Parenteral nutrition solutions containing selenium sources

Abstract

To provide parenteral nutrition solutions containing selenium sources.SOLUTION: According to the present invention, there is provided a pharmaceutical product for preventing or correcting selenium deficiency in a patient, the pharmaceutical product comprising a solution contained in at least one chamber of a multi-chamber container having at least two chambers, the solution comprising at least one of selenate and / or selenoamino acid.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 a flexible container, characterized in that the solution comprises selenate and / or at least one seleno-amino acid, such as selenomethionine or selenocysteine.

[0003] In an embodiment, the pharmaceutical solution of the present invention contains at least one additional trace element. The solution 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 of synthetic or plastic materials, 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. In embodiments, the material is oxygen-impermeable.

[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, micronutrients may be added to the mixture or macronutrients via an inlet on a container or bag (septum) or added to an infusion line via a Y-connector, in the sense that they are administered to a patient. 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 a nutritional multi-chamber bag have already been developed, such as Pediaven, a binary parenteral nutrition solution for infants, children, and adolescents containing trace elements in a glucose chamber. 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.

[0009] It is known in the art that selenium, iodine, and copper can undergo chemical reactions, especially under extreme conditions such as heat sterilization steps and storage periods, making them difficult to include in nutritional bags (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).

[0010] Furthermore, various formulation studies have observed significant stability problems, particularly loss 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 sodium selenite (and selenious acid) is prone to adsorption, for example, to 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 to selenium dioxide at low pH, which is also a volatile substance under certain conditions. Furthermore, nutrient solutions containing selenate salts are not known in the art.

[0011] 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.

[0012] Thus, to date, no ready-to-prepare pharmaceutical product, including a solution for parenteral administration to patients in need thereof, is available that contains selenium and is stable over an extended period of time. Specifically, no such ready-to-prepare product provided in a flexible bag has been utilized to date. Selenium, and potentially other trace elements, must be manually added to the prepared solution immediately prior to administration. This process is associated with a significant risk of error, e.g., regarding the amount of trace elements, or of introducing contamination into the sterile product. Contamination could include potential infectious agents, which pose a significant and unpopular risk to already compromised hospital patients, particularly those receiving and requiring nutritional solutions, such as parenteral administration.

[0013] In light of the prior art, there remains a significant need for a ready-to-use, sterile medical product for intravenous or parenteral administration used to prevent or correct selenium deficiency in patients. Specifically, there is a lack of a product that is simple and easy to use while avoiding an additional mixing step. Because selenium in solution is unstable, such products are not readily available. Summary of the Invention

[0014] In light of the prior art, the technical problem underlying the present invention is to provide a pre-prepared, ready-to-use medical product for preventing or correcting selenium deficiency in a patient, comprising a solution containing selenium provided in a flexible container, preferably a flexible container made from an oxygen-impermeable material.

[0015] This problem is solved by the features of the independent claims. Preferred embodiments of the invention are provided by the dependent claims.

[0016] Accordingly, the present invention relates to a medical product for preventing or correcting selenium deficiency in a patient, comprising a solution provided in a flexible container, characterized in that it comprises at least one of selenate and / or selenoamino acids, such as selenomethionine or selenocysteine.

[0017] In an embodiment, the present invention relates to a medical product for preventing or correcting selenium deficiency in a patient, comprising a solution provided in a flexible container, wherein the solution comprises at least one of selenate, selenomethionine, or selenocysteine.

[0018] In embodiments of the present invention, the medical product solutions of the present invention comprise selenate. In some embodiments, the medical product solutions of the present invention comprise selenomethionine. In some embodiments, the medical product solutions of the present invention comprise selenocysteine.

[0019] It was quite surprising that selenate, selenomethionine, or selenocysteine ​​was stable in the solution provided in the flexible container of the medical product of the present invention. This is particularly unexpected, since these selenium-containing compounds are generally expected to be unstable due to decomposition and adsorption processes. Furthermore, the reduction process is thought to lead to instability of the selenium-containing compounds. In this regard, vitamins have been reported to be sensitive to oxygen when stored in sealed containers, such as sealed flexible bags.

[0020] However, the present invention is based on the unexpected discovery that selenates, specifically sodium selenate or potassium selenate, but also selenomethionine or selenocysteine, are stable in the solutions provided in the flexible containers of medical nutritional products.

[0021] In embodiments of the medical products of the present invention, selenate, selenomethionine and / or selenocysteine ​​are stable in solution for at least 3 months when stored at temperatures between 1 and 50° C. It was unexpected that comparative experiments could demonstrate that the listed selenium-containing compounds are stabilized in solution for extended periods of time, such as at least 3 months, at various temperatures tested in the range of 1 to 50° C.

[0022] In embodiments, selenate, selenomethionine and / or selenocysteine ​​are stable in solution for at least 3 months when stored at up to 40° C. Additionally, in embodiments, selenate, selenomethionine and / or selenocysteine ​​are stable in solution for at least 6 months when stored at up to 40° C.

[0023] In a further embodiment of the invention, the selenate, selenomethionine and / or selenocysteine ​​are stable in solution for at least 6 months, preferably 12 months, more preferably 18 months, and most preferably 24 months.

[0024] In an embodiment of the invention, selenate, selenomethionine and / or selenocysteine ​​are stable in solution at temperatures up to 30°C for at least 6 months, preferably 12 months, more preferably 18 months, and most preferably 24 months.

[0025] In a further embodiment of the invention, selenate, selenomethionine and / or selenocysteine ​​are stable in solution for at least 6 months, preferably 12 months, more preferably 18 months, and most preferably 24 months at a temperature of about 18-25°C.

[0026] In a further embodiment of the present invention, the selenate, selenomethionine and / or selenocysteine ​​are stable for at least 6 months, preferably at least 12 months, more preferably at least 18 months, and most preferably at least 24 months at normal storage temperatures, for example, but not limited to, room temperature, which varies from 15 to 30°C, more preferably from 18 to 25°C, or under refrigerated conditions, such as from 1 to 10°C, preferably from 2 to 8°C, or from 3 to 7°C.

[0027] In embodiments of the invention, the pharmaceutical solution is a sterile solution. In some embodiments, the pharmaceutical solution of the invention may be sterile.

[0028] An important advantage of the solutions of the present invention is that they can be sterilized after preparation and packaging in flexible bags that can remain airtight and liquid-tight without significant loss of trace elements, particularly selenate, selenomethionine, and / or selenocysteine. In embodiments, the solutions of the present invention undergo terminal heat sterilization after preparation of the solutions. Sterilization can be carried out before or after filling the solutions into the flexible bags of the medical products of the present invention.

[0029] Sterilization of the product 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.

[0030] In the context of the present invention, the terms "flexible bag" and "flexible container" can be used interchangeably.

[0031] It is a great advantage of the present invention that selenium provided as selenate, selenomethionine and / or selenocysteine ​​is stable in the context of the medical products of the present invention, since there is no need to establish complex technical means for stabilization, including complex technical instrumentation and solution manipulation.

[0032] In an embodiment, the medical product solution comprises a selenate salt, preferably selected from the group consisting of sodium selenate, potassium selenate, barium selenate, and ammonium selenate, more preferably sodium selenate and potassium selenate. The use of selenate salts, particularly sodium selenate and potassium selenate, in the context of the present invention is particularly advantageous, since these salts have been found to be very stable in solution, especially at neutral and acidic pH. This was quite surprising, since other selenium sources, such as sodium selenite, have been reported and observed to be unstable in acidic or neutral solutions without further characterization.

[0033] The medical product of any one of the preceding claims, wherein the solution 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. A particular advantage of the solutions of the present invention is that selenate, selenomethionine, and / or selenocysteine ​​are stable in solutions at acidic pHs, as well as near-neutral pHs in the range of 7 to 7.5. Selenium in products of the present invention is particularly stable at acidic pHs, e.g., within the ranges of 1 to 4, 1.5 to 3.5, 1.8 to 3.4, 2 to 3.3, 2.1 to 3.2, 2.2 to 3.1, 2.3 to 3.0, 2.4 to 2.9, 2.5 to 2.8, and 2.6 to 2.7. The indicated ranges include the stated endpoints. Ranges incorporating any combination of the disclosed endpoints are considered embodiments of the invention.

[0034] Such stability at acidic pH conditions is especially important when the solution contains other trace elements that are not stable at neutral pH but are stable only under acidic conditions, which is particularly the case for iodide(I), which has been reported to be more stable in acidic pH solutions.

[0035] However, it also contains some of the trace elements copper (Cu), zinc (Zn), iron (Fe), manganese (Mn), chromium (Cr), fluoride (F), and molybdenum (Mo). It is therefore an important advantage of embodiments of the medical products of the present invention that a solution having an acidic pH can stabilize not only selenium but also other trace elements in the solution over long storage periods.

[0036] 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 50 mM to 400 mM, preferably 190 mM to 220 mM, more preferably in the range of about 200 mM.

[0037] 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.

[0038] In another particular embodiment, the solution comprises malic acid. In an embodiment, the solution comprises malic acid at a concentration ranging from 50 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.

[0039] 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, 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.

[0040] In an embodiment of the pharmaceutical product of the present invention, the solution does not contain macronutrients, preferably they are selected from the group comprising carbohydrates, proteins and lipids, and preferably the solution does not contain other nutrients.

[0041] In further embodiments, the solution does not contain carbohydrates. In embodiments, the solution does not contain proteins or amino acids, optionally in addition to containing selenium. In embodiments, the solution does not contain lipids. In embodiments, the solution may 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 besides water (if water is considered a nutrient).

[0042] 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] In an embodiment, the pharmaceutical solutions of the present invention contain at least zinc, iron, manganese, copper, fluoride and molybdenum as additional trace elements.

[0050] 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.

[0051] 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.

[0052] As additional nutritional components in addition to selenium, the pharmaceutical of the present invention may contain at least one of the following nutrients: carbohydrates, primarily dextrose, dextrin, polyols; amino acids, peptides and / or proteins; electrolytes, such as sodium, magnesium, potassium, calcium and / or phosphate; lipids, such as olive oil, soybean oil, fish oil, algae oil, rapeseed oil, structured lipids of long-, medium- and short-chain fatty acids; vitamins, such as A, B1, B2, B3, B5, B6, B8, B9, B12, C, D, E and / or K.

[0053] 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.

[0054] In the context of the present invention, the claimed medical product solution may contain selenate, selenomethionine and / or selenocysteine ​​in an amount equivalent to 10-200 μg, preferably 40-100 μg, more preferably about 55 μg-75 μg, most preferably about 60-70 μg of selenium.

[0055] 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.

[0056] For solutions of the present invention, selenium is provided as selenate, selenomethionine, and / or selenocysteine. Thus, for example, if 70 μg of selenium is provided in the form of sodium selenate (NaSeO) having a molar mass of 188.947 g / mol, where selenium has a molar mass of 78.97 g / mol, this corresponds to approximately 167.5 μg of sodium selenate.

[0057] Therefore, 70 μg of selenium is converted to selenomethionine (SeMet or CH), which has a molar mass of 196.106 g / mol. 11 When provided in the form of NOSe, selenium has a molar mass of 78.97 g / mol, which corresponds to approximately 173.7 μg of selenomethionine.

[0058] Furthermore, if 70 μg of selenium is provided in the form of selenocysteine ​​(Se-Cys or C3H7NO2Se) having a molar mass of 168.065 g / mol, where selenium has a molar mass of 78.97 g / mol, this corresponds to approximately 148.9 μg of selenocysteine.

[0059] 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.

[0060] 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.

[0061] In pharmaceutical embodiments of the present invention, the solution in the flexible container has a volume of approximately 25 ml. In such embodiments, 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. Preferred Se concentrations in the present invention range from 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.

[0062] 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.

[0063] 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.

[0064] [Table 1]

[0065] 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.

[0066] 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.

[0067] [Table 2]

[0068] In the context of the pharmaceutical preparation of the present invention, the volume of the solution containing selenate, selenomethionine and / or selenocysteine ​​may be 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 range 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.

[0069] 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.

[0070] 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 selenate, selenomethionine and / or selenocysteine.

[0071] 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 selenate, selenomethionine and / or selenocysteine.

[0072] 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 selenate, selenomethionine and / or selenocysteine ​​in a further chamber, optionally together with other trace elements.

[0073] 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 containing selenate, selenomethionine and / or selenocysteine ​​is present in a fourth chamber.

[0074] In an embodiment 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, and the solution preferably comprises sodium selenate or potassium selenate. In an embodiment of the invention, the container is made from a flexible material.

[0075] In certain embodiments comprising 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 a selenate salt, preferably sodium selenate or potassium selenate. In embodiments of the invention, the container is made from a flexible material.

[0076] In an embodiment of the present invention, the solution is prepared by dissolving selenate, selenomethionine, and / or selenocysteine ​​in a liquid medium. In a preferred embodiment, the liquid medium is water, preferably ultrapure water (UPW; also called deionized water (DI)) or water for injection. UPW water has been purified of organic particles and dissolved gases by techniques known in the art. Water for injection is ultra-high quality water without significant contamination.

[0077] 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 selenate, selenomethionine, and / or selenocysteine ​​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 adjusting the solution to an acidic pH, preferably by providing an organic acid such as malic acid, and optionally adding at least one additional trace element, preferably selected from the group comprising zinc, iron, copper, manganese, chromium, iodine, fluoride and molybdenum; c. Sterilize the solution, preferably by heat sterilization This includes:

[0078] Sterilization of the solution can be carried out before or after the solution is filled into the flexible container of the present invention.

[0079] The optional method step of adjusting the pH of the solution to an acidic pH may be achieved by dissolving an acid, such as an organic acid selected from the group including malic acid, tartaric acid, citric acid, maleic acid and fumaric acid.

[0080] 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.

[0081] The present invention further relates to a sterile or sterilized solution for parenteral administration comprising at least one compound selected from the group comprising selenate, selenomethionine and / or selenocysteine ​​for use in preventing or correcting selenium deficiency in a patient.

[0082] 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 selenate, selenomethionine and / or selenocysteine.

[0083] 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.

[0084] In relation to the method of preventing or correcting selenium deficiency in a patient, in one embodiment the patient is an adult patient. In another embodiment, the patient is a pediatric patient.

[0085] As used herein, the term "adult," as used herein, refers to a person 20 years of age or older. The term "child" refers to newborns, e.g., preterm (earlier than expected) babies up to 1 month of age, full-term and post-term babies, infants 1 month to 1 year of age, infants 1-12 years of age, and adolescents 13-19 years of age.

[0086] 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]

[0087] [Figure 1]FIG. 1 refers to a solution containing selenium as sodium selenate. [Figure 2] FIG. 2 refers to a solution containing selenium as selenomethionine. [Figure 3] FIG. 3 refers to a solution containing selenium as selenious acid. DETAILED DESCRIPTION OF THE INVENTION

[0088] All cited references, both patent and non-patent, are incorporated herein by reference in their entirety.

[0089] The present invention is a sterile pharmaceutical product for preventing or correcting selenium deficiency in a patient, comprising a solution provided in a flexible container containing at least one compound selected from the group consisting of selenate, selenomethionine, and selenocysteine.

[0090] 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 for medical purposes to prevent or correct selenium deficiency in a patient.

[0091] 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.

[0092] 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.

[0093] 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

[0094] 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 those 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.

[0095] 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.

[0096] 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.

[0097] 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. RDAs are higher than the EAR and identify 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].

[0098] In the context of the present invention, a pharmaceutical product comprises a flexible container or bag containing at least one compound selected from the group consisting of selenate, selenomethionine and / or selenocysteine,

[0099] Selenite ion is SeO4 2- Selenates are similar to sulfates and have similar chemical properties. They are highly soluble in aqueous solutions at ambient temperature. Under strongly acidic conditions, the hydrogen selenate ion HSeO4 - is formed. This corresponds to selenate, H2SeO4, a strong acid. Unlike sulfates, selenate is a somewhat better oxidizing agent. It can be reduced to selenite or selenium. Selenate is a component of various salts, including sodium selenate, potassium selenate, barium selenate, and ammonium selenate.

[0100] Sodium selenate is an inorganic compound with the formula Na2SeO4 and should not be confused with sodium selenite. It exists as the anhydrous salt, heptahydrate, and decahydrate. Sodium selenate can be produced by first oxidizing selenium with nitric acid to produce selenious acid, which is neutralized to form sodium selenite. Sodium selenite is oxidized in hydrogen peroxide in a basic medium to form selenic acid, which is then spray-dried.

[0101] Potassium selenate (K2SeO4) is an odorless white solid formed as the potassium salt of selenic acid. Potassium selenate can be produced by the reaction of selenium trioxide with potassium hydroxide. Alternatively, it can be produced by the reaction of selenious acid with potassium hydroxide and then oxidizing the resulting potassium selenite with bromine.

[0102] Selenomethionine (SeMet) is a naturally occurring amino acid. The enantiomer of L-selenomethionine is the predominant form of selenium found in Brazil nuts, cereals, soybeans, and grassland legumes, while Se-methylselenocysteine ​​or its γ-glutamyl derivative is found in Astragalus, Allium, and Brassica species. In the body, selenomethionine is randomly incorporated in place of methionine. Selenomethionine is readily oxidized. Selenomethionine has antioxidant activity resulting from its ability to deplete reactive oxygen species. Selenium and methionine also play distinct roles in the formation and recycling of glutathione, an important endogenous antioxidant in many organisms, including humans.

[0103] Selenocysteine ​​(symbol Sec, U, or Se-Cys) is considered the 21st proteinogenic amino acid and occurs naturally in all three domains of life as a building block for selenoproteins, but not in all lineages. Selenocysteine ​​is a cysteine ​​analogue that contains a selenium-containing selenol group instead of a sulfur-containing thiol group. Selenocysteine ​​is present in several enzymes, including glutathione peroxidase, tetraiodothyronine 5'-deiodinase, thioredoxin reductase, formate dehydrogenase, glycine reductase, selenophosphate synthetase 2, methionine-R-sulfoxide reductase B1 (SEPX1), and several hydrogenases.

[0104] 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.

[0105] 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 single-celled eukaryotes such as Plasmodium) and 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.

[0106] According to one embodiment of the present invention, sterilization is carried out by heating. According to another embodiment of the present invention, the method includes 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, with or without pressure. According to one embodiment of the present invention, sterilization by moist heat is preferred. Generally, this moist heat sterilization can be used for medicines, medical devices, disposable instruments such as plastic bags, glass containers, surgical dressings, etc.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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) may be 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), cerotic acid (C26); monounsaturated fats, such as myristyl, pentadecanoic, palmitoyl, 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).

[0114] 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.

[0115] In the pharmaceutical preparations of the present invention, trace elements are provided as chloride, potassium or sodium salts such as zinc chloride, iron chloride, copper chloride, sodium selenate, manganese chloride, sodium fluoride, potassium iodide, chromium chloride, sodium molybdate, etc.

[0116] 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 (folic acid), 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)).

[0117] Electrolytes such as sodium, potassium, chloride, calcium, magnesium, phosphate and bicarbonate may also be classified as nutrients.

[0118] The pharmaceutical preparations of the present invention include a solution provided in a flexible container containing at least one compound selected from the group consisting of selenate, selenomethionine, and / or selenocysteine. The pharmaceutical preparations may further include solutions containing nutrients, such as macronutrients and micronutrients. The pharmaceutical preparation solutions can be reconstituted prior to administration to a patient. Administration of one or more solutions of the product can be via various routes of administration, such as parenterally, orally, or enterally, potentially after reconstitution of the one or more solutions.

[0119] 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.

[0120] 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.

[0121] In the context of the pharmaceutical product of the present invention, the solution is provided in a flexible container. In embodiments 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.

[0122] 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.

[0123] 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.

[0124] For example, 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).

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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 selenate, selenomethionine and / or selenocysteine.

[0132] 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.

[0133] 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.

[0134] 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.

[0135] 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.

[0136] The oil phase of the lipid emulsion may contain unsaturated 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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).

[0143] 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.

[0144] Lipid emulsions can be prepared according to generally known methods (see, for example, 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.

[0145] 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.

[0146] 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.

[0147] Figures 1-3: The recovery of the initial concentrations of the different trace elements is shown in percent (%) and is indicated on the Y-axis of the figure. The analyzed time points are indicated on the X-axis. Time point -0.5 corresponds to the results of TE dosing for the unsterilized sample at TO. Time point 0 corresponds to the results of TE dosing immediately after sterilization. Time point 0.5 corresponds to the results of TE dosing after an accelerated stability stress cycle (i.e., 5°C / 50°C, 48h / 48h repeated three times). Time points 1, 3, and 6 correspond to the results of TE dosing after 1 month, 3 months, and 6 months of storage at 40°C / 25% RH. [Example]

[0148] 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.

[0149] Example 1: Lab-scale production of selenium-containing solutions for parenteral nutrition or administration To prepare the selenium-containing solution of 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 selenate, selenomethionine, or selenocysteine ​​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. The solution can then be filled into containers, successively sealed / sealed, and terminally heat sterilized.

[0150] 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, as needed. In the next step, the required amount of each trace element (sodium selenate and / or selenomethionine and / or selenocysteine) is weighed and added to the solution with constant stirring or agitation until completely dissolved. For certain trace elements, if the required amount 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. After the sample is filled, the container is closed / sealed and can undergo terminal heat sterilization.

[0151] Example 3: Stabilization of selenium by using selenate, selenomethionine, or selenocysteine Selenite, along with other trace elements, was introduced in a separate chamber from the macronutrients. Better stability of all components was achieved at an acidic pH of 1-4, preferably 2.2-3.5.

[0152] Better stability was achieved with the addition of organic acids such as malic acid, tartaric acid, citric acid, maleic acid or fumaric acid.

[0153] Sodium selenate, selenomethionine, and selenocysteine ​​each remained stable when introduced into specific separation chambers (after 6 months of storage at 40°C / 25% RH) either alone or together with other trace elements in solution.

[0154] Another method of introduction is to include sodium selenate and / or selenomethionine in the glucose, amino acid or lipid chamber.

[0155] Example 4: Evaluation of selenium stability using solutions containing selenate, selenomethionine, or selenite Figures 1-3 show that the stability of selenium when introduced as selenate (Figure 1) or selenomethionine (Figure 2) is superior to that of selenite (Figure 3) after 3 months of storage. Selenite and selenomethionine remained stable for up to 6 months. Analysis of selenite was discontinued after 3 months due to its lack of stability.

[0156] For the three test solutions containing different forms of selenium, selenium was mixed with other TEs (Zn, Cu, Mn, F, I, Mo, Cr, Fe) introduced as chloride salts. The solutions were acidified to pH 2.2 using malic acid and underwent terminal heat sterilization before storage.

[0157] The results, shown in Figures 1-3, show that selenium concentrations remained stable in solutions containing selenate or selenomethionine, whereas selenium concentrations decreased significantly in solutions containing selenium as selenite. Concentrations of other TEs remained nearly stable under all conditions tested.

Claims

1. 1. A pharmaceutical product for preventing or correcting selenium deficiency in a patient, the pharmaceutical product comprising a solution contained in at least one chamber of a multi-chamber container having at least two chambers, the solution comprising at least one of selenate and / or selenoamino acid.

2. 2. The pharmaceutical product of claim 1, wherein the selenate and / or selenoamino acid is stable 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 selenate and / or selenoamino acid is stable 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. 10. The pharmaceutical product of claim 1, wherein the solution comprises a selenate salt selected from the group consisting of sodium selenate, potassium selenate, barium selenate, and ammonium selenate.

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

7. 10. 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.

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

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

10. 10. The pharmaceutical product of claim 1, wherein the solution does not contain macronutrients selected from the group comprising carbohydrates, proteins and lipids.

11. 10. The pharmaceutical product of claim 1, wherein the solution is adapted for parenteral use.

12. 2. The pharmaceutical product of claim 1, wherein the solution contains selenate and / or selenoamino acids in an amount corresponding to 10 to 200 μg of selenium.

13. 2. The pharmaceutical product of claim 1, wherein the multi-chamber 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 the first, second and / or third chambers contain selenate and / or selenoamino acids.

14. 2. The pharmaceutical product of claim 1, wherein selenate and / or selenoamino acid is present in the fourth chamber.

15. 10. The pharmaceutical product of claim 1, wherein the solution comprises sodium selenate or potassium selenate.

16. The pharmaceutical product according to claim 1, wherein the selenoamino acid is selenomethionine or selenocysteine.

17. 4. The pharmaceutical product of claim 3, wherein the selenate and / or selenoamino acid is stable in solution for at least 24 months.

18. 8. The pharmaceutical product according to claim 7, wherein the concentration of the organic acid is in the range of 50 mM to 400 mM.

19. 10. The pharmaceutical product of claim 9, wherein the solution has a pH of 1 to 4.

20. 10. The pharmaceutical product of claim 1, wherein the multi-chamber container comprises electrolytes and / or vitamins in the first chamber, the second chamber and / or the third chamber.

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