 mM malic acid (to confirm iodide stability) at pH 2.2 and stored in glass bottles (containing approximately 3 ppm dissolved oxygen). The solution was heat sterilized and stored at 40°C or 5°C (T6M 40°C and T6M 5°C, respectively) for 6 months. The concentrations of each trace element recovered after 6 months at the two temperatures are summarized in Table 4.

[0196] Table 4. The initial (theoretical) concentration of each TE and the concentration recovered after 6 months at 5°C or 40°C, along with the corresponding percentage of TE recovered, are shown.

[0197] [Table 4]

[0198] All TE recoveries are approximately 80-90% at both temperatures. While excessive dilution may explain the lower than expected recoveries, samples at 5°C are known to be stable, and therefore can be considered reference. Comparison of the two samples showed that neither TE was significantly degraded after 6 months of storage at 40°C, confirming the hypothesis that selenite is stable in the presence of small amounts of dissolved oxygen. The presence of this oxygen is not detrimental to the stability of the other TE.

[0199] It can be demonstrated that the introduction of oxygen is not a manufacturing problem. For example, instead of flushing the solution with nitrogen as in the past, it should be kept under ambient air to allow sufficient oxygen to dissolve in the solution. This oxygen content could be monitored at any time as an in-process control. During the filling, sterilization, and storage steps, the dissolved oxygen could be maintained in the solution by using oxygen-impermeable bag materials. Such materials neither allow oxygen to enter the bag nor to be removed from the bag (even when in contact with oxygen absorbers). In this way, oxygen remains trapped in the TE solution, avoiding the degradation of Se throughout the product's shelf life.

[0200] Example 6: Tests performed with oxygen semi-permeable and oxygen impermeable barrier membranes Tests were conducted with two different membranes: an oxygen semi-permeable membrane (EU2-S) and an oxygen impermeable membrane (EU2-F).

[0201] The semipermeable membrane is a coextruded membrane with the structure PP|Tie|PA|Tie|PP / SEBS / LLDPE. "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" refers to a special adhesive polymer or "Tie resin," a common polyethylene copolymer of polar and non-polar repeating units, with or without functional reactive groups, used to improve adhesion between the main layers of the multilayer membrane. The oxygen barrier of the membrane is 100% of the polyamide layer (~50 cc / m). 2 / day). Corresponding membranes are described, for example, in US 2010 / 0247935 A1. Semipermeable membranes allow some oxygen to pass through.

[0202] The oxygen impermeable membrane is made from a co-extruded polyolefin material laminated to polyester with a silicon oxide deposit to provide an oxygen barrier, i.e., the oxygen barrier provided by PET-SiOx is <1 cc / m 2 / day.

[0203] In the tests described in Examples 6 and 7, 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 one port tube, made of either semipermeable or oxygen-impermeable material as described above.

[0204] After mixing, each solution was flushed with nitrogen to achieve a DO of less than 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 3). Each container was sealed and wrapped in an oxygen-impermeable aluminum overpouch, and an oxygen absorber was added. Each container was then subjected to moist heat sterilization. The following results were observed:

[0205] As shown in Figure 4, selenite in the EU-2S batch (semipermeable) was found to fall below 80% recovery after approximately 5 months (Figure 4A). It can be concluded that oxygen was drawn out of solution due to the presence of an oxygen absorber in the outer bag and the semipermeable primary membrane, which allowed oxygen to pass through. This did not occur in the EU2-F bag (oxygen impermeable) due to the oxygen barrier membrane (Figure 4B). Selenite was retained and remained above the 80% recovery threshold. Therefore, an oxygen barrier membrane is advantageous for ensuring the stability of selenate-containing solutions. Importantly, as shown in Figure 3, this process was faster in the case of the EU2S semipermeable membrane, and in both cases, the DO dropped from saturation to essentially 0 ppm DO, despite the effect of the oxygen absorber.

[0206] Thus, despite the use of an oxygen barrier membrane, the DO content decreased. For example, some components in the solution, including other trace elements or malic acid, were found to appear to consume DO even though they were no longer lost by permeating the membrane. For example, the presence of malic acid was found to affect DO consumption in such a scenario. Without wishing to be bound by theory, we hypothesize that the redox potential in the solution favors the consumption of (reaction with) oxygen.

[0207] Importantly, selenite remains stable and can be recovered at rates of 80% or greater over a 5-month period as long as the DO concentration does not fall below 0.5 ppm. This is achieved by having a DO greater than 6 ppm at the time of loading, preferably 6-8 ppm (to essentially saturation).

[0208] Example 7: Headspace Relevance In this example, Milli-Q water was used, which was kept in ambient air and therefore saturated with oxygen. The solution volume used was 15 ml.

[0209] As shown in Figure 5(A), without a headspace, the DO content was found to rapidly fall below the 0.5 ppm threshold (in contrast to the setup described above, which includes a headspace), even when an oxygen-impermeable membrane was used. Therefore, the headspace filled with ambient air can be shown to provide an "oxygen stock" to replace the oxygen lost from the container due to the presence of the port tube. Oxygen from the headspace slowly dissolves into the solution until equilibrium is reached. Therefore, in the presence of a headspace, the DO can be maintained above 0.5 ppm over time. Without a headspace (filled gray circle), the selenite would lose DO over time and would not be able to stabilize.

[0210] Therefore, the port tube is another embodiment that can contribute to DO loss because the port tube must be sealed between the membrane layers, and this portion of the seal is difficult to make completely oxygen-tight. Therefore, it is advantageous to improve the oxygen-tightness of the port tube used in the setup described herein, or, if possible, to remove the port tube entirely. In Figure 5A, it is clear that without headspace and port tube (open black circle), DO is higher over time compared to the port tube with present (closed gray circle), and that a 5 ml headspace, for example, cannot fully compensate for the loss over the port tube (open black triangle). Preferably, there is no headspace and, if possible, no port tube to stabilize the selenite-containing solution in the oxygen barrier bag. In such a setup, DO can essentially be maintained (filled gray triangle).

[0211] Figure 5B focuses on the headspace volume. As mentioned above, headspace is necessary to maintain the required DO level in the composition, as oxygen present in the solution at the time of filling is consumed by components present in the solution (DO is consumed by redox reactions in the solution, see black circles, dashed line) or otherwise lost from the container. Neither 2 ml of headspace nor 15 ml of solution per 25 ml container / chamber volume is completely insufficient (black triangles). With 6 ml of headspace, the 0.5 ppm threshold can be nearly met with the presence of a port tube (gray square, continuous line) and without the presence of a port tube (gray square, dashed line). Best results are obtained with 10 ml of headspace per 15 ml of solution in the chamber / container (filled gray circles, continuous line), even with the presence of a port tube (filled gray circles, dashed line).

Claims

1. 1. A pharmaceutical product for preventing or correcting selenium deficiency in a patient, the pharmaceutical product comprising: an oxygen-impermeable flexible container; and a solution provided in the oxygen-impermeable flexible container, the solution comprising at least one selenium compound in the form of Se(IV) selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, the solution comprising 0.5 ppm to 8 ppm of dissolved oxygen (DO).

2. 10. The pharmaceutical product of claim 1, wherein the DO stabilizes the at least one selenium compound in solution for at least 3 months when stored at a temperature between 1 and 50°C.

3. 10. The pharmaceutical product of claim 1, wherein the DO stabilizes the at least one selenium compound in solution at a temperature of about 18°C ​​to 25°C for at least 6 months.

4. 10. The pharmaceutical product of claim 1, wherein the solution is a sterile solution.

5. The pharmaceutical product according to claim 1 , wherein the DO concentration is 0.5 ppm to 2 ppm.

6. 2. The pharmaceutical product according to claim 1, wherein the DO concentration is 1 ppm to 2 ppm.

7. 10. The pharmaceutical product of claim 1, wherein the oxygen-impermeable flexible container further comprises a headspace having a gas composition comprising oxygen.

8. 10. The pharmaceutical product of claim 1, wherein the at least one selenium compound comprises sodium selenite.

9. 10. The pharmaceutical product of claim 1, wherein the solution has an acidic pH ranging from 1 to 4.

10. 2. The pharmaceutical product of claim 1, wherein the solution comprises an organic acid selected from the group consisting of malic acid, tartaric acid, citric acid, maleic acid, and fumaric acid, and the concentration of the organic acid ranges from 100 mM to 400 mM.

11. 10. The pharmaceutical product of claim 1, wherein the solution comprises malic acid.

12. 10. The pharmaceutical product of claim 1, wherein the solution does not contain macronutrients selected from the group consisting of carbohydrates, proteins, and lipids, and the solution does not contain any other nutrients.

13. 10. The pharmaceutical product of claim 1, wherein the solution comprises at least one additional trace element selected from the group consisting of zinc, iron, copper, manganese, chromium, iodine, fluoride, and molybdenum.

14. 10. The pharmaceutical product of claim 1, wherein the solution is for parenteral administration.

15. 2. The pharmaceutical product of claim 1, wherein the at least one selenium compound is present in an amount corresponding to 10 to 200 μg.

16. 10. A pharmaceutical product for preventing or correcting selenium deficiency in a patient according to claim 1, wherein the oxygen-impermeable flexible container is a multi-chamber container and the solution is contained within a chamber of the multi-chamber container.

17. 17. The pharmaceutical product of claim 16, wherein the oxygen-impermeable flexible container comprises a first chamber containing a carbohydrate formulation, a second chamber containing an amino acid formulation, and a third chamber containing a lipid formulation, and at least one of the first chamber, the second chamber, or the third chamber contains a solution.

18. 17. The pharmaceutical product of claim 16, wherein the oxygen-impermeable flexible container comprises 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.

19. 17. The pharmaceutical product of claim 16, wherein the at least one selenium compound comprises sodium selenite.

20. The solution is as follows: a. dissolving at least one selenium compound in the form of Se(IV), preferably selected from the group consisting of sodium selenite, selenious acid and / or selenium dioxide, in a liquid medium, preferably water for injection, to produce a solution having a selenium concentration of 0.28 to 28 mg / L; b) optionally further dissolving, alone or together with the selenium compound in the form of Se(IV), an organic acid selected from the group comprising malic acid, tartaric acid, citric acid, maleic acid and fumaric acid, and / or at least one additional trace element selected from the group comprising zinc, iron, copper, manganese, chromium, iodine, fluoride and molybdenum; c. adjusting the solution to a dissolved oxygen concentration of 0.5 ppm to 8 ppm; and d. Sterilizing the solution, preferably by heat sterilization.

20. A method for preparing a medicament for preventing or correcting selenium deficiency in a patient according to any one of claims 1 to 19, the medicament being prepared by the steps comprising:

21. 1. A sterile solution for oral administration comprising at least one selenium compound in the form of Se(IV) selected from the group consisting of sodium selenite, selenious acid, and selenium dioxide, wherein the sterile solution is formulated to prevent or correct selenium deficiency in a patient, the solution comprises dissolved oxygen (DO), and the sterile solution is contained in an oxygen-impermeable flexible container.

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