Parenteral nutrition formulation

Abstract

To provide parenteral nutrition formulations.SOLUTION: The present disclosure relates to multi-chamber containers and to parenteral nutrition formulations, including ready-to-use parenteral nutrition formulations reconstituted from and amino acid formulations. More specifically, the present disclosure relates to formulations comprising butyrate derivatives, specifically arginine butyrate, for use in adult or pediatric patients. The present disclosure further provides methods for reducing or preventing systemic and local inflammation in patients receiving parenteral nutrition, as well as methods for maintaining or improving their systemic and local immunity and intestinal barrier function.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Technology field The present disclosure relates to parenteral nutrition formulations, including ready-to-use parenteral nutrition formulations reconstituted from multi-chamber containers and amino acid formulations. More specifically, the present disclosure relates to formulations containing butyrate derivatives, specifically arginine butyrate, for use in pediatric or adult patients. The present disclosure also provides methods for reducing or preventing systemic and local inflammation in patients receiving parenteral nutrition, and for maintaining or improving the patient's systemic and local immunity and intestinal barrier function. [Background technology]

[0002] 2. Description of Related Art Parenteral nutrition (PN) prevents progressive malnutrition and provides life-saving treatment for many patients with gastrointestinal disorders. However, PN appears to be associated with increased incidence of infection and inflammation, both local and systemic, in critically ill patients receiving long-term parenteral nutrition who are unable to receive any nutrition orally or enterally. Research also suggests that impaired intestinal barrier function may be at least partially responsible (Fukatsu and Kudsk, Surg Clin North Am. 2011;91(4):755-770). Thus, the intestinal barrier (used interchangeably herein as "intestinal barrier," "gut barrier," or simply "barrier"), local and systemic inflammation, and local and systemic (nonspecific) immunity have been the subject of investigation for many years.

[0003] The intestinal tract is lined with a single layer of columnar epithelial cells, forming the aforementioned intestinal barrier that allows selective absorption of nutrients while restricting access to pathogens and food-borne antigens. Therefore, precise regulation of epithelial barrier function is necessary to maintain mucosal homeostasis, which in part depends on the balance between intraepithelial barrier-forming elements and pro- and anti-inflammatory factors in the mucosa. Pathologies such as inflammatory bowel disease (IBD) involve leakage of the epithelial barrier, resulting in excessive exposure to microbial antigens, leukocyte recruitment, release of soluble mediators, and ultimately mucosal damage. The inflammatory microenvironment (referred to herein as "local inflammation") affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial cell-cell junctions through direct and indirect mechanisms (Luissint et al., Inflammation and the Intestinal Barrier: Leukocyte-Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair. Gastroenterology 2016;151(4):616-632).

[0004] Another important aspect of the intestinal defense relates to the immune system. In particular, the mucosal immune system provides approximately 50%-60% of the body's total immunity and produces approximately 7% of the antibodies produced by the human body. For example, it produces specific antibodies against luminal bacteria in the form of secretory IgA (sIgA), which functions not through inflammation but through adhesion and bacterial clearance. In the context of the present invention, this is referred to as "local immunity" of the intestine. The protective role of secretory IgA has generally been evaluated in the context of mucosal infections, where it has been shown to act as a first line of defense by preventing microbial adherence to and access to the epithelium, a process known as immune clearance. However, IgA also appears to play an important role in maintaining the complex interactions between commensals, the epithelium, and the immune system (Kato et al., Immunological Reviews, 2014;260:76-75).

[0005] Although a brief pause in oral intake minimizes changes to the mucosal / microbial interface, severe illness with concomitant acidosis, prolonged gastrointestinal starvation, exogenous antibiotics, and disruption of mucosal defenses can render the host increasingly vulnerable to bacterial attack. Therefore, much research has been conducted to evaluate new chemical entities and their potential role in developing improved parenteral nutrition formulations that avoid or reduce the effects of long-term PN on the intestine, as described above. The term "long-term PN," as used herein, refers to total parenteral nutrition for more than 7 days, especially more than 10 days, in patients receiving approximately 95%–100% of their energy requirements from parenteral nutrition. "Total parenteral nutrition" (TPN) refers to patients receiving parenteral nutrition as their only source of nutrition.

[0006] Nutritional pathways are also known to affect inflammatory responses generated by both innate and adaptive immunity. Enterally fed animals have been found to have elevated levels of intestinal IgA, which may help neutralize bacteria in the lumen. As mentioned above, intestinal starvation by parenteral nutrition did not increase intestinal (or pulmonary) IgA, indicating a deficit in both innate and adaptive mucosal immunity.

[0007] The above issues are relevant to all patients receiving PN, including pediatric and adult patients. For example, preterm infants often require parenteral nutrition for the first few weeks of life due to the transient and immature nature of their intestines. Children suffering from intestinal failure (IF) may even require long-term parenteral nutrition. In addition to the gastrointestinal disturbances associated with long-term PN, providing sufficient protein and energy to maintain growth and neurodevelopment is a challenge. It has been shown that early parenteral nutrition (PN) containing more than 2.5 g / kg / day of amino acids and at least 40 kcal / kg / day of energy from the first day of life provides sufficient nutritional intake to prevent malnutrition and postnatal growth restriction in preterm infants (Rigo and Senterre, The Journal of Nutrition 143(12), 2913, 2066S-2070S).

[0008] Therefore, it is crucial to understand how parenteral nutrition affects intestinal barrier function, immune cells, and inflammatory mediators, and how the composition of TPN preparations can reduce the adverse effects on barrier function, local and systemic immunity, and local and systemic inflammation. In doing so, key structural components of the intestinal barrier, specifically the luminal structures called villi and crypts typical of the small intestine, are also being investigated. Short-chain fatty acids, in particular, have been studied for their ability to affect intestinal barrier function and, to some extent, IgA production.

[0009] Short-chain fatty acids (SCFAs) are abundant intraluminal solutes in the large intestine and are the primary energy source for the colonic epithelium. They are produced by anaerobic fermentation of undigested complex carbohydrates, with acetate, propionate, and butyrate being the most abundant SCFAs. Physiological and clinical studies have shown that SCFAs in general, and butyrate specifically, may have trophic effects on both the small and large intestine and may be useful in the prevention and treatment of several acute and chronic conditions. IV administration of SCFAs has been shown to improve mucosal atrophy, and butyrate-supplemented PN (Bu-PN) increased intestinal mucosal protein synthesis and stimulated jejunal and ileal cell proliferation in a bowel resection model (Murakoshi et al., Journal of Parenteral and Enteral Nutrition 2011;35(4):465-472). Butyrate-supplemented PN was found to moderately but significantly restore Peyer's patch lymphocyte counts and intestinal and bronchoalveolar IgA levels compared with standard PN. Small intestinal villus height and crypt depth were significantly reduced in the standard PN group versus the control group, whereas Bu-PN appeared to restore intestinal morphology.

[0010] Another study compared the effects of sodium acetate, sodium propionate, and sodium butyrate in rats and found that both intracecal and intravenous infusion of the aforementioned SCFAs reduced mucosal atrophy (Koruda et al., Am J Clin Nutr 1990;51:685-689).

[0011] Pratt et al., Short-Chain Fatty Acid-Supplemented Total Parenteral Nutrition Improves Nonspecific Immunity After Intestinal Resection in Rats. Journal of Parenteral and Enteral Nutrition 1996;20(4):264-271, contemplates that the short fatty acids sodium acetate, sodium propionate, and sodium butyrate may be beneficial in improving components of the nonspecific immune response and in alleviating some aspects of TPN-associated immunosuppression after major surgery.

[0012] Tappenden et al., "Short-Chain Fatty Acid-Supplemented Total Parenteral Nutrition Enhances Functional Adaptation to Intestinal Resection in Rats." Gastroenterology 1997;112:792-802, also reported that intravenous SCFAs promote intestinal adaptation after resection by increasing basolateral intestinal nutrient transport and that the addition of SCFAs to current TPN formulations may be permitted to improve functional characteristics of the gastrointestinal tract. This study also used sodium acetate, sodium propionate, and sodium butyrate in the nutrient solution.

[0013] Milo et al., Effects of Short-Chain Fatty Acid-Supplemented Total Parenteral Nutrition on Intestinal Pro-Inflammatory Cytokine Abundance Digestive Diseases and Sciences 2002;47:2049-2055 discusses how the short-chain fatty acids acetate, propionate, and butyrate beneficially increase the abundance of IL-1β and IL-6 in the small intestine during total parenteral nutrition administration, but do not affect systemic production of these cytokines or intestinal inflammation.

[0014] Bartholome et al., Supplementation of Total Parenteral Nutrition With Butyrate Acutely Increases Structural Aspects of Intestinal Adaptation After an 80% Jejunoileal Resection in Neonatal Piglets.Journal of Parenteral and Enteral Nutrition 2004;28(4):210-223 describes how administration of TPN supplemented with SCFAs (acetate, propionate, and n-butyrate) or butyrate alone improves structural indices of intestinal adaptation in neonatal pigs after extensive small bowel resection by increasing proliferation and decreasing apoptosis.

[0015] Jirsova et al., The Effect of Butyrate-Supplemented Parenteral Nutrition on Intestinal Defense Mechanisms and the Parenteral Nutrition-Induced Shift in the Gut Microbiota in the Rat Model. BioMed Research International 2019;2019:1-14 concluded that, in summary, these findings support the hypothesis that butyrate alleviates the deleterious effects of PN on intestinal permeability through stimulation of tight junction protein expression.

[0016] US Patent No. 5,919,822 discloses the use of free fatty acids, triglycerides, diglycerides, monoglycerides, phospholipids or short-chain fatty acids in lipids for parenteral or enteral nutrition to maintain gastrointestinal integrity and function in patients with compromised intestinal flora.The free fatty acids mentioned include acetic acid, propionic acid, butyric acid and caproic acid.It is mentioned that the composition can support disease resistance and immune function.

[0017] US Patent No. 7,947,303 discloses the use of butyrates, particularly tributyrin, in oral formulations to improve digestion and absorption in the intestinal tract and improve the immune status of patients.

[0018] WO95 / 11699 describes certain butyric acid derivatives with the treatment of different diseases.For example, it is suggested to use physiologically stable and safe compounds, including butyrate, butyric acid derivatives and their combinations, to treat or prevent gastrointestinal disorders, including colitis, inflammatory bowel disease, Crohn's disease and ulcerative colitis.Specifically, it is proposed to administer this composition orally or by enema preparation, or by rectal irrigation, to maximize contact with and effectiveness on gastrointestinal system.Arginine butyrate is also generally mentioned, even though it is not a component of parenteral nutrition preparations and is not related to any of the above-mentioned intestinal symptoms.

[0019] U.S. Patent Application Publication No. 2010 / 222271 describes an oral formulation comprising a protein, a polyunsaturated fatty acid, a short-chain fatty acid, and glutamine, wherein the short-chain fatty acid is butyrate, and the formulation may further comprise arginine. The present invention further discloses a method for promoting gastrointestinal health by orally administering such a formulation to a patient.

[0020] WO 2019 / 211605 discloses parenteral nutrition formulations for neonates containing greater than 12% (w / v) arginine and their use in the treatment of hypoargininemia, hyperammonemia, negative nitrogen balance and prevention of weight loss.

[0021] Thus, the beneficial effects of SCFAs, especially butyrate derivatives, on intestinal health have been well documented. Previous studies have focused primarily on the administration of sodium butyrate and, to some extent, tributyrin. Sodium butyrate, in particular, is not an ideal candidate for PN formulations because sodium loading inevitably increases patient discomfort. Meanwhile, tributyrin can only be combined with lipid emulsions for parenteral nutrition, which may not always be the optimal formulation, especially in cases where peripheral administration is preferred or indicated, such as in very young infants. Currently, no such TPN product containing butyrate derivatives is available. Therefore, there is a need to provide a parenteral nutrition formulation containing butyrate derivatives that can maintain or improve intestinal barrier function, reduce local and preferably systemic inflammatory events, and maintain or improve local and preferably systemic immunity, while being stable and safe for central or peripheral administration in adults and, particularly, infants.

[0022] Arginine butyrate (L-arginine, butanoate (3:4)), the butyrate salt of the amino acid arginine, has been described in some detail in the prior art. However, it has not been considered in connection with the intestinal disorders mentioned above, nor has it been considered as a supplementary or active ingredient in parenteral nutrition formulations. Vianello S, Yu H, Voisin V, et al., Arginine butyrate: a therapeutic candidate for In Duchenne muscular dystrophy. FASEB J. 2013;27(6):2256-2269, arginine butyrate (AB) was discussed as a potential drug for treating Duchenne muscular dystrophy, combining two pharmacological activities: nitric oxide pathway activation and histone deacetylase inhibition. Here, arginine was provided as an aqueous solution, where arginine was prepared in water and n-butyrate was added to provide a 26% solution (1 M arginine / 1 M butyrate, pH 7) for continuous chronic infusion and a 12.5% ​​solution (0.76 M arginine / 1 M butyrate, pH 5.5) for intermittent infusion.

[0023] The prior art also notes that in EBV-associated lymphoma, arginine butyrate induces EBV thymidine kinase transcription and acts synergistically with the antiviral drug ganciclovir to inhibit cell proliferation and reduce cell viability. Furthermore, the butyrate moiety inhibits histone deacetylase, resulting in hyperacetylation of histones H3 and H4. Acetylated histones have reduced affinity for chromatin; this reduced histone-chromatin affinity may allow chromosome unfolding, potentially increasing the expression of genes associated with tumor cell growth arrest and apoptosis.

[0024] McMahon et al., A randomized phase II trial of Arginine Butyrate with standard local therapy in refractory sickle cell leg ulcers. bjh 2010;151(5):516-524 describes the use of arginine butyrate for the treatment of refractory sickle cell leg ulcers.

[0025] It has now been found that arginine butyrate can be stably and safely formulated into parenteral nutrition compositions, such as, for example, amino acid formulations, multi-chamber bags containing an amino acid formulation, a carbohydrate formulation, and optionally also a lipid formulation, and that arginine butyrate can be safely and stably administered after reconstitution. Summary of the Invention [Means for solving the problem]

[0026] overview Thus, the present inventors have found that arginine butyrate can improve the intestinal health of patients receiving parenteral nutrition, for example, by maintaining or improving local immunity, maintaining or improving local inflammation, reducing local inflammation, and maintaining or improving intestinal barrier function. Arginine butyrate was surprisingly superior to butyric acid derivatives, specifically sodium butyrate and tributyrin, which are known to be beneficial to intestinal health. Arginine butyrate (AB) was found to be particularly effective in reducing local inflammation and increasing local immunity. The initial results also show that AB can reduce systemic inflammation and increase systemic immunity, further improving intestinal barrier properties and cellular structure. At the same time, arginine butyrate was found to be stable and safe when formulated into, for example, an amino acid preparation for parenteral nutrition, making it suitable for use in patients requiring peripheral administration of parenteral nutrition products.

[0027] In a first aspect of the present invention, which in the light of the disclosure herein is not intended to limit the scope of the present invention in any way, but which may be combined with any other aspect recited herein unless otherwise specified, a multi-chamber container (MCB) for parenteral administration comprises a carbohydrate formulation present in a first chamber and an amino acid formulation present in a second chamber, wherein at least the first or second chamber comprises arginine butyrate.

[0028] According to a second aspect of the invention, the multi-chamber container further comprises a lipid formulation present in a third chamber, wherein at least the first, second or third chamber of the MCB comprises arginine butyrate.

[0029] According to a third aspect of the present invention, the multi-chamber container comprises arginine butyrate at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, preferably 0.1 mmol to 1000 mmol per liter of reconstituted multi-chamber container, 0.5 mmol to 600 mmol per liter of reconstituted multi-chamber container, 1 mmol to 500 mmol per liter of reconstituted multi-chamber container, and particularly preferably 1 mmol to 300 mmol per liter of reconstituted formulation for administration to a patient in need thereof.

[0030] According to a fourth aspect of the invention, the arginine butyrate is present in the amino acid chamber of a multi-chamber container.

[0031] According to a fifth aspect of the invention, the amino acid formulation of MCB comprises an aqueous solution of one or more amino acids, dipeptides and / or oligopeptides, and optionally one or more electrolytes selected from the group of electrolytes comprising sodium, potassium, magnesium, calcium, phosphate compounds, and containing polyvalent anions of organic acids consisting of malate, citrate, acetate, lactate, gluconate, glucoheptonate, gluconoglucoheptonate, glucose-phosphate, or inorganic acids consisting of sulfate, chloride.

[0032] According to a sixth aspect of the present invention, the amino acid preparation contains about 1 g to 30 g of amino acids per 100 mL of the amino acid preparation.

[0033] According to a seventh aspect of the present invention, arginine butyrate is present in a carbohydrate formulation of a multi-chamber container, or in a carbohydrate formulation for parenteral administration, at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, preferably 0.1 mmol to 1000 mmol per liter of reconstituted multi-chamber container, 0.5 mmol to 600 mmol per liter of reconstituted multi-chamber container, 1 mmol to 500 mmol per liter of reconstituted multi-chamber container, particularly preferably 1 mmol to 300 mmol per liter of reconstituted multi-chamber container, and the carbohydrate formulation is not a component of an MCB.

[0034] According to an eighth aspect of the invention, the carbohydrate preparation comprises 1 g to 100 g of glucose and / or maltose and / or trehalose per 100 mL of carbohydrate preparation, and optionally one or more electrolytes selected from the group of electrolytes consisting of sodium, potassium, magnesium, calcium, phosphate or glycerophosphate.

[0035] According to a ninth aspect of the present invention, arginine butyrate is present in the lipid formulation of the third chamber, or in the lipid formulation for parenteral administration, at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, preferably 0.1 mmol to 1000 mmol per liter of reconstituted multi-chamber container, 0.5 mmol to 600 mmol per liter of reconstituted multi-chamber container, 1 mmol to 500 mmol per liter of reconstituted multi-chamber container, and particularly preferably 1 mmol to 300 mmol per liter of reconstituted multi-chamber container, and the lipid formulation is not a component of the MCB.

[0036] According to a tenth aspect of the invention, the lipid formulation comprises an aqueous phase and an oil phase in an amount of 1 g to 40 g of oil per 100 ml of lipid formulation.

[0037] According to an eleventh aspect of the present invention, the lipid formulation comprises at least one pharmaceutically acceptable antioxidant selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocotrienol and ascorbic acid. Preferably, the lipid formulation comprises α-tocopherol.

[0038] According to a twelfth aspect of the present invention, the oil phase of the lipid formulation comprises one or more oils selected from the group consisting of olive oil, soybean oil, safflower oil, palm oil, fish oil, fish oil extract, krill oil, medium chain triglycerides (MCT), algal oil, fungal oil, corn oil, sunflower oil, palm kernel oil and rapeseed oil, preferably one or more oils selected from the group consisting of olive oil, soybean oil, fish oil, fish oil extract, MCT, algal oil and fungal oil.

[0039] According to a thirteenth aspect of the present invention, at least one of the first chamber, the second chamber and the third chamber of the multi-chamber container further comprises vitamins and / or trace elements.

[0040] According to a fourteenth aspect of the invention, the multi-chamber container comprises, in addition to the first, second and / or third chamber, at least one further chamber, for example four, five or six chambers, containing a vitamin and / or trace element formulation.

[0041] According to a fifteenth aspect of the present invention, arginine butyrate is present in a concentration of 1 mmol to 300 mmol per liter of reconstituted multi-chamber container, 5 mmol to 300 mmol per liter of reconstituted multi-chamber container, 1 mmol to 250 mmol per liter of reconstituted multi-chamber container, 5 mmol to 150 mmol per liter of reconstituted multi-chamber container, 5 mmol to 75 mmol per liter of reconstituted multi-chamber container, or 5 mmol to 50 mmol per liter of reconstituted multi-chamber container.

[0042] According to a sixteenth aspect of the present invention, the lipid formulation in the third chamber of the MCB comprises tributyrin at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, preferably 1 mmol to 300 mmol per liter of reconstituted multi-chamber container, and the total concentration of butyric acid equivalents does not exceed 301 mmol per liter of formulation reconstituted from the multi-chamber container.

[0043] According to the seventeenth aspect of the present invention, the pH of the formulation reconstituted from the multi-chamber container is 4.5 to 8.0.

[0044] According to a further eighteenth aspect of the present invention, there is provided an amino acid preparation for parenteral administration, the amino acid preparation comprising arginine butyrate at a concentration of 1 mmol to 300 mmol per liter of amino acid preparation.

[0045] According to a nineteenth aspect of the present invention, arginine butyrate is present in the amino acid formulation at a concentration of 0.05 mmol to 1400 mmol per liter of amino acid formulation, 0.1 mmol to 1000 mmol per liter of amino acid formulation, 0.5 mmol to 600 mmol per liter of amino acid formulation, 1 mmol to 500 mmol per liter of amino acid formulation, 1 mmol to 300 mmol per liter of amino acid formulation, 2 mmol to 250 mmol per liter of amino acid formulation, 5 mmol to 150 mmol per liter of amino acid formulation, 5 mmol to 75 mmol per liter of amino acid formulation, or 5 mmol to 50 mmol per liter of amino acid formulation.

[0046] According to a twentieth aspect of the present invention, the amino acid preparation comprises alanine (Ala), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), glycine (Gly), histidine (His), leucine (Leu), isoleucine (Ile), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine ( The aqueous solution of one or more amino acids selected from the group consisting of: acetyl-tyrosine (Ac-Tyr), valine (Val), cysteine ​​(Cys), ornithine (Orn), acetyl-tyrosine (Ac-Tyr), acetyl-cysteine ​​(Ac-Cys), taurine, and asparagine (Asn), optionally further comprising one or more electrolytes selected from the group consisting of sodium, potassium, magnesium, calcium, phosphate, and glycerophosphate.

[0047] According to a twenty-first aspect of the present invention, the amino acid formulation comprises one or more oligopeptides consisting of at least three amino acids and / or dipeptides selected from the group consisting of alanyl-glutamine (Ala-Gln), glycyl-glutamine (Gly-Gln), alanyl-tyrosine (Ala-Tyr) and glycyl-tyrosine (Gly-Tyr).

[0048] According to a twenty-third aspect of the invention, the amino acid formulation comprises one or more anions of organic acids selected from malate, citrate, acetate, lactate, gluconate, glucoheptonate, glucono-glucoheptonate, glucose-phosphate, and / or inorganic acids selected from sulfate and chloride.

[0049] According to a 24th aspect of the present invention, the amino acid preparation contains about 1 g to 30 g of amino acids per 100 mL of the amino acid preparation.

[0050] According to a 25th aspect of the present invention, the amino acid preparation comprises 20 mg to 25 g / liter of a choline compound selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, cytidine diphosphate choline (CDP) salts and glycerophosphocholine (GPC).

[0051] According to a 26th aspect of the present invention, the amino acid preparation further comprises vitamins and / or trace elements.

[0052] According to yet another twenty-seventh aspect of the present invention there is provided a composition reconstituted from a multi-chamber container or an amino acid formulation according to the present invention for parenteral administration to a patient in need of parenteral nutrition when oral and enteral nutrition is impossible, insufficient or contraindicated.

[0053] According to a twenty-eighth aspect of the present invention, compositions for parenteral administration are provided to pediatric or adult patients, each composition comprising respectively:

[0054] According to a 29th aspect of the present invention, a parenteral composition is provided for intensive care patients, critically ill patients, patients with short bowel syndrome, patients with intestinal failure, patients experiencing metabolic stress, immunocompromised patients, cancer patients, cachexia patients, malnourished patients, patients suffering from or at risk of developing a compromised intestinal barrier, hyperglycemia and / or hypertriglyceridemia, ICU patients for whom enteral nutrition is contraindicated, surgical patients with persistent ileus or persistently fasting (NPO), patients with enterocutaneous fistula, preterm infants, patients with extremely short bowel syndrome, and / or home parenteral nutrition (HPN) patients who meet 95-100% of their energy needs from parenteral nutrition. This composition is particularly beneficial for intensive care patients, critically ill patients, patients with short bowel syndrome, and patients with intestinal failure.

[0055] According to a thirtieth aspect of the present invention, a composition for parenteral administration is provided to a patient suffering from or at risk of developing systemic and / or local inflammation in the intestine.

[0056] According to a thirty-first aspect of the present invention, a composition for parenteral administration is provided for sustaining or improving local immunity in the intestine and / or lungs of a patient.

[0057] According to yet another aspect and a thirty-second aspect of the present invention, there is provided a method of treating a patient in need of parenteral nutrition when oral and enteral nutrition is not possible, insufficient or contraindicated, wherein said patient is treated with a composition reconstituted from a multi-chamber container or an amino acid formulation according to the present invention.

[0058] According to a thirty-third aspect of the present invention there is provided a method of treating a pediatric or adult patient.

[0059] According to a 34th aspect of the present invention there is provided a method of treating intensive care patients, critically ill patients, short bowel patients, intestinal failure patients, patients undergoing metabolic stress, immunocompromised patients, cancer patients, cachexia patients, malnourished patients and / or patients suffering from or at risk of developing a compromised intestinal barrier, hyperglycemia and / or hypertriglyceridemia, ICU patients in whom enteral nutrition is contraindicated, surgical patients with persistent ileus or persistently non-permanent fasting (NPO), patients with enterocutaneous fistula, preterm infants, extremely short bowel patients and / or home parenteral nutrition (HPN) patients who cover 95-100% of their energy needs from parenteral nutrition.

[0060] According to a thirty-fourth aspect of the present invention there is provided a method of treating a patient suffering from systemic and / or local inflammation in the gut.

[0061] According to a thirty-fifth aspect of the present invention, a method of treating a patient is provided to sustain or improve local immunity in the gut and / or lungs.

[0062] According to a 36th aspect of the present invention, a method of treating a patient comprises administering a composition according to the present invention to reach an arginine butyrate dose of 2 mg / kg / day to 10 g / kg / day.

[0063] According to a 37th aspect of the present invention, a method of treating a patient comprises administering a composition according to the present invention to achieve an arginine butyrate dose of 2 mg / kg / day to 10 g / kg / day or 100 mg / kg / day to 2.5 g / kg / day.

[0064] Further features and advantages of the disclosed formulations will be described in and become apparent from the following detailed description and drawings. The features and advantages described herein are not all-inclusive, and in particular, many additional features and advantages will be apparent to those skilled in the art upon consideration of the drawings and description. Also, any particular embodiment does not necessarily have all of the advantages listed herein. Furthermore, it should be noted that the language used herein has been selected primarily for readability and descriptive purposes, and is not intended to limit the scope of the present subject matter. [Brief explanation of the drawings]

[0065] The present disclosure will be described and explained with additional specificity and detail through the use of the accompanying drawings, it being understood that the drawings depict only certain embodiments of the invention and are not to be considered as limiting the scope of the disclosure.

[0066] [Figure 1] Figure 1 shows the average energy delivered to piglets in groups A, B, C, D, E, or P (see Table 1) in kcal / kg body weight / day over 10 days (D1 to D10). Group E refers to piglets fed milk replacer ad libitum. Group P refers to the group receiving standard parenteral nutrition (S-PN), while groups A, B, C, and D received SCFA-PN, i.e., parenteral nutrition supplemented with 10 mmol / L (group A) or 30 mmol / L (group B) tributyrin, 10 mmol / L (group C) arginine butyrate, and 10 mmol / L (group D) 1,2-dipalmitoyl-3-butyrylglycerol. Energy intake was comparable for all piglets receiving S-PN or SCFA-PN.

[0067] [Figure 2] Figure 2 shows the average protein delivered in g (protein) / kg (body weight) / day to piglets in groups A, B, C, D, E, or P (see Table 1) over 10 days (D1–D10). Group E refers to piglets fed milk replacer ad libitum. Group P refers to the group receiving standard parenteral nutrition (S-PN), while groups A, B, C, and D received SCFA-PN, i.e., parenteral nutrition supplemented with 10 mmol / L (group A) or 30 mmol / L (group B) tributyrin, 10 mmol / L (group C) arginine butyrate, and 10 mmol / L (group D) 1,2-dipalmitoyl-3-butyrylglycerol. The amount of protein delivered was comparable for all piglets receiving S-PN or SCFA-PN.

[0068] [Figure 3] Figure 3 shows the average weight progression in kg over the study period (10 days from D0, the day of central catheter placement) for piglets in groups A, B, C, D, E, or P (see Table 1). Group E refers to piglets fed milk replacer ad libitum. Group P refers to the group receiving standard parenteral nutrition (S-PN), while groups A, B, C, and D received SCFA-PN, i.e., parenteral nutrition supplemented with 10 mmol / L (group A) or 30 mmol / L (group B) tributyrin, 10 mmol / L (group C) arginine butyrate, and 10 mmol / L (group D) 1,2-dipalmitoyl-3-butyrylglycerol. Body weight progression was similar in all groups.

[0069] [Figure 4]Figure 4 shows the mean change in abdominal circumference in cm / kg body weight over the study period (10 days, D1–D10) for piglets in groups A, B, C, D, E, or P (see Table 1). Group E refers to piglets fed milk replacer ad libitum. Group P refers to the group receiving standard parenteral nutrition (S-PN), while groups A, B, C, and D received SCFA-PN, i.e., parenteral nutrition supplemented with 10 mmol / L (group A) or 30 mmol / L (group B) tributyrin, 10 mmol / L (group C) arginine butyrate, and 10 mmol / L (group D) 1,2-dipalmitoyl-3-butyrylglycerol. Abdominal circumference changed similarly in all groups.

[0070] [Figure 5] Figure 5 shows the mean colon weight in g / cm (colon) over the study period (10 days from D0, the day of central catheter placement) for piglets in groups A, B, C, D, E, or P (see Table 1). Group E refers to piglets fed milk replacer ad libitum. Group P refers to the group receiving standard parenteral nutrition (S-PN), while groups A, B, C, and D received SCFA-PN, i.e., parenteral nutrition supplemented with 10 mmol / L (group A) or 30 mmol / L (group B) tributyrin, 10 mmol / L (group C) arginine butyrate, and 10 mmol / L (group D) 1,2-dipalmitoyl-3-butyrylglycerol. Fisher's LSD test was used to evaluate outcomes based on grouping information. Groups not sharing letters are significantly different.

[0071] [Figure 6] Figure 6 shows illustrative examples of sections prepared to assess the effects on intestinal histomorphology of the jejunum (A) and ileum (B). Sections were stained with hematoxylin and eosin. Sections were used to determine duodenal villus length and duodenal crypt length (Figures 7 and 8).

[0072] [Figure 7]Figure 7 shows the mean duodenal villus length for each study group (A, B, C, and D) (see Table I) and group P, designated "PN" in this Figure. Group E is not shown. The mean duodenal villus length for group E was 810 μm. Based on analysis of the data by Fisher's LSD test, a significant difference was found for group PN (S-PN), which showed a significant decrease in villus length, while groups B (tributyrin supplemented, 30 mmol / L TPN, TB-PN) and D (1,2-dipalmitoyl-3-butyrylglycerol supplemented, 10 mmol / L TPN, DPBG-PN) showed increased villus length compared to the other study groups, especially the PN (S-PN) group. Groups A and C showed similar results, only slightly below the mean values ​​determined for groups B and D.

[0073] [Figure 8] Figure 8 shows the mean duodenal crypt length for each test group (A, B, C, and D) (see Table I) and group P, designated "PN" in this Figure. Group E is not shown. The mean duodenal crypt depth for group E was 152 μm. Based on analysis of the data by Fisher's LSD test, a significant difference was again found for the PN (S-PN) group, which exhibits the lowest crypt depth. Groups A (tributyrin supplementation, 10 mmol / L TPN, TB-PN), C (arginine butyrate supplementation, 10 mmol / L TPN, AB-PN), and D (DPBG supplementation, 10 mmol / L TPN, DPBG-PN) gave the best results, with group C performing slightly better than groups A and D. Group B (tributyrin supplementation, 30 mmol / L TPN, TB-PN) exhibited better crypt depth than S-PN, but not as well as groups A, C, and D.

[0074] [Figure 9]Figure 9 shows the mean jejunal villus length for each test group A, B, C, and D (see Table I) as well as group P, designated "PN" in this Figure 9. Group E is not shown. The mean jejunal villus length for group E was 152 μm. Based on analysis of the data by Fisher's LSD test, significant differences were found, especially in group C (arginine butyrate supplementation, 10 mmol / L TPN, AB-PN), which achieved the best results. Jejunal villus length was relatively low in group B (TB-PN, 10 mmol / L TPN), and group D (DPBG-PN) also achieved relatively good results.

[0075] [Figure 10] Figure 10 shows the mean jejunal crypt length for each test group A, B, C, and D (see Table I) as well as group P, designated "PN" in this Figure 10. The mean jejunal crypt depth for EN is shown by a horizontal column for comparison. Based on analysis of the data by Fisher's LSD test, significant differences were again found, especially for group C (arginine butyrate supplementation, 10 mmol / L TPN, AB-PN), which obtained the best results. Jejunal crypt depth was lower in groups A, B, and D, and lowest in group P ("PN").

[0076] [Figure 11] Figure 11 shows the mean ileal crypt depth for each study group A, B, C, and D (see Table I) as well as group P, designated "PN" in this Figure 11. The mean jejunal crypt depth for EN is 155 μm. Based on analysis of the data by Fisher's LSD test, significant differences were found for group A (tributyrin supplementation, 10 mmol / L TPN, TB-PN) and group D (1,2-dipalmitoyl-3-butyrylglycerol supplementation, 10 mmol / L TPN, DPBG-PN), closely followed by group C. Jejunal crypt depth was again lowest in group P ("PN").

[0077] [Figure 12]Figure 12 shows the mean colonic crypt depth for each study group A, B, C, and D (see Table I) and group P, designated "PN" in this Figure 12. The mean jejunal crypt depth for EN is 76 μm. Based on analysis of the data by Fisher's LSD test, a significant difference was again found for group C (arginine butyrate supplementation, 10 mmol / L TPN, AB-PN). Jejunal crypt depth was again lowest in group P ("PN").

[0078] [Figure 13] Figure 13 shows the mean jejunal sIgA concentrations for each test group A, B, C, and D (see Table I) and group P, designated "PN" in Figure 13. Based on analysis of the data by Fisher's LSD test, a significant difference was again found for group C (arginine butyrate supplementation, 10 mmol / L TPN, AB-PN), which was even more pronounced than group E, and even more pronounced than group P ("PN").

[0079] [Figure 14A] Figure 14 provides the CS response times of piglets from each group used to assess cognitive function. Figure 14A shows the unconditioned stimulus (US-CS) response times over the five days of the study, and Figure 14B shows the conditioned stimulus (CS) response times over the five days of the study. No significant differences in cognitive function were observed between the groups. [Figure 14B] Figure 14 provides the CS response times of piglets from each group used to assess cognitive function. Figure 14A shows the unconditioned stimulus (US-CS) response times over the five days of the study, and Figure 14B shows the conditioned stimulus (CS) response times over the five days of the study. No significant differences in cognitive function were observed between the groups.

[0080] [Figure 15] Figure 15 shows the serum levels of IL-6 in pg / ml of serum found in each of the study groups A, B, C, D, and E (see Table I) and group P, designated "PN" in this Figure 15. While group E was lowest, it can be seen that the mean IL-6 concentration in group C was significantly lower than the standard PN group and compared to the other study (or intervention) groups.

[0081] [Figure 16] Figure 16 shows the serum levels of Il1-beta ("Il1-b") in pg per ml of serum found in each of the study groups A, B, C, D, and E (see Table I) and the P group, designated "PN" in this Figure 15. While Group E is lowest, the mean Il1-beta concentration in Group C is again significantly lower than the standard PN group and compared to the other study (or intervention) groups.

[0082] [Figure 17] Figure 17 shows the serum levels of TNF-alpha ("TNF-a") in pg per ml of serum found in each of the test groups A, B, C, D, and E (see Table I) and the P group, designated "PN" in this Figure 15. The TNF-a concentration in test group C is again lower than the other test (or intervention) groups, resulting in approximately the same value as in group E.

[0083] [Figure 18] FIG. 18 shows the serum levels of Il-10 in pg per ml of serum found in each of the test groups A, B, C, D, and E (see Table I) and the P group, designated "PN" in this FIG. 15. The TNF-α concentration in test group E is again lower than the other test (or intervention) groups. The Il-α concentration is almost or nearly as low in test (or intervention) group D. Test groups A, B, and C all have lower Il-10 concentrations than the standard PN group P.

[0084] [Figure 19] Figure 19 is a schematic diagram of several features of the small intestinal wall, some of which are also investigated in the context of the present invention. A simple epithelium (3) containing cells with luminal microvilli (5) forms the luminal outer layer of the intestinal tract. The intestinal tract is characterized by prominent villi (1) and crypts (2). The villi are interlaced with blood vessels (4), which allow rapid transport of absorbed products. Lactylic ducts (6) absorb lipids from the intestinal tract into the lymphatic system. DETAILED DESCRIPTION OF THE INVENTION

[0085] Detailed Description Certain embodiments described herein generally relate to the field of parenteral nutrition.More specifically, some embodiments described herein are parenteral administration amino acid or carbohydrate preparations, wherein the amino acid preparation comprises arginine butyrate.Related embodiments described herein relate to a multi-chamber container for parenteral administration, wherein the container comprises a carbohydrate preparation in a first chamber, an amino acid preparation in a second chamber, and optionally a lipid preparation in a third chamber, and arginine butyrate is contained in any of the above-mentioned chambers.

[0086] Thus, medical products for parenteral nutrition (PN) are provided that contain arginine butyrate at concentrations of 1 to 300 mmol per liter of reconstituted formulation. For example, such formulations are reconstituted from multi-chamber containers. PN products are often provided side-by-side in three-chamber bags, and lipids, carbohydrates, and amino acids can be mixed prior to administration by breaking the non-permanent peel seal between the respective chambers. Electrolytes may also be included in the nutrient solution. Trace elements and vitamins are often added to the PN solution before administration to the patient or administered separately from the PN solution. Lipids are a concentrated energy source provided as an oil-in-water emulsion. However, lipids can also be infused separately, especially when patients require high protein and / or minimal fluids and do not have increased energy requirements.

[0087] Thus, one aspect of the present invention provides a product for central or peripheral administration, comprising an amino acid formulation, preferably further comprising electrolytes, and a carbohydrate formulation, preferably comprising glucose and, optionally, calcium, wherein arginine butyrate is contained in the amino acid chamber, the carbohydrate chamber, or both chambers of the product. According to another aspect of the present invention, the product does not comprise a lipid formulation and thus comprises a two-chamber container. According to one embodiment, the chambers are designed to contain a formulation that, upon reconstitution, results in a volume of 0.8 to 2.2 L. However, the bag may have a volume of up to 3.0 L, or even as small as 300 mL to 650 mL. Preferably, the volume obtained after reconstitution is 1.0 to 2.0 L, e.g., 1.0, 1.5, or 2.0 L. Obviously, the volumes of the first and second chambers may be varied to yield the final reconstituted volumes disclosed above. However, the lipid formulation may be added prior to administration or provided separately from the administration of the medical product according to the present invention.

[0088] According to another aspect of the present invention, such lipid preparation can be combined with amino acid and carbohydrate preparation in the product (then comprising three chambers).In this case, arginine butyrate can be present in any of the three chambers: amino acid chamber, carbohydrate chamber or lipid chamber.Preferably, arginine butyrate is present in the amino acid chamber.Various alternatives and embodiments of the present invention will be described in more detail below.

[0089] As used herein, the term "child" refers to newborns, including premature (early), full-term, and postmature newborns up to 1 month of age; infants 1 month to 1 year old; children 1 to 12 years old; and adolescents 13 to 21 years old. The formulations according to the present invention are particularly suitable for newborns, including premature, full-term, and postmature newborns. The formulations are particularly suitable for premature newborns, who may have a birth weight of less than 2500g, less than 2000g, less than 1800g, less than 1500g, less than 1200g, less than 1100g, or less than 1000g.

[0090] As used herein, the term "short-chain fatty acid" or "SCFA" refers to a fatty acid having less than six carbon atoms. Table 1 provides a list of short-chain fatty acids, their common names, systematic names, and their formulas. [Table 1] Table 1: List of short chain fatty acids and their respective names and formulas

[0091] Short-chain fatty acids are liquid at room temperature and generally have a pungent or foul odor, making them difficult to use in parenteral nutrition solutions. Their alkali metal salts are hydrolyzed in aqueous solution. They are described in some detail in Schoenfeld and Wojtczak, "Short- and medium-chain fatty acids in energy metabolism: the cellular perspective." J Lipid Res 2016;75(6):943-954. According to the present invention, the term "short-chain fatty acid" encompasses glycerol esters of the above SCFAs, including, but not limited to, tributyrin.

[0092] As used herein, the term "parenteral nutrition" (PN) refers to the intravenous administration of nutritional components, which may include proteins, carbohydrates, fats, minerals and electrolytes, vitamins, and trace elements, to patients who are unable to ingest or absorb sufficient food through tube (enteral) feeding to maintain adequate nutritional status. Diseases and conditions for which PN is indicated include, but are not limited to, short bowel syndrome, gastrointestinal fistulas, intestinal obstruction, critically ill patients, and severe acute pancreatitis. Patients receiving PN include premature infants or neonates, infants, children, and adults.

[0093] As used herein, the term "parenteral nutrition solution" generally refers to a sterile liquid chemical formula suitable for parenteral nutrition and administered directly into a patient's bloodstream via an intravenous (IV) catheter. For example, a parenteral nutrition solution provided in a multi-chamber container is considered a medical product.

[0094] As used herein, the expression "total parenteral nutrition (TPN)" means that all of a patient's macronutrient (carbohydrates, nitrogen, and lipids) and micronutrient (vitamins, trace elements, and minerals) and fluid requirements are met by intravenous nutritional solutions and no significant nutrition is obtained from other sources.

[0095] As used herein, the term "intestine" refers to the intestinal tract. These terms are used interchangeably herein. The intestinal tract consists of the small intestine, colon (large intestine), and rectum. The small intestine is divided into the duodenum, jejunum, and ileum.

[0096] As used herein, the term "reconstitution" refers to the mixing of fluids contained in separate chambers within a multi-chamber bag by opening or breaking one or more non-permanent (peel) seals separating the chambers and the fluids contained therein. Thus, a "reconstituted" fluid is a fluid obtained by mixing two or more fluids located in different chambers of a multi-chamber bag. Such reconstitution generally occurs immediately prior to administering the reconstituted fluid to a patient.

[0097] As used herein, the term "systemic inflammation" refers to inflammation that affects the entire body, rather than a single organ or body part (which is referred to herein as "local inflammation"). As used herein, the term "inflammation" refers to the response of body tissues to harmful stimuli, including the production of eicosanoids and cytokines released by injured or infected cells.

[0098] As used herein, the term "systemic immunity" refers to a state in which a person has sufficient biological defenses to fight infection, disease, or other undesirable biological invasion. As used herein, "local immunity" or "local immunity" refers to the ability of a body part or organ to fight infection, disease, or other undesirable biological invasion. In the context of the present invention, "local immunity" refers to the ability of the intestine to effectively respond to such infection, disease, or other undesirable biological invasion.

[0099] The multi-chamber container (MCB) of the present invention contains a nutritional formulation for parenteral administration to a patient. For example, the container may be in the form of a bag with multiple compartments or chambers. The container contains at least two chambers, but can also contain three, four, five, or more chambers. Suitable containers, including bags, are typically sterile, non-pyrogenic, disposable, and / or ready-to-use products. Multi-chamber containers are particularly useful for holding parenteral nutrition products and generally provide a carbohydrate formulation disclosed herein in a first chamber, an amino acid formulation disclosed herein in a second chamber, and optionally a lipid formulation disclosed herein in a third chamber of the container. The multi-chamber container may also provide a fourth or fifth chamber containing selected vitamins and / or trace elements that cannot be mixed with the carbohydrate, amino acid, or lipid formulation, for example, for stability reasons or because their addition is intended to be optional.

[0100] As used herein, the term "peripheral parenteral nutrition (PPN)" refers to the administration of PN solutions via a cannula inserted into a peripheral vein. The term "peripheral" refers to superficial veins, most often the upper extremities. PPN is indicated for short-term PN when central venous catheterization is contraindicated or impossible, for example, in cases of catheter-related sepsis or bacteremia. In contrast, "total parenteral nutrition" refers to parenteral nutrition (PN) given via a central vein. Central access allows for the use of highly concentrated, hypertonic solutions and is often used for patients requiring PN for more than two weeks. Either a temporary central venous catheter (CVC) or a long-term CVC, such as a tunneled catheter, implantable port, or peripherally inserted central catheter (PICC), can be used. CVCs are used when peripheral parenteral nutrition (PPN) is indicated because they can increase the risk of catheter-associated bloodstream infections.

[0101] Multi-chamber containers of the present invention, such as three-chamber bags, can include vertical chambers. A suitable multi-chamber container is disclosed in U.S. Patent Application Publication No. 2007 / 0092579. For example, a multi-chamber container may be configured as a bag containing two or three adjacent chambers or compartments. If necessary, frangible barriers or reclosable seals (e.g., peel seals or frangible seals) are used to separate the chambers of the multi-chamber container. A multi-chamber container may also include three chambers for containing a lipid emulsion, a carbohydrate formulation, and an amino acid formulation, and may further include at least one, and in certain embodiments, two or three smaller chambers containing, for example, a vitamin formulation and / or a trace element formulation. In one specific embodiment, a multi-chamber container of the present invention has a first chamber containing a lipid emulsion according to the present invention, a second chamber containing an amino acid formulation, a third chamber containing a carbohydrate formulation, a fourth chamber containing a vitamin formulation, and a fifth chamber containing a trace element formulation. The reclosable seals of the multi-chamber containers described above allow formulations to be stored separately and mixed / reconstituted immediately prior to administration, thereby enabling the storage of formulations that should not be stored as a mixture for long periods in a single container. Opening the seals allows communication between the chambers and mixing of the contents of each chamber. The outer seal of the multi-chamber container is strong enough to withstand fluid pressure applied to open weak peel seals or fragile seals between the chambers. In some embodiments, the reclosable seals of the multi-chamber containers may 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.

[0102] Multi-chamber containers according to the present invention may be provided with instructions outlining the desired order of opening the peel seals so that the constituent fluids are mixed in the desired order. The tear strength of two or more peel seals may be varied to facilitate opening of the seals in the desired order. For example, the tear strength of the first peel seal may be 1 / 3 to 1 / 2 of the tear strength required to open the next peel seal.

[0103] Although the container can be made primarily from flexible polymeric materials, the container can also include non-polymeric materials such as metal foil without departing from the present disclosure. Numerous polymeric films have been developed for use in containers. Suitable films can be monolayer or multilayer structures. Monolayer structures can be made from a single polymer or from a polymer blend. Multilayer structures can include layers such as solution contact layers, scratch-resistant layers, barrier layers to prevent gas permeation (such as carbon dioxide, oxygen, or water vapor), tie layers, or other layers. The use of two or more film webs on one or both side walls is also contemplated. Suitable polymeric materials are generally selected from homopolymers and copolymers of polyolefins, polyamides, polyesters, polybutadienes, styrene and hydrocarbon copolymers, polyimides, polyester-polyethers, and polyamide-polyethers, to name a few. It is preferred to use non-PVC materials for the primary packaging, including the film and port tube and thread protector. According to one embodiment of the present invention, the film of the primary packaging of the medical product of the present invention is a four-layer coextruded film prepared from poly(cyclohexylene dimethylene) cyclohexane dicarboxylate copolymer (PCCE) (outer layer), maleic anhydride-modified poly(ethylene vinyl acetate) (tie layer), poly(ethylene vinyl acetate) (EVA) (inner layer), and poly(ethylene-propylene) copolymer (PP / PE) and styrene-ethylene-butylene-styrene block polymer (SEBS) (sealant layer). According to another embodiment, the port tube is a PVC-free polyolefin-based three-layer coextruded part. The outer layer is prepared from a blend of PP / PE and SEBS, the middle layer is prepared from a blend of SEBS, EVA, PP, and PE, and the inner layer is prepared from EVA. The middle layer is optional and can be replaced by a virtual layer consisting essentially of the same material as the outer layer. According to yet another aspect of the present invention, the TOP can be made from a blend of PP, EVA, and SEBS, and can optionally include a color, such as Polybatch® Blue. The TOP is preferably PVC-free.

[0104] The sealing layer for the container of the product of the present invention should exhibit bimodal behavior. Bimodal behavior means that the material can form a permanent seal under one set of sealing or manufacturing conditions and a peelable seal under a second set of sealing or manufacturing conditions. The sealing layer can be a homophase polymer or a matrix phase polymer system. Suitable homophase polymers include polyolefins and polypropylene, specifically propylene and ethylene copolymers.

[0105] As mentioned above, typical components of a multi-chamber container for providing a formulation for parenteral nutrition are an amino acid and / or carbohydrate formulation. The carbohydrate formulation typically provides calories in the form of glucose. Maltose or trehalose can also be used. A mixture of glucose with maltose and / or trehalose is also possible. In particular, the carbohydrate formulation provides a sufficient amount of carbohydrate to avoid adverse effects, such as hyperglycemia, observed in patients receiving parenteral nutrition. Typically, the carbohydrate formulation contains 1 to 100 grams of glucose, maltose, trehalose, or a mixture thereof per 100 mL. In certain embodiments of the present invention, the carbohydrate formulation contains 20 to 50 grams or 15 to 30 grams of glucose, maltose, trehalose, or a mixture thereof per 100 mL of carbohydrate formulation.

[0106] In one embodiment, glucose is present in an amount of 30-40 grams per 100 ml of carbohydrate formulation. In another embodiment, glucose is present in an amount of 24-30 grams per 100 ml of glucose. For example, glucose compositions such as those described in U.S. Patent Application No. 16 / 562014 can be supplemented with arginine butyrate according to the present invention.

[0107] The carbohydrate formulation may further comprise a water-soluble form of choline selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, cytidine diphosphate choline (CDP) choline salt, and glycerophosphocholine. In preferred embodiments, the water-soluble form of choline is present at a concentration of 20 mg to 25 g choline equivalents per liter of reconstituted multi-chamber container, e.g., about 30 mg to 20 g, about 30 mg to 15 g, about 30 mg to about 10 g, about 30 mg to 5 g, about 30 mg to 1 g, about 30 mg to 800 mg, about 100 mg to 1 g, about 500 mg to 1 g, about 800 mg to 10 g, or about 1 g to 10 g choline equivalents per liter of reconstituted multi-chamber container. The carbohydrate formulation may also comprise calcium at a concentration of 0.1 mmol to 10 mmol. In such cases, calcium may be provided in the form of calcium chloride 2·H2O or calcium gluconate.

[0108] The amino acid preparation according to the present invention may be a component of the aforementioned multi-chamber container, or may be a separate product for parenteral nutrition and administration to a patient in need thereof. The amino acid preparation comprises a sterile aqueous solution of one or more amino acids, dipeptides and / or oligopeptides, and optionally one or more electrolytes. Unless otherwise specifically indicated, the terms "amino acid" or "multiple amino acids" are used generally herein and include amino acids, dipeptides and oligopeptides.

[0109] Typically, the amino acid formulation contains about 1 gram to about 30 grams of amino acid per 100 mL of amino acid formulation, for example, about 3 grams to about 25 grams, about 4 grams to about 20 grams, about 5 grams to about 15 grams, and about 5 grams to about 10 grams of amino acid per 100 mL of amino acid formulation. Amino acid formulations generally comprise one or more amino acids selected from the group consisting of alanine (Ala), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), glycine (Gly), histidine (His), leucine (Leu), isoleucine (Ile), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val), cysteine ​​(Cys), ornithine (Orn), taurine, and asparagine (Asn). The amino acid preparation according to the present invention may further comprise an oligopeptide consisting of at least three amino acids and / or dipeptides selected from the group consisting of acetyl-cysteine ​​(Ac-Cys), acetyl-tyrosine (Ac-Tyr), alanyl-glutamine (Ala-Gln), glycyl-glutamine (Gly-Gln), and glycyl-tyrosine (Gly-Tyr). Furthermore, the tyrosine content can be increased, for example, by adding acetyl-tyrosine (Ac-Tyr).

[0110] The amino acid preparation according to the invention may further comprise electrolytes such as sodium, potassium, calcium, magnesium and / or phosphate ions and / or anions of organic acids selected from malate, citrate, acetate, lactate, gluconate, glucoheptonate, glucono-glucoheptonate, glucose-phosphate, and / or inorganic acids selected from sulfates and chlorides. For example, the amino acid formulation may contain, per 100 mL of the amino acid formulation, 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). When calcium and phosphorus are present together in the same heat-sterilized solution, insoluble calcium phosphate precipitation can occur. The use of organic salts of phosphorus, such as sodium glycerophosphate 5·H2O or calcium glycerophosphate, allows for increased amounts of calcium and phosphate without solubility problems and without providing excess sodium or chloride. In amino acid formulations, sodium can be provided in the form of sodium chloride or sodium acetate, calcium in the form of calcium chloride 2·H2O or calcium gluconate, magnesium in the form of magnesium acetate 4·H2O, magnesium sulfate 5·H2O, or magnesium chloride, and potassium in the form of potassium acetate or potassium chloride.

[0111] The amino acid formulation may further comprise a water-soluble form of choline selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, cytidine diphosphate choline (CDP) choline salt, and glycerophosphocholine. In a preferred embodiment, the water-soluble form of choline is present at a concentration of 20 mg to 25 g choline equivalents per liter of reconstituted multi-chamber container, e.g., about 30 mg to 20 g, about 30 mg to 15 g, about 30 mg to about 10 g, about 30 mg to 5 g, about 30 mg to 1 g, about 30 mg to 800 mg, about 100 mg to 1 g, about 500 mg to 1 g, about 800 mg to 10 g, or about 1 g to 10 g choline equivalents per liter of reconstituted multi-chamber container.

[0112] The multi-chamber container according to the present invention can also contain a lipid formulation in a third chamber. Such lipid formulations are emulsions of an oil phase, an aqueous phase, and an emulsifier that renders 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 and water 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 review 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.

[0113] Typically, the lipid formulation contains about 1 g to 40 g of oil per 100 ml of lipid formulation. For example, the lipid formulation contains about 1 g to 35 g, about 5 g to 35 g, about 5 g to 30 g, about 10 g to 30 g, about 10 g to 25 g, about 15 g to 20 g, or about 12 g to 18 g of oil per 100 ml of lipid formulation.

[0114] The lipid emulsion contained in one chamber of a multi-chamber device according to the present invention can contain glycerophosphocholine (GPC) at a concentration of 0.1 g to 15.0 g per liter. In some embodiments, the GPC concentration in such a multi-chamber device can be 1.0 g to 12 g per liter of lipid emulsion, 1.0 g to 10.0 g per liter of lipid emulsion, 2 g to 9.0 g per liter of lipid emulsion, 1.0 g to 5.0 g per liter of lipid emulsion, or 2.0 g to 4.0 g per liter of lipid emulsion. Lipid emulsions containing GPC are further described in International Publication No. WO 2019 / 0232054, which is incorporated herein in its entirety. Other water-soluble forms that can be added to the lipid emulsion alone or in combination with GPC or each other can be selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, and choline cytidine diphosphate choline (CDP) salts (e.g., sodium, potassium, or inner salts). In preferred embodiments, GPC or choline chloride is present at a concentration of 0.1 g to 12 g choline equivalents per liter of lipid emulsion.

[0115] The oil phase of the lipid emulsion that can be combined with the amino acid and glucose preparation of the present invention generally comprises polyunsaturated fatty acids, such as long-chain polyunsaturated fatty acids, which can exist as free acids, as ionized forms 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 (for example, 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 an alkenyl group having 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, and is H, a counterion, an alkyl group (for example, methyl, ethyl, or propyl), or a glyceryl group (for example, R(C=O)OR' is a monoglyceride, diglyceride, or triglyceride). 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 may be present 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 are present in triglyceride form.

[0116] The oil phase and its components can be obtained from a single source or from different sources (see, for example, Fell et al., Advances in Nutrition, 2015, 6(5), 600-610). Among vegetable oils, currently used sources include, but are not limited to, soybean oil and olive oil, as well as safflower oil, corn oil, sunflower oil, rapeseed oil, coconut oil, or palm kernel oil. The oil phase can further contain medium-chain triglycerides (MCTs). Another source is algae, including microalgae such as Crypthecodinium cohnii and Schizochytrium sp. When used in parenteral lipid emulsions, marine oils, generally fish oils or fish oil extracts, are found primarily in cold water and are processed from oily fish, including, but not limited to, herring, shad, and sardines. However, other marine organisms, such as krill, such as Antarctic krill (Euphausia superba Dana), can also be used as oil sources. The oil used in the lipid formulation of the present invention can be one or more of the above sources.Preferred combinations are, for example, a combination of soybean and olive oil, a combination of soybean oil, olive oil, MCT and fish oil or fish extract, or a combination of soybean oil, olive oil, MCT, fish oil or fish extract and krill oil.Preferably, the lipid formulation of the present invention has a phytosterol content of less than 175 mg, 150 mg, or 120 mg per 100 g of oil phase, preferably less than 100 mg, and particularly preferably less than 70 mg.Such lipid formulations and methods for their preparation are described in WO2019 / 232044 and WO2020 / 007758.

[0117] The lipid formulations disclosed herein may further contain additional components such as surfactants (also known as emulsifiers), co-surfactants, isotonicity agents, pH adjusters, and antioxidants. Surfactants are generally added to stabilize emulsions by reducing the interfacial tension between the oil and aqueous phases. Surfactants typically contain a hydrophobic portion and a hydrophilic portion, and the amount of surfactant / emulsifier included in the formulation is determined based on the amount necessary 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%, and / or about 0.05% to about 1.8% (by weight), based on the total weight of the lipid formulation.

[0118] Suitable surfactants and co-surfactants include surfactants approved for parenteral use, including, but not limited to, phospholipids (e.g., egg phosphatides and soybean lecithin), oleates, and combinations thereof. Krill oil can also be used as an emulsifier in lipid emulsions, where the lipid emulsion contains approximately 0.5 to 2.2% by weight of krill oil based on the total weight of the emulsion, and the emulsion does not contain egg yolk lecithin (U.S. Patent Application Publication No. 2018 / 0000732). Another exemplary surfactant is lecithin, including both natural and synthetic lecithins, such as those derived from eggs, corn, soybeans, or mixtures thereof. In some cases, lecithin is included in an amount of approximately 1.2% based on the total weight of the lipid formulation.

[0119] 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%, 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 surfactant and co-surfactant, for example, 1.2% lecithin and 0.03% oleate. In some cases, sodium oleate is contained in an amount of about 0.03% (by weight) based on the total weight of the lipid formulation.

[0120] An isotonicity agent can be added to the lipid emulsion to adjust the osmolality 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 formulation has an osmolality of about 180 to about 300 mmol / L, e.g., about 190 to about 280 mmol / L, and / or about 200 to about 250 mmol / L. In some cases, the lipid emulsion contains an isotonicity agent in an amount of 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% 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.

[0121] A pH adjuster can be added to the lipid emulsion to adjust the pH to a desired level, e.g., a physiologically acceptable pH for parenteral use. Suitable pH adjusters 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.

[0122] The lipid formulation may further comprise an antioxidant. Suitable antioxidants may be pharmaceutically acceptable antioxidants, including, but not limited to, tocopherols (e.g., alpha tocopherol, beta tocopherol, gamma tocopherol, delta tocopherol), tocotrienols, ascorbic acid, ascorbyl palmitate, or combinations thereof. In some cases, the lipid emulsion formulation comprises an antioxidant, such as, preferably, alpha-tocopherol, in an amount of about 0 to about 300 mg / L, for example, about 10 to about 250 mg / L, about 40 to about 180 mg / L, about 50 to about 120 mg / L, or about 75 to about 100 mg / L.

[0123] The aqueous (or water) phase of all intravenous formulations, including amino acids, carbohydrates and lipid emulsions, must conform to the pharmacological requirements that make it suitable for injection, i.e., the water must be sterile water for injection.

[0124] The reconstituted formulation for parenteral administration from the multi-chamber container according to the present invention contains arginine butyrate at a concentration of 1 to 300 mmol / L. Therefore, depending on the configuration of the multi-chamber container (2, 3, 4, 5 or more chambers) and the respective volumes of the chambers, the amount of arginine butyrate to be added, for example, to the amino acid chamber must be calculated based on the final volume of the reconstituted solution in the multi-chamber container.

[0125] The arginine butyrate-supplemented amino acid formulation and arginine butyrate-supplemented formulation can be prepared by dissolving a concentrated solution of arginine butyrate in water for injection, from which the amount required to produce the desired final concentration is added to the amino acid formulation or carbohydrate formulation, respectively.

[0126] For example, an arginine butyrate-supplemented amino acid formulation can be prepared by filling a washed and nitrogen-flushed mixing tank with a first batch of water for injection. Once the required temperature is reached, the amino acids, arginine butyrate, electrolytes as needed, and, for example, glacial acetic acid or malic acid are added to the tank. Agitation is initiated, and the solution is adjusted to the final volume with water for injection. The pH of the solution is measured and adjusted to the required pH with glacial acetic acid or malic acid, as needed. The solution is visually checked to ensure a clear solution. Dissolved oxygen and solution density are measured.

[0127] The arginine butyrate-supplemented carbohydrate formulation can be prepared, for example, by filling a washed and nitrogen-flushed mixing tank with water for injection. Once the required temperature is reached, trehalose and / or maltose, and optionally calcium chloride, are added to the tank. Agitation is initiated. The pH of the solution is measured and adjusted to the required pH, if necessary, with, for example, 25% hydrochloric acid. The solution is visually checked to ensure a clear solution. The dissolved oxygen and density of the solution are measured.

[0128] During the filling process, the supplemented amino acid or carbohydrate solution is filtered online through a 0.45 μm membrane. Fill volume is determined gravimetrically and checked periodically throughout the filling process to ensure uniformity throughout the batch. Furthermore, dissolved oxygen is measured in the first filled container. The container is then sealed. Each filled and sealed container is placed in an overpouch along with an oxygen absorber. The interior space of the overpouch is flushed with nitrogen to reduce the oxygen level, and the overpouch is heat-sealed. The overpacked bag is then placed on a sterilization tray for moist heat sterilization. The product can be terminally sterilized at 121°C and 2.2 bar using a moist heat sterilization process adapted to the selected size / volume of the container. For example, a steam-air blending process can be used. The exposure time is set according to the size of the container.

[0129] The concentration of arginine butyrate can be varied relatively widely over the disclosed range, which has been found to be stable in amino acid formulations at 25° C. and 40% relative humidity (RH) during production, sterilization, and over a shelf life of at least 12 months (see also Example 1 and Table 5).

[0130] For example, arginine butyrate can be present at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multichamber vessel, 0.1 mmol to 1000 mmol per liter of reconstituted multichamber vessel, 0.5 mmol to 600 mmol per liter of reconstituted multichamber vessel, 1 mmol to 500 mmol per liter of reconstituted multichamber vessel, 1 mmol to 300 mmol per liter of reconstituted multichamber vessel, 2 mmol to 250 mmol per liter of reconstituted multichamber vessel, 5 mmol to 150 mmol per liter of reconstituted multichamber vessel, 5 mmol to 75 mmol per liter of reconstituted multichamber vessel, or 5 mmol to 50 mmol per liter of reconstituted multichamber vessel.

[0131] For example, arginine butyrate, depending on the container size and / or patient population (e.g., pediatric or adult), may be 0.05 mmol to 0.5 mmol per liter of reconstituted multi-chamber container, 0.1 mmol to 1.5 mmol per liter of reconstituted multi-chamber container, 0.45 mmol to 5.0 mmol per liter of reconstituted multi-chamber container, 1.0 mmol to 15 mmol per liter of reconstituted multi-chamber container, 4.0 mmol to 50 mmol per liter of reconstituted multi-chamber container, 10 mmol to 150 mmol per liter of reconstituted multi-chamber container, 40 mmol to 500 mmol per liter of reconstituted multi-chamber container, or 120 mmol to 1400 mmol per liter of reconstituted multi-chamber container, e.g., 0.05 mmol / L, 0.1 mmol / L, 0.5 mmol / L, 1.0 mmol / L, 2 mmol / L, 3 mmol / L, 4 mmol / L, 5 mmol / L, 8 mmol / L, 10 mmol / L It can be present in concentrations such as 15mmol / L, 20mmol / L, 25mmol / L, 30mmol / L, 35mmol / L, 40mmol / L, 45mmol / L, 50mmol / L, 100mmol / L, 150mmol / L, 200mmol / L, 300mmol / L, 400mmol / L, 500mmol / L, 750mmol / L, 1000mmol / L, 1200mmol / L or 1400mmol / L.

[0132] According to another aspect of the invention, the lipid chambers of the multi-chamber container according to the invention further comprise tributyrin at a concentration of, for example, 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, e.g., 0.05 mmol to 0.5 mmol per liter of reconstituted multi-chamber container, 0.1 mmol to 1.5 mmol per liter of reconstituted multi-chamber container, 0.45 mmol to 5.0 mmol per liter of reconstituted multi-chamber container, 1.0 mmol to 15 mmol per liter of reconstituted multi-chamber container, 4.0 mmol to 50 mmol per liter of reconstituted multi-chamber container, 10 mmol to 150 mmol per liter of reconstituted multi-chamber container, 40 mmol to 500 mmol per liter of reconstituted multi-chamber container, or 120 mmol to 1400 mmol per liter of reconstituted multi-chamber container, wherein the total concentration of butyric acid equivalents does not exceed 1401 mmol per liter of reconstituted multi-chamber container. In other words, the multi-chamber container according to the present invention may contain arginine butyrate in the amino acid or carbohydrate formulation (or both), and the lipid formulation contains tributyrin. However, the final concentration of butyric acid equivalents should not exceed 1401 mmol / L in the reconstituted multi-chamber container. Therefore, care should be taken to adjust the respective concentrations, keeping in mind that one molecule of tributyrin provides three equivalents of butyric acid. Methods for preparing tributyrin-containing lipid formulations are known in the art and are described, for example, in U.S. Patent No. 5,919,822.

[0133] According to yet another aspect of the present invention, the lipid chambers of the multi-chamber containers of the present invention comprise a structured lipid containing one or two equivalents of butyric acid, such as dipalmitoyl-3-butyrylglycerol (DPBG), as further detailed above, at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, the total concentration of equivalents of butyric acid not exceeding 1401 mmol per liter of reconstituted multi-chamber container. Other examples of structured lipids that can be used according to the present invention include, but are not limited to, 1-palmitoyl-2-oleoyl-3-butyrylglycerol and 1-oleoyl-2-palmitoyl-3-butyrylglycerol. In other words, the multi-chamber container according to the present invention comprises arginine butyrate in either the amino acid or carbohydrate formulation (or both), and the lipid formulation comprises a structured lipid containing 1 or 2 equivalents of butyric acid, such as dipalmitoyl-3-butyrylglycerol, 1-palmitoyl-2-oleoyl-3-butyrylglycerol, and / or 1-oleoyl-2-palmitoyl-3-butyrylglycerol, etc. However, the final concentration of butyric acid equivalents in the reconstituted multi-chamber container again must not exceed the aforementioned 1401 mmol / L.

[0134] According to a further aspect of the present invention, the lipid chamber of a multi-chamber container according to the present invention contains dipalmitoyl-3-butyrylglycerol (DPBG) and tributyrin, and the total concentration of butyric acid equivalents does not exceed 1401 mmol / L of the reconstituted multi-chamber container. In other words, the multi-chamber container according to the present invention contains arginine butyrate in an amino acid or carbohydrate formulation (or both), and the lipid formulation contains dipalmitoyl-3-butyrylglycerol. However, the final concentration of butyric acid equivalents must not exceed 1401 mmol / L of the reconstituted multi-chamber container.

[0135] In yet another embodiment of the present invention, dipalmitoyl-3-butyrylglycerol can be present in the lipid chamber as the only butyric acid derivative present in the multi-chamber container. Accordingly, the present invention also provides a multi-chamber container comprising at least three chambers, each containing a carbohydrate formulation, an amino acid formulation, and a lipid formulation, wherein the lipid formulation comprises DPBG at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container. The container and amino acid formulation, carbohydrate formulation, and lipid formulation are as described herein. Such a multi-chamber container may also contain additional chambers, such as a fourth or fifth chamber containing vitamins and / or trace elements.

[0136] The pH of the multi-chamber container formulation is preferably adjusted to reach a value of 4.5 to 8.0 in the reconstituted multi-chamber container solution, for example a pH of 5.0, 5.5, 6.0, 6.5, 7.0 or 7.5.

[0137] The present disclosure also provides a method for treating patients who require parenteral nutrition when oral and enteral nutrition is impossible, insufficient or contraindicated.The method comprises using the multi-chamber container and amino acid preparation disclosed herein.In particular, the method comprises parenterally administering the contents of the multi-chamber container and / or amino acid preparation disclosed herein to the patient.

[0138] In pediatric patients, the formulations according to the invention are administered to reach an arginine butyrate dose of 2 mg / kg / day to 10 g / kg / day, e.g., 2 mg / kg / day to 100 mg / kg / day, 100 mg / kg / day to 1000 mg / kg / day, or 750 mg / kg / day to 7.5 g / kg / day. The dose may need to be adapted depending on the age of the pediatric patient and / or nutritional intake by other than parenteral routes. For example, if the pediatric patient also receives enteral nutrition, the dose may need to be adapted or reduced.

[0139] It should be understood that the initial dose may be low (e.g., 2 mg / kg / day or 3 mg / kg / day) and gradually increased (e.g., to 5 mg / kg / day, 10 mg / kg / day, 50 mg / kg / day, 100 mg / kg / day, 200 mg / kg / day, 500 mg / kg / day, 800 mg / kg / day, 1 g / kg / day, 2 g / kg / day, 5 g / kg / day, 7.5 g / kg / day, or 10 g / kg / day), and that the dose may need to be adapted depending on nutritional intake via routes other than parenteral, for example, where the infant is additionally given infant formula and / or breast milk. The required dose can be administered, for example, by adjusting the flow rate at which TPN is administered. For example, PN products such as NUMETA G13E can be administered at flow rates as high as 127.9 ml / kg / day. In a phase I clinical trial in patients with metastatic colorectal cancer, arginine butyrate was well tolerated at a dose of 3 g / kg / day in aqueous solution at pH 7.7 (Douillard et al., Phase I trial of interleukin-2 and high-dose arginine butyrate in metastatic colorectal cancer. Cancer Immunology Immunotherapy 2000;49:56-61).

[0140] In adult patients, the formulations according to the present invention are administered to achieve a dose of arginine butyrate of 2 mg / kg / day to 10 g / kg / day, e.g., 10 mg / kg / day to 8 g / kg / day, or 500 mg / kg / day to 1 g / kg / day, or 1 g / kg / day to 10 g / kg / day. The dose may need to be adapted depending on nutritional intake other than parenteral, for example, if the patient also receives enteral nutrition. The required dose can be administered, for example, by adjusting the flow rate at which TPN is administered. For example, PN products such as Olimel N9E (see also the Examples) can be administered at a flow rate as low as 20 ml / kg / day. For Peds, Numeta G13 can be administered at a maximum flow rate of 127.9 ml / kg / day.

[0141] Preferably, the maximum dose of arginine butyrate is 10 g / kg / day, particularly preferably 1 g / kg / day.

[0142] The small intestine has three distinct regions: the duodenum, jejunum, and ileum. The shortest, the duodenum, is where absorption begins, preparing compounds for absorption through tiny finger-like projections called villi. The jejunum is specialized for absorption through its lining by enterocytes: small nutrient particles predigested by enzymes in the duodenum are taken up. The ileum's primary function is to absorb compounds such as vitamin B12, bile salts, and other digestive products not absorbed by the jejunum. Villi are projections into the lumen lined primarily with the mature absorptive enterocytes mentioned above, occasionally accompanied by mucus-secreting goblet cells. Each villi is approximately 0.5–1.6 mm long (in humans) and has many microvilli protruding from its epithelial enterocytes, which collectively form a striated or brush border. Each of these microvilli is much smaller than a single villi. Intestinal villi are again much smaller than any of the circular folds within the intestine. Crypts are moat-like invaginations of epithelium surrounding the villi and are largely lined with young epithelial cells primarily involved in secretion. Importantly, towards the base of the crypt, stem cells divide continuously, providing the source of all epithelial cells in the crypts and villi.

[0143] Healthy villi and crypts, along with their cellular lining (Figure 19), are important markers of a functional small intestine. Villi increase the internal surface area of ​​the intestinal wall for efficient absorption. Increasing the absorption area is useful because digested nutrients (including, for example, amino acids) enter the semipermeable villi via diffusion, which is only effective over short distances. In other words, increasing the surface area (in contact with intraluminal fluid) shortens the average distance traveled by nutrient molecules, which in turn increases the effectiveness of diffusion and nutrient uptake. Villi are connected to blood vessels, thereby transporting nutrients away. Atrophied villi tend to be shorter, and crypts tend to be less prominent and shallower in depth. Therefore, assessing the length of the villi and the depth of the crypts in various parts of the small intestine, i.e., the duodenum, jejunum, and ileum, provides relevant information about small intestinal health (Burrin et al., Translational Advances in Pediatric Nutrition and Gastroenterology: New Insights from Pig Models. Annu). Rev Anim Biosci 2020;8:321-354). Total PN is associated with shorter villi and crypts, more goblet cells, increased inflammatory and immune cells, increased paracellular permeability, and decreased blood flow.

[0144] As further described in Example 3.2, to understand the effect of various short chain fatty acids on intestinal integrity and functionality, villus height, mid-villus width and crypt depth were measured accordingly.

[0145] It is also known that there is a relationship between intestinal epithelial integrity and intestinal health (Thomson et al., The Ussing chamber system for measuring intestinal permeability in health and disease, BMC Gastroenterology 2019;19:98). Impaired barrier function is associated with intestinal diseases, such as ulcerative colitis and Crohn's disease. The so-called Ussing system provides an ex vivo measurement of permeability, or duodenal mucosal resistance. This system allows for the measurement of the aforementioned duodenal mucosal (transepithelial) resistance (TER), which can be determined to provide an overall measure of intestinal integrity. Low TER values ​​indicate increased permeability. Previous studies have shown that decreased TER under inflammatory conditions is associated with the downregulation of "sealing" tight junction proteins. Therefore, determining epithelial integrity using an Ussing chamber constitutes one option for assessing the impact of various nutritional options (e.g., EN vs. PN) and various PN compositions (see Example 3.5) on intestinal health, particularly local inflammatory events.

[0146] The data in the context of the present invention were obtained from studies using pigs. Pigs have become an increasingly important animal model for modeling human pediatric nutrition and gastroenterology and complementing mechanistic studies in rodents. The comparative advantages in size and physiology of newborn pigs have led to new translational and clinically relevant models of important gastrointestinal and hepatic diseases in premature infants (Burrin et al., Annu Rev Anim Biosci 2020;8:321-354). Thus, comparative data were obtained based on a pig model (non-resection model, newborn pig) to evaluate the effects of different SCFAs in PN and SCFA-PN on intestinal barrier properties, local and systemic inflammation and immunity, and enterocyte structure compared to standard PN and normal nutritional intake. Experiments were performed as further described in Example 1.

[0147] In the aforementioned study evaluating arginine butyrate in comparison with standard parenteral nutrition and other butyrate derivatives, specifically tributyrin and dipalmitoyl-3-butyrylglycerol, the effects on intestinal barrier function and associated local and systemic effects on inflammation and immunity were determined (see Examples). Table 2 summarizes the high-level results of the study, showing that all intervention groups (those receiving PN with butyrate derivative-supplemented formulations) demonstrated better outcomes than those receiving standard PN with respect to intestinal structure, systemic and local inflammation, and systemic and local immunity. Some of these effects have been previously described in similar studies focusing primarily on the effects of butyrate salts provided as sodium butyrate or tributyrin. Surprisingly, significant differences were found for formulations containing arginine butyrate derivatives, which have not previously been used in parenteral nutrition compositions. Arginine butyrate proved particularly beneficial with regard to intestinal structure, as evidenced by villus height, crypt depth, and tight junction (duodenal mucosal resistance) analysis; local and systemic inflammation as indicated by determination of pro- and anti-inflammatory cytokines; and improved local immunity as evidenced by sIgA. No differences in cognitive effects or brain development were observed for each intervention group. [Table 2] Table 2: Summary of the effects found in the intervention group receiving PN with different butyrate derivatives. + indicates a positive effect (compared to standard PN), ++ indicates a very positive effect. - indicates no difference. Results are villus height and crypt depth listed as "total", which encompasses the results of all sections considered (duodenum, jejunum, ileum, colon).

[0148] Immediate high-level comparison of the results of intervention group C, which received arginine butyrate, and intervention groups A and B, which received tributyrin, known to potentially have a positive effect on gut health, with standard PN and enteral nutrition (EN) supports the finding that arginine butyrate-containing formulations have unexpectedly superior effects on tested markers of intestinal barrier function, local inflammation, local immunity, gut structure, and systemic inflammation (Table 3). The trends shown in Table 3 for systemic inflammation are further explored. [Table 3] Table 3: High-level comparison of the effects of arginine butyrate and tributyrin on selected markers of intestinal barrier function, local inflammation, local immunity, intestinal structure, and systemic inflammation. +++ indicates P<0.01; ++ indicates P<0.05; + indicates a positive trend; = indicates a non-significant P value; - indicates a negative trend. 1 ) compared to standard PN (s-PN). 2 ) As good as enteral nutrition;( 3 ) Better than enteral;( 4 ) Reduction of pro-inflammatory cytokines, downregulation of anti-inflammatory secretions;( 5 ) enteral;( 6 )Same tendency as local inflammation, further confirmation required.

[0149] Therefore, in pediatric patients, particularly full-term and preterm infants, the formulations disclosed herein can be used to support the development of healthy intestinal morphology and / or growth and / or body composition. Furthermore, they can support immune responses and gut microbiota. They are also useful in resolving inflammation and improving nutrient utilization. They can also be used to prevent or treat sepsis, chronic lung disease, cachexia, inflammatory diseases, and / or necrotizing enterocolitis.

[0150] Formulations according to the present disclosure are particularly useful for providing parenteral nutrition to infants, particularly premature newborns, but may also be used to provide total or partial parenteral nutrition to adults.

[0151] The preparations according to the present invention specifically support local and systemic immune responses and intestinal flora in adult patients, and reduce local inflammation. Therefore, they can be used to resolve inflammation and improve nutrient utilization in patients at risk of inflammation or who have already developed inflammation. Furthermore, they can be used to prevent or treat sepsis, chronic lung disease, cachexia, or inflammatory diseases. For example, the preparations according to the present invention can be used to treat or prevent cachexia and / or impaired immune response in cancer patients, sepsis in critically ill patients, metabolically stressed patients, or parenteral nutrition-related problems in patients with short bowel syndrome or intestinal failure. They can also be used to support the immune response of critically ill patients, cancer patients, immunocompromised patients, the intestinal flora in metabolically stressed patients, and improve nutrient utilization in malnourished patients.

[0152] Lipid emulsions containing choline derivatives have been shown to have the potential to prevent and / or treat hepatic steatosis, which can lead to liver metabolic dysfunction, inflammation, and progressive nonalcoholic fatty liver disease (NAFLD), particularly in parenteral nutrition, and are problematic in the treatment of pediatric patients as well as adult patients (WO 2019 / 0232054, WO 2019 / 232044). NAFLD encompasses a spectrum of diseases ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cirrhosis and hepatocellular carcinoma. Therefore, a multi-chamber container according to the present invention, which contains a lipid emulsion in the third chamber and further contains a choline derivative, preferably choline chloride or GPC, can address two major problems that arise in total parenteral nutrition for patients, particularly pediatric patients. Therefore, the present disclosure also provides a method for treating hepatic steatosis, liver metabolic dysfunction, inflammation, and progressive nonalcoholic fatty liver disease (NAFLD) in pediatric and / or adult patients. Specifically, the multi-chamber container and the formulations contained therein can be used to treat long-term TPN patients who have or are at risk of developing both hepatic steatosis, liver metabolic dysfunction, inflammation, and advanced forms of non-alcoholic fatty liver disease (NAFLD) and intestinal barrier compromise, which is the breakdown of intestinal structure, and who suffer from the development of chronic or acute inflammation (local and systemic), and who have or are at risk of developing local and systemic immune compromise.

[0153] The formulations according to the invention can be administered according to methods known in the art, for example, through a central or peripheral catheter or can be administered subcutaneously. [Example]

[0154] Example 1: Materials and Methods A pig model was selected to evaluate the effects of enteral, standard parenteral, and non-parenteral nutrition, supplementing standard PN formulations with various butyrate derivatives (see Table 4). Currently, preterm pigs born at 90% gestation are estimated to be equivalent to preterm human infants at 75% gestation (30-32 weeks) (Burrin et al., Translational Advances in Pediatric Nutrition and Gastroenterology: New Insights from Pig Models. Annu Rev Anim Biosci 2020;8:321-354). 1.1 Research design

[0155] Newborn Yorkshire / Landrace crossbred piglets (n=72; 12 replicates, 6 from the same litter) were obtained from Oak Hill Genetics (Ewing, IL) after sows had been housed for 48 hours for colostrum intake and iron supplementation. The piglets were randomly divided into groups (12 piglets / group) and fed for 10 days as shown in Table 4. [Table 4] Table 4: Nutrition provided to groups of piglets over a 10-day period.

[0156] All formulations used were based on Olimel N9E (see Table 4). Tributyrin and 1,2-dipalmitoyl-3-butyrylglycerol supplements were provided in the lipid chamber of the 3CB product Olimel N9E, and arginine butyrate was added to the amino acid chamber. All concentrations given relate to the final reconstituted solution (TPN). Therefore, the administered formulations and concentrations are completely equivalent, regardless of the initial chamber to which the supplements were added. One bulk package of Infuvite Pediatric (Baxter Healthcare), containing vitamins for intravenous infusion after dilution, was added to each bag of administered Olimel N9E. MICRO+6, containing trace elements, was also added. One vial of Pediatric Injection (Baxter Healthcare Corp.) was added to each bag of Olimel N9E. [Table 5] Table 5: Compositions used in this study. LE stands for lipid emulsion. The underlined values ​​indicate which components of Olimel N9E were changed by the addition of the supplement. Olimel N9E alone: ​​amino acid chamber: 14.2%; carbohydrate chamber: 27.5%; lipid emulsion chamber: 20.0%.

[0157] Butyrate concentrations were measured in a similarly structured study (Bartholome et al., J Parent The dietary intake was selected within a range known to be well tolerated in the NIH (Nutr 2014;28(4):210-223). A daily infusion rate of 253 kcal / kg / day was provided to achieve a daily amino acid content of 12.9 g / kg / day. To minimize the risk of malnutrition, the infusion rate was 307 kcal / kg / day only on the first day immediately after surgery. To fully capture the turnover cycle, a 10-day study period was selected based on the typical turnover time of intestinal epithelial cells, which is 5 to 7 days. 1.2 Surgical procedure

[0158] Upon arrival (day 1), piglets were fitted with a central venous line. A 3 cm incision was made in the right clavicle region, and the external jugular vein was isolated for catheter insertion (a 3.5 French polyvinyl chloride catheter). After blunt dissection, the jugular vein was ligated with two 3-0 silk sutures placed cranially (anatomically closer to the head) and cardiacly (anatomically closer to the heart) relative to the central venous line insertion site. Once the cranial ligature was ligated, a small incision was made in the jugular vein to insert a pre-measured central venous line (a 3.5 French PVC catheter), which was inserted 6 cm (pre-measured and marked at 6 cm) through the external jugular vein in the superior vena cava for PN infusion. After placement of the central venous line, cardiac sutures were ligated to secure the line, and the end was tunneled subcutaneously between the scapulae. Once in place, the central venous line was flushed with heparinized saline until attached to the PN pump. The incision site was closed with a single layer closure using Vicryl in a continuous subcutaneous suture pattern. The suture site was monitored and covered with petrolatum overlaid with sterile gauze secured with Transpore tape. 1.3 Animal Care and Housing

[0159] The animals were allowed to recover under constant supervision and monitored for respiratory rate, heart rate, and signs of pain to ensure recovery of consciousness. After recovery, the piglets were fitted with a jacket with a swivel tether (Lomir Biomedical Inc., Quebec, Canada) attached to secure the catheter and infusion line and allow free movement. Due to the young age of the animals and the need to minimize time without nutrition and hydration, no preoperative jacket acclimation was performed. PN was administered immediately after surgery to provide 307 kcal / kg / day to minimize the risk of malnutrition. The PN dose was 120% (20% higher) than the nutritional requirements of a piglet of this age and size (200 kcal / kg / day) to compensate for surgical stress. Daily, the animals underwent clinical evaluation for both research and animal health purposes. A complete clinical evaluation was performed daily, including weight (grams), chest circumference (cm), temperature, respiratory rate, heart rate, activity level, catheter insertion site healing, and animal behavior and pain scores. A partial clinical assessment (minus weight and waist circumference measurements) was performed each evening to reassess the health of the piglets. 1.4 Nutritional interventions

[0160] Milk replacer (OptiLac Baby Pig Milk Replacer; Hubbard Feeds, Mankato, Minnesota, USA) was prepared fresh daily according to the manufacturer's recommendations. The volume of milk replacer was calculated based on morning body weight and provided 253 kcal / kg. The prepared amount of milk replacer was provided to Group E and was available ad libitum.

[0161] All PN solutions were formulated by the manufacturer (Baxter Healthcare Corp.) as a 3-in-1 solution (bag volume: 1000 mL), delivered at the beginning of each experimental cycle, and maintained at 40°C during administration. Each PN solution contained dextrose, amino acids, and lipid emulsion in separate compartments until use. The PN solutions also contained assigned vitamins, minerals, and experimental amounts of butyrate derivatives (Tables 4 and 5). All PN solutions were continuously infused using an AVA 6000CMS MultiTherapy infusion pump (AVA Biomedical, Wilmette, IL) to provide 253 kcal / kg / day and 12.8 grams of amino acids / kg / day. All milk replacer feeds and PN infusions were performed to ensure isocaloric feeding for all piglets. Mean energy delivery (Figure 1) and mean protein delivery (Figure 2) were recorded. The figures demonstrate that the experimental groups were studied under the same conditions. 1.5 Cognitive Assessment

[0162] Eyeblink conditioning is an established Pavlovian method for assessing the cerebellum and associated brainstem circuits, including the hippocampus, which are essential for learning and memory. The eyeblink conditioning procedure was performed in a sound-attenuating chamber. A fan was placed inside the chamber, and the entire experiment was performed over ambient noise (70 dB). A speaker attached to the wall of the chamber delivered a tone conditioned stimulus (CS). A small plastic air-puff delivery nozzle (San Diego Instruments, San Diego, CA) was fixed approximately 2 cm from the pig's left eye to deliver the unconditioned stimulus (US). After adaptation to the conditioning apparatus on the third day of testing, a total of five CS-US conditioning sessions were conducted 4–8 days after testing. Each conditioning session consisted of 90 CS-US pairing trials and 10 CS-alone trials, for a total of 100 trials / session. A CS-alone trial was conducted every 10th trial. CS-US paired trials included a 500-ms auditory CS (1 kHz, 85 dB tone), a 400-ms interstimulus interval (ISI), followed by a 100-ms corneal air-puff US (10 psi). Both the CS and US ended at exactly the same time. CS-alone trials were followed by a 500-ms auditory CS (1 kHz, 85 dB tone) and a 400-ms interstimulus interval (ISI). The conditioning sessions consisted of only a 100 kHz, 85 dB tone. There was a random inter-trial interval of 20 seconds throughout each session. Each conditioning session lasted ≤35 minutes. San Diego Instruments eyeblink software was used to record instantaneous infrared reflectance data for the conditioning sessions. The results are shown in Figure 14. No significant differences were detected between groups. 1.6 Assessment of brain structural development and body composition

[0163] On study day 9, piglets underwent magnetic resonance imaging (MRI) using an Agilent 9.4 Tesla MRI system (Santa Clara, CA) to assess brain structural development and body composition. Heart rate and respiration were monitored throughout the MRI scan. For brain anatomical evaluation targeting the hippocampus, images were acquired using a 3D T1-weighted magnetization-prepared gradient-echo sequence: repetition time = 1,900 ms; echo time = 2.48 ms; inversion time = 900 ms; flip angle = 9°; matrix = 256 × 256 (interpolated to 512 × 512); slice thickness = 1.0 mm. For body composition evaluation, the trunk region (longissimus muscle / fat / muscle) was imaged using multislice spin-echo technology: echo time = 20 ms; recovery time = 400 ms; 4-signal averaging. The slice thickness for each image was 4.9 mm, with no gap between images. Total imaging time did not exceed 1 h per piglet. Total scan time was approximately 60 minutes, as it included both brain and body composition scans. MRI images were analyzed using OsiriX (Bernex, Switzerland). Brain structure was found to show no significant differences between the test groups. The average weight and abdominal circumference of the piglets in the test groups were also monitored. Figure 3 shows that weight developed similarly in all test groups. Figure 4 shows that average abdominal circumference also developed similarly in the test groups. 1.7 Research Sample Collection

[0164] Upon completion of the study period, the animals were euthanized by lethal injection (1 mL / 10 lbs; Lethal Plus; Veterinary Laboratories, Inc., Lenexa, Kansas) delivered via a central venous line. Urine and blood samples were collected for chemistry, high-performance liquid chromatography (HPLC), and enzyme-linked immunosorbent assay (ELISA) measurements. The digestive tract was removed and separated into different anatomical segments for histomorphology, electrophysiology, nutrient transport, and ELISA testing. Kidney, liver, spleen, and muscle samples were also collected from each piglet for histological and chemical evaluations. Fecal samples were collected and preserved for microbiota analysis. The mean colon weights of the test groups were determined (Figure 5). Groups A–D, which received butyrate derivative-supplemented PN, and the group receiving enteral nutrition outperformed the group receiving standard PN. Example 2: PN Composition

[0165] The compositions used are listed in Tables 4 and 5. Each butyrate derivative was compounded into each chamber of the bag. After sterilization, free butyrate was measured in the lipid chamber (for tributyrin and DPBG compositions) and the butyrate content in the amino acid chamber was determined. As shown in Table 5, only very limited amounts of butyrate were released during sterilization of the bags. In the case of the amino acid chamber, the recovered butyrate after sterilization corresponded to that introduced. Therefore, no degradation of the salt occurred during or after sterilization. The stability of the compositions over time (12 months, 25°C, 40% RH) was also confirmed. Free butyrate can be quantified by GC-FID after sample preparation by liquid-liquid extraction of the lipid emulsion or directly from the amino acid solution. These methods are known in the art. Example 3: Methods for assessing study endpoints 3.1 Fisher's least significant difference (LSD) test

[0166] The Fisher's least significant difference (LSD) test method is described, for example, by Williams and Abdi in Neil Salkind (Ed.), Encyclopedia of Research Design. Thousand Oaks, CA: Sage. 2010. Fisher's LSD test is essentially a set of individual tests. It is used only as a follow-up to ANOVA. After a one-way (or two-way) analysis of variance (ANOVA), it is possible to compare the mean of one group with the mean of another group. One way to do this is to use the Fisher's least significant difference (LSD) test. This test follows the principle of calculating the least significant difference (i.e., LSD) between two means as if these means were the only means being compared (i.e., using a t-test), and declaring a significant difference greater than the LSD. 3.2 Histomorphology and preparation of ileal and jejunal sections

[0167] Formalin-fixed intestinal samples were embedded in paraffin, sliced ​​to a thickness of approximately 5 μm using a microtome, and stained with hematoxylin and eosin (Figure 6). Villus height, mid-villus width, and crypt depth were measured in 8–10 well-oriented villi and crypts using a Nikon Optiphot-2 microscope (Nikon, Melville, NY) and Image-Pro Express software (version 4.5; Media Cybernetics, Inc., Silver Spring, MD). Villus surface area (villus height × mid-villus width) was also calculated. Intestinal perimeter was also measured, and intestinal surface area was estimated. The results are shown in Figures 7–12 (see there for details). Table 6 shows the results of the histomorphometric analysis of the test groups. The table summarizes the mean difference (% of each intervention group (A, B, C, D) vs. the PN group) in villus height and crypt depth in different parts of the intestine, namely the duodenum, jejunum, ileum, and colon. The intervention groups show improved villus height compared to the s-PN group. Overall, group C shows the most significant improvement in intestinal structure. [Table 6] Table 6: Histomorphological results of the intervention groups. Provides the mean differences (% of each intervention group (A, B, C, D) vs. the PN group) in villus height and crypt depth in different parts of the intestine. 3.3 Plasma glucagon-like peptide 2 (GLP-2) concentration

[0168] Plasma GLP-2 concentrations are quantified by extracting plasma samples with 75% ethanol and centrifuging at 3000 x g for 30 minutes at 4 °C. The supernatant is decanted, lyophilized, and resuspended in assay buffer (80 mmol / L Na3PO4 - The plasma was reconstituted to the original plasma volume in 0.01 mmol / L valine-pyrrolidide, 0.1% (w / v) human serum albumin, 10 mmol / L EDTA, 0.6 mmol / L thimerosal, pH 7.5. Approximately 300 μL of the extracted sample and human GLP-2 standard were incubated with 100 μL of rabbit GLP-2 antiserum (final dilution 1:25,000) at 4°C for 24 hours, after which free and bound peptides were separated by absorption onto plasma-coated charcoal (see also Bartholome et al., J Parent Nutr 2004;28(4):210-223 for the standard used). This antiserum was raised against the NH2-terminal fragment of human GLP-2 and specifically recognizes the NH2-terminal region of both human and porcine GLP-2. 3.4 IgA quantification

[0169] Small intestinal probes for measuring IgA levels were obtained by flushing the small intestine with chilled HBSS (Hank's Balanced Salt Solution). Nasal and bronchoalveolar lavage for measuring airway IgA levels were obtained by lavage with 1 mL of phosphate-buffered saline under anesthesia. The lavage fluid was stored in a -80°C freezer until IgA analysis. IgA was measured in small intestinal and airway lavage fluids by sandwich enzyme-linked immunosorbent assay using polyclonal goat anti-mouse IgA (Sigma) to coat the plates, purified mouse IgA (Zymed Laboratories, San Francisco, CA) as a standard, and horseradish peroxidase-conjugated goat anti-mouse IgA (Sigma). The results are shown in Figure 13. 3.5 Duodenal mucosal resistance

[0170] Duodenal mucosal resistance was determined according to known methods and according to Tappenden et al., Short-Chain Fatty Acid-Supplemented Total Parenteral Nutrition Enhances Functional Adaptation to Intestinal Resection in Rats. Gastroenterology 1997;112:792-802. Intestinal segments (1 cm 2 ) was excised and the tissue was mounted as a flat sheet in an incubation chamber containing oxygenated Krebs bicarbonate buffer (pH 7.4) at 37°C. The tissue disc was pre-incubated in this buffer for 15 minutes to equilibrate to this temperature. After pre-incubation, the chamber was 3The 14C probe molecules were transferred to other beakers containing [H] inulin and various 14C probe molecules in oxygenated Krebs bicarbonate (pH 7.4 and 37°C). The solute concentrations were 4, 8, 16, 32, or 64 mmol / L for D-glucose and 16 mmol / L for L-glucose. The pre-incubation and incubation solutions were mixed with a circular magnetic bar at the same stirring speed, which was regulated by a strobe. A stirring speed of 600 rpm was selected to achieve a low effective resistance of the unstirred intestinal water. The experiment was terminated by removing the chamber and quickly rinsing the tissue with cold saline for approximately 5 seconds. The exposed mucosal tissue was then excised from the chamber with a circular steel punch. For all probes, the tissue was dried overnight in a 55°C oven. The dry weight of the tissue was determined, and the samples were saponified with 0.75 N NaOH. Scintillation fluid was added (Beckman Radioactivity was determined by volumetric external standardization technique using Ready Solv HP (Beckman, Mississauga, Ontario) to correct for variable extinction of the two isotopes. Mucosa weight was determined after intestinal scraping from adjacent samples not used in the uptake study. The weight of mucosa in the samples used to measure uptake was determined by multiplying the dry weight of the intestinal sample by the percentage of the intestinal wall consisting of mucosa. Results for all groups are shown in Table 7.

[0171] Intervention groups A, B, C, and D were found to be significantly different from the P(S-PN) reference group with respect to duodenal mucosal resistance (see Table 2). Furthermore, all intervention groups were non-inferior to or not statistically different from group E (enteral nutrition). Intervention group D resulted in duodenal resistance nearly as good as group E (enteral nutrition). Notably, group C showed significantly less loss of mucosal resistance compared to the other intervention groups and even better than group E (enteral nutrition), indicating that the addition of arginine butyrate is surprisingly effective in maintaining or supporting duodenal mucosal resistance and improving intestinal health, including reduced susceptibility to local inflammation. [Table 7] Table 7: Mean duodenal mucosal resistance for each intervention, Groups A-D, compared with S-PN (standard PN) and EN (enteral nutrition), as determined by Fisher's least significant difference (LSD) test. Group C (AB-PN) shows significantly better tolerance compared with the other intervention groups and enteral nutrition Group E. 3.6 Cytokine quantification

[0172] Milo et al., Effects of Short-Chain Fatty Acid-Supplemented Total Parenteral Nutrition on Intestinal Pro-Inflammatory Cytokine The effect of each supplement on systemic inflammation was investigated by determining serum levels of IL-6, IL-1β, TNF-α, and IL-10 in the intervention group compared with EN and PN, according to the study in Abundance.Digestive Diseases and Sciences 2002;47:2049-2055. Jejunal and ileal samples were homogenized in double-distilled water, and a Bradford protein assay (Biorad, Hercules, CA, USA) was performed on the homogenates and plasma samples. Proteins (30 μg) from each sample were denatured by boiling and separated by size using 12.5% ​​sodium dodecyl sulfate polyacrylamide gel electrophoresis. The separated proteins were transferred to polyvinylidene difluoride membranes (Biorad) using a semi-dry transfer apparatus (Biorad). Western blot analysis for TNF-α, IL-1β, IL-10, and IL-6 was performed using porcine-specific polyclonal antibodies (Endogen, Woburn, MA, USA). Mouse anti-porcine monoclonal TNF-α antibody was used to detect TNF-α (17,000 kDa). Rabbit anti-porcine polyclonal antibodies specific for IL-1β and IL-6 were used to detect IL-1β (17,500 kDa), IL-10 (18,600 kDa), and IL-6 (26,000 kDa). Membranes were developed using the Opti-4 CN kit (Biorad) and analyzed by FOTO / Analyst Image. Photographs were taken using an Analysis System (Fotodyne, Inc., Hartland, Wisconsin, USA). Measurement of TNF-α, IL-1β, IL-6, and IL-10 concentrations was performed using Collage Image Analysis Software 4.0 (Fotodyne, Inc.). The results are shown in Figure 15 (IL-6), Figure 16 (IL-1-β), Figure 17 (TNF-α), and Figure 18 (IL-10). The present invention provides, for example, the following items. (Item 1) A multi-chamber container for parenteral administration, comprising: (i) a carbohydrate formulation present in a first chamber; (ii) an amino acid formulation present in a second chamber; and Including, A multi-chamber container, wherein at least the first chamber or the second chamber contains arginine butyrate. (Item 2) (iii) The multi-chamber container of item 1, further comprising a lipid formulation present in a third chamber, wherein at least the first chamber, the second chamber, or the third chamber comprises arginine butyrate. (Item 3) 3. The multi-chamber container according to item 1 or 2, wherein the arginine butyrate is present at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container. (Item 4) 4. The multi-chamber container of any one of items 1 to 3, wherein the arginine butyrate is present in the amino acid formulation of the second chamber. (Item 5) 5. The multi-chamber container according to any one of items 1 to 4, wherein the amino acid formulation comprises an aqueous solution of one or more amino acids, dipeptides and / or oligopeptides and optionally one or more electrolytes selected from the group of electrolytes comprising sodium, potassium, magnesium, calcium, phosphate compounds, and contains polyvalent anions of organic acids consisting of malate, citrate, acetate, lactate, gluconate, glucoheptonate, gluconoglucoheptonate, glucose-phosphate, or inorganic acids consisting of sulfate, chloride. (Item 6) 6. The multi-chamber container according to any one of items 1 to 5, wherein the amino acid preparation contains approximately 1 g to 30 g of amino acids per 100 mL of the amino acid preparation. (Item 7) 7. The multi-chamber container of any one of items 1 to 3 and 5 to 6, wherein the arginine butyrate is present in the carbohydrate formulation of the first chamber. (Item 8) 8. The multi-chamber container according to any one of items 1 to 7, wherein the carbohydrate preparation comprises 1 g to 100 g of glucose and / or maltose and / or trehalose per 100 mL of carbohydrate preparation, and optionally one or more electrolytes selected from the group of electrolytes consisting of sodium, potassium, magnesium, calcium, phosphate or glycerophosphate. (Item 9) 9. The multi-chamber container of any one of items 2, 3, 5, 6 and 8, wherein the arginine butyrate is present in the lipid formulation of the third chamber. (Item 10) 10. The multi-chamber container according to any one of items 2 to 9, wherein the lipid formulation comprises an aqueous phase and an oil phase in an amount of 1 g to 40 g of oil per 100 ml of lipid formulation. (Item 11) 11. The multi-chamber container of any one of items 2 to 10, wherein the lipid formulation comprises at least one pharmaceutically acceptable antioxidant selected from the group consisting of α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocotrienol, ascorbyl palmitate, and ascorbic acid. (Item 12) 12. The multi-chamber container according to item 10 or 11, wherein the oil phase comprises one or more oils selected from the group consisting of olive oil, soybean oil, safflower oil, palm oil, fish oil, fish oil extract, krill oil, medium chain triglycerides (MCT), algal oil, fungal oil, corn oil, sunflower oil, palm kernel oil, and rapeseed oil. (Item 13) 13. The method according to any one of items 1 to 12, wherein at least one of the first chamber, the second chamber, and the third chamber further comprises vitamins and / or trace elements. The multi-chamber container according to any one of claims 1 to 14. (Item 14) 14. Multi-chamber container according to any one of the preceding items, wherein the multi-chamber container comprises at least one further chamber containing a vitamin and / or trace element preparation. (Item 15) 15. The multi-chamber container of any one of items 1 to 14, wherein arginine butyrate is present at a concentration of 0.1 mmol to 1000 mmol per liter of reconstituted multi-chamber container, 0.5 mmol to 600 mmol per liter of reconstituted multi-chamber container, 1 mmol to 500 mmol per liter of reconstituted multi-chamber container, 1 mmol to 300 mmol per liter of reconstituted multi-chamber container, 2 mmol to 250 mmol per liter of reconstituted multi-chamber container, 5 mmol to 150 mmol per liter of reconstituted multi-chamber container, 5 mmol to 75 mmol per liter of reconstituted multi-chamber container, or 5 mmol to 50 mmol per liter of reconstituted multi-chamber container. (Item 16) 16. The multi-chamber container according to any one of items 2 to 15, wherein the lipid formulation in the third chamber comprises tributyrin at a concentration of 0.05 mmol to 1400 mmol per liter of reconstituted multi-chamber container, and wherein the total concentration of butyric acid equivalents does not exceed 1401 mmol per liter of reconstituted multi-chamber container. (Item 17) 17. The multi-chamber container of claim 16, wherein the arginine butyrate is present in the amino acid chamber. (Item 18) 18. The multi-chamber container according to any one of items 1 to 17, wherein the pH of the formulation in the reconstituted multi-chamber container is 4.5 to 8.0. (Item 19) 1. An amino acid preparation for parenteral administration, comprising arginine butyrate at a concentration of 0.05 mmol to 1400 mmol per liter of the amino acid preparation. (Item 20) Item 20. The amino acid formulation of item 19, wherein arginine butyrate is present at a concentration of 0.1 mmol to 1000 mmol per liter of the amino acid formulation, 0.5 mmol to 600 mmol per liter of the amino acid formulation, 1 mmol to 500 mmol per liter of the amino acid formulation, 1 mmol to 300 mmol per liter of the amino acid formulation, 2 mmol to 250 mmol per liter of the amino acid formulation, 5 mmol to 150 mmol per liter of the amino acid formulation, 5 mmol to 75 mmol per liter of the amino acid formulation, or 5 mmol to 50 mmol per liter of the amino acid formulation. (Item 21) The amino acid preparation may contain alanine (Ala), arginine (Arg), aspartic acid (Asp), glutamic acid (Glu), glutamine (Gln), glycine (Gly), histidine (His), leucine (Leu), isoleucine (Ile), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr), valine (Val), cis-amino acid (Tc ... 21. The amino acid formulation of item 19 or 20, comprising a solution of one or more amino acids selected from the group consisting of acetylcysteine ​​(Ac-Cys), ornithine (Orn), taurine, asparagine (Asn), acetyl-cysteine ​​(Ac-Cys), and acetyl-tyrosine (Ac-Tyr), optionally further comprising one or more electrolytes selected from the group consisting of sodium, potassium, magnesium, calcium, phosphate, and glycerophosphate. (Item 22) 22. The amino acid formulation of any one of items 19 to 21, wherein the formulation comprises one or more oligopeptides consisting of at least three amino acids and / or dipeptides selected from the group consisting of acetyl-tyrosine (Ac-Tyr), alanyl-glutamine (Ala-Gln), glycyl-glutamine (Gly-Gln), glycyl-tyrosine (Gly-Tyr) and alanyl-tyrosine (Ala-Tyr). (Item 23) 23. The amino acid formulation of any one of items 19 to 22, wherein the formulation comprises one or more anions of organic acids selected from malate, citrate, acetate, lactate, gluconate, glucoheptonate, glucono-glucoheptonate, glucose-phosphate, and / or inorganic acids selected from sulfate and chloride. (Item 24) 24. The amino acid preparation according to any one of items 19 to 23, wherein the preparation comprises about 1 g to 30 g of amino acid per 100 mL of the amino acid preparation. (Item 25) 25. The amino acid preparation of any one of items 19 to 24, wherein the preparation comprises 20 mg to 25 g of choline equivalent per liter of amino acid preparation selected from the group consisting of choline chloride, choline bitartrate, choline citrate, choline gluconate, choline malate, cytidine diphosphate choline (CDP) salt, and glycerophosphocholine (GPC). (Item 26) 26. The amino acid preparation according to any one of items 19 to 25, wherein the amino acid preparation further comprises vitamins and / or trace elements. (Item 27) 27. A composition reconstituted from the multi-chamber container of any one of items 1 to 18 or the amino acid formulation of any one of items 19 to 26, for parenteral administration to a patient in need of parenteral nutrition when oral and enteral nutrition is impossible, insufficient or contraindicated. (Item 28) 28. The composition for parenteral administration according to item 27, wherein the patient is a pediatric or adult patient. (Item 29) 29. The composition for parenteral administration according to item 27 or 28, wherein the patient is an intensive care patient, a critically ill patient, a short bowel patient, an extremely short bowel patient, a patient with intestinal failure, a patient undergoing metabolic stress, an immunocompromised patient, a cancer patient, a cachexia patient, a malnutrition patient, a patient suffering from or at risk of developing a compromised intestinal barrier, hyperglycemia and / or hypertriglyceridemia, an ICU patient in whom enteral nutrition is contraindicated, a surgical patient with persistent ileus or persistently non-permanent fasting (NPO), a patient with an enterocutaneous fistula, a preterm infant, or a home parenteral nutrition (HPN) patient who covers 95 to 100% of their energy needs from parenteral nutrition. (Item 30) 30. The composition for parenteral administration according to any one of items 27 to 29, wherein the patient is suffering from or at risk of developing systemic and / or local inflammation in the intestine. (Item 31) 31. A composition for parenteral administration according to any one of items 27 to 30, for sustaining or improving local immunity in the intestine and / or lungs of a patient. (Item 32) 27. A method of treating a patient in need of parenteral nutrition when oral and enteral nutrition is not possible, insufficient or contraindicated with a composition reconstituted from the multi-chamber container of any one of items 1 to 18 or the amino acid formulation of any one of items 19 to 26. (Item 33) 33. The method of item 32, wherein the patient is a pediatric or adult patient. (Item 34) 34. The composition for parenteral administration according to Item 32 or 33, wherein the patient is an intensive care patient, a critically ill patient, a short bowel patient, an extremely short bowel patient, a patient with intestinal failure, a patient undergoing metabolic stress, an immunocompromised patient, a cancer patient, a cachexia patient, a malnutrition patient, a patient suffering from or at risk of developing a compromised intestinal barrier, hyperglycemia and / or hypertriglyceridemia, an ICU patient in whom enteral nutrition is contraindicated, a surgical patient with persistent ileus or persistently non-permanent fasting (NPO), a patient with an enterocutaneous fistula, a preterm infant, or a home parenteral nutrition (HPN) patient who covers 95 to 100% of their energy needs from parenteral nutrition. (Item 35) 30. The composition for parenteral administration according to any one of items 27 to 29, wherein the patient is suffering from or at risk of developing systemic and / or local inflammation in the intestine. (Item 36) 35. The method of any one of items 32 to 34, wherein the patient is suffering from systemic and / or local inflammation in the intestine. (Item 37) 36. The method according to any one of items 32 to 35, for maintaining or improving local immunity in the intestine and / or lung. (Item 38) 37. The method of any one of items 32 to 36, wherein the composition is administered to the patient to achieve an arginine butyrate dose of 2 mg / kg / day to 10 g / kg / day. (Item 39) 37. The method of any one of items 32 to 36, wherein the composition is administered to the patient to achieve an arginine butyrate dose of 100 mg / kg / day to 2.5 g / kg / day.

Claims

[Claim 1] The invention described in the specification.

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