EP0168425A4 - Parenteral nutrition with medium and long chain triglycerides. - Google Patents

Parenteral nutrition with medium and long chain triglycerides.

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Publication number
EP0168425A4
EP0168425A4 EP19850900428 EP85900428A EP0168425A4 EP 0168425 A4 EP0168425 A4 EP 0168425A4 EP 19850900428 EP19850900428 EP 19850900428 EP 85900428 A EP85900428 A EP 85900428A EP 0168425 A4 EP0168425 A4 EP 0168425A4
Authority
EP
European Patent Office
Prior art keywords
mcts
composition
lcts
emulsion
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP19850900428
Other languages
German (de)
French (fr)
Other versions
EP0168425A1 (en
Inventor
George L Blackburn
Vigen K Babayan
Bruce R Bistrian
Lyle L Moldawer
Richard Cotter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Clintec Nutrition Co
Beth Israel Deaconess Medical Center Inc
Original Assignee
New England Deaconess Hospital
Baxter Travenol Laboratories Inc
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Filing date
Publication date
Application filed by New England Deaconess Hospital, Baxter Travenol Laboratories Inc filed Critical New England Deaconess Hospital
Publication of EP0168425A1 publication Critical patent/EP0168425A1/en
Publication of EP0168425A4 publication Critical patent/EP0168425A4/en
Ceased legal-status Critical Current

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms

Definitions

  • This relates to total parenteral nutrition of patients with liver disease or septicemia. It is particularly concerned with providing such nutrition via lipid emulsions.
  • Lipid emulsions for parenteral nutrition are available commercially or can be manufactured in accordance with known processes. Generally, such emulsions have been made using the triglycerides of long chain fatty acids (LCTs). LCTs are obtained conventionally from soybean or safflower oil. Long chain fatty acids are fatty acids having 14 or more carbon atoms, usually 16 or 18 carbon atoms.
  • MCTs medium chain fatty acids
  • Emulsions of this type are disclosed in European Patent Application 0071995 and Eckart et al., "J. Parenteral and Enteral Nutrition” 4(4):360-366 (1980).
  • MCT-derived fatty acids are absorbed by the intestinal cell at a rate twice the absorption rate of LCT-derived fatty acids.
  • the most striking difference between MCT and LCT was shown to be the mechanism of transport to sites of utilization and, as a result, their predominant mode of utilization.
  • MCT-derived fatty acids pass through the intestinal epithelial cell without reesterlflcation to MCT. They then enter the portal vein, bind to albumin, and are transported in this bound form in the bloodstream.
  • LCT-derived fatty acids after absorption are reesterified in intestinal cells to form LCT and packaged with protein and phospholipids to form lipid particles (chylomicrons) that enter the lymph system and, later, the circulatory system for distribution to the tissues of utilization.
  • chylomicrons lipid particles
  • MCTs are much more readily utilized for caloric energy, but are less effectively incorporated into tissue lipids. MCTs, when administered orally, are believed to be metabolized primarily in the liver, while LCTs are metabolized throughout the body (Scheig, R. In: Medium Chain Triglycerides, J.R. Senior, Ed. pp 39-49 [1968]).
  • Liver disease as this term is used herein means a primary or secondary disorder of the liver parenchyma that results in reduced hepatic function.
  • the etiology of the disease may include but not be limited to any one of the following common disorders: Alcoholic cirrhosis, acute hepatocellular damage secondary to drug abuse or poisoning, genetic deficiencies such as tyrosinosis, trauma to the liver, hepatitis, primary biliary cirrhosis, liver abscess, Budd-Chiarf syndrome, Wilson's disease, or primary or secondary liver neoplasms.
  • liver function tests such as serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase and billrubin, reductions in indocyanin green or bromosulphopthalein clearance, tissue biopsy, and/or neurological manifestations such as encephalopathy.
  • Liver disease as defined herein excludes the subclinically mild and reversible hepatic dysfunction induced by parenteral nutrition (Eckart et al. Ibid).
  • Patients with septicemia include patients having subclinical septicemia or susceptibility to septicemia. Patients in this group include patients recuperating from abdominal surgery, patients with respiratory diseases and those with active infections such as abcesses or infected wounds.
  • Intravenous calorie intake in liver diseased patients is hampered by chronic carbohydrate and fluid intolerance.
  • current LCT emulsions although calorically dense, are contraindicated in liver disease because liver dysfunction is frequently associated with an impaired ability to metabolize LCT.
  • MCTs have been included in oral formulations for the nutrition of stressed (including liver diseased) patients.
  • An example is the Travasorb ® Hepatic formulation sold by Travenol Laboratories, Inc.
  • the doses of MCT to be delivered with such formulations have been low, however, on the order of about 0.2 mg MCT/Kg body weight (BW)/min. when following the instructions for use.
  • MCTs are added to these nutrient formulations because they are believed necessary to circumvent the maladsorption of LCTs that accompanies deficient bile secretion by diseased livers.
  • the low doses were believed mandated by the prevalent belief in the art that MCTs are harmful to liver diseased patients. See, for example, N. Greenberger et al. "Ann.
  • MCTs can be parenterally administered to recipients with liver disease or septicemia, and in dosages heretofore believed to be potentially hazardous, without toxic side effects.
  • MCTs can supply nutritionally adequate calories to such patients without resulting in the liver fatty deposits or the reductions in the efficacy of the reticuloendothelial system (RES) noted when supplying LCTs as a significant calorie source.
  • RES reticuloendothelial system
  • the improvement herein comprises parenterally administering a composition comprising MCTs to a liver diseased patient or a patient with septicimia. It further comprises administering greater than about 0.35 mg MCTs/Kg BW/min. to such patients, preferably about from 0.5 to 2 mg MCTs/Kg BW/min., and selecting a weight proportion of MCTs to LCTs no greater than about 3 to 1.
  • compositions including (1) a composition comprising (a)lipids wherein about from 25% to 75% by weight of the lipids are MCTs and the remainder are LCTs and (b)the branched chain amino acids, valine, leucine and/or isoleucine or the keto analogues of valine, leucine and/or valine.
  • composition comprising MCTs and at least one branched chain amino acid, or preferably an amino acid mixture in which greater than about 35% of the mole weight of amino acids are valine, isoleucine and/or leucine or the keto analogues of valine, isoleucine and/or leucine.
  • the MCTs to be used herein will be C 6 , C 8 , C 10 and/or C 12 mixtures in proportions ranging in weight percent about from 0% to 3%, 50% to 100%, 50% to 100%, and 0% to 3%, respectively.
  • C 8 and C 10 fatty acids will be present, in ratios of about from 1:3 to 3:1.
  • the proportions C 6 , C 8 , C 10 and C 12 fatty acids will be ⁇ 2%, 65-80%, 20-35%, and ⁇ 2%.
  • the MCT compositions can contain free fatty acids at up to about 0.005/mEq/g (USP), will have a saponification value of about from 325-365 (USP) and an iodine value (USP Method II) of up to about 1.0 gl 2 /100g. Color (Lovibond, AOCS Cc 13h.45) is preferably 1.0 R. Unsaponifiable matter (USP), hydroxyl value (USP), and heavy metals (USP Method II) should be less than about 1.0%, 10.0 and 10 ppm, respectively.
  • the refractive index (USP) and specific gravity (USP) range from about 1.440 to 1.460 and 0.920 to 0.960, respectively. These specifications are not critical.
  • MCT oils of this type are commercially available as lauric oils from coconut oil.
  • the MCTs are used alone or incorporated with minor proportions of LCTs into the oil phase of an oil-in-aqueous emulsion.
  • the proportion of MCTs to LCTS is preferably no more than about 3:1 by weight.
  • emulsions containing MCTs as the sole lipid source are suitable for use at physiologic nonprotein calorie intakes for the nutrition of liver diseased patients.
  • MCT dosages of up to about 4mg MCTs/Kg/hr can be administered on a continuous basis, although the physician will need to tailor the maximum dose to the capabilities of the patient and be observant for toxicity symptoms such as vomiting and lethargy.
  • MCT toxicity can be ameliorated by supplying a proportion of non-protein calories as LCTs.
  • a given hyperphysiological dose of MCTs may result in MCT toxicity symptoms, but the same dose accompanied by an approximately equal or minor proportion of LCTs will not produce the symptoms.
  • the MCT emulsions contain a proportion of LCTs, i.e., about from 15% to 50% by weight of the total lipids.
  • the MCT-containing emulsions may contain other substances besides LCTs. These include surfactants such as egg or soya phospholipid, tonicity adjusting agents such as glycerol, carbohydrate nutrients such as dextrose, and electrolytes, amino acids, vitamins and trace minerals.
  • surfactants such as egg or soya phospholipid
  • tonicity adjusting agents such as glycerol
  • carbohydrate nutrients such as dextrose
  • electrolytes amino acids
  • vitamins and trace minerals trace minerals.
  • concentration by weight of the oil in the emulsion is about from 5% to 20%, with 20% being preferred.
  • the amino acid compositions used in the a ⁇ ueous phase of the emulsions for use with liver diseased patients preferably will have one or more of the following characteristics: (a) The total mole percent of the amino acids serine, glycine, threonine, tryptophan, glutamine and histidine will range about from 8% to 16%;
  • the amino acid compositions optimally will include essential and nonessential amino acids, in the latter group especially arginine and histidine. These last two amino acids are known to be desirable in the nutrition of liver diseased patients.
  • a representative amino acid composition is disclosed in PCT International Application published as WO 83/00085.
  • Other representative compositions that have been urged to be useful in the nutrition of liver diseased patients are disclosed in U.S. patents 3,950,529; 4,100,293; 3,832,465; and 4,259,353; and U.K. patent 2,037,161A, all of the foregoing being incorporated by reference.
  • the amino acids are desirably supplied in the crystalline form rather than as protein hydrolysates. The amount of amino acids included in the emulsions will be sufficient to maintain patients' nitrogen requirements at the planned rate of infusion of MCT and/or LCT calories.
  • the lipid particles in the emulsion will have a diameter of less than about 0.75 ⁇ m and preferably less than about 0.5 ⁇ m.
  • the emulsions will be sterile and ordinarily are packaged in glass containers. They can be made by known methods. For example see U.S. patent 3,169,094 and European Patent Application 0071995.
  • MCT dosage may vary about from 0.35 mg/Kg BW/min. to 2.05 mg/Kg BW/min., preferably about from 0.4 mg/Kg BW/min. to 1.00 mg/Kg BW/min. and optimally about from 0.5 to .75 mg/Kg BW/min.
  • the remaining nonprotein calories are carbohydrates or a mixture of LCTs and carbohydrates.
  • a convenient method for preparing and administering the emulsion herein is for the hospital or user pharmacy to sterile mix the emulsion components using commercially available equipment.
  • the MCT and LCT emulsions are mixed with sterile aqueous solutions of other desirable additives: Amino acids in proportions suitable for disease nutrition, vitamins, carbohydrates such as dextrose, electrolytes such as potassium and sodium chloride drugs, and trace minerals such as zinc ions.
  • the resulting product is a sterile, emulsion of MCTs and LCTs, in an aqueous solution containing amino acids in proportions characterized above, carbohydrate and, optionally, drugs, trace minerals and vitamins.
  • the MCTs and LCTs can be mixed as oils, then emulsified and combined with the other additives noted above.
  • Drugs which have heretofore been conventionally administered to liver disease patients (cymeditine or steroids) or septictmia patients (antibiotics) may be included in the emulsion.
  • the emulsions herein are packaged and stored in hermetically sealed containers for long or short term storage.
  • the additives to be included in the emulsions will depend upon how long the emulsions are to be stored. Long term storage is acceptable for emulsions with aqueous phases containing sugar, the amino acids and some electrolytes. Dextrose should not be included in emulsions prepared for long term storage. They are administered continuously or discontinuously by infusion into the subclavian vein as is the conventional practice in total parenteral nutrition. When LCT and MCT emulsions are combined in pharmacies or are mixed with other solutions for short-term storage as discussed above they may be stored in flexible containers now available commercially for temporary storage of LCT emulsion admixtures.
  • a suitable mixing vessel 2.0 kg of MCT oil consisting of approximately 75% octanoic acid and 25% decanoic acid, 120 g of purified egg phospholipids, 225 g of glycerol, USP, and a suitable quantity of water for injection, USP, are mixed to produce a coarse emulsion.
  • This emulsion is then homogenized repeatedly at high pressure to produce an emulsion of mean particle diameter of less than 0.75 ⁇ m.
  • the pH of the emulsion is adjusted to a physiological range with sodium hydroxide.
  • the final volume is adjusted, if necessary, with water for injection, USP, to 10 L and the emulsion filtered Into glass containers and heat sterilized by the normal procedure.
  • a 2 L plastic bag suitable for intravenous admixtures (TravamulsionTM container) is added 385 mis of a 10% crystalline amino acid solution (Travasol ® 10%; Travenpl Laboratories, Inc.), 535 mis of 4% isomolar branched amino acid (leucine, isoleucine, and valine) solution, 430 mis of 70% hydrous dextrose, 63 mis of 20% soybean oil emulsion (TravamulslonTM 10%; Travenol Laboratories, Inc.), 217 mis of a 20% MCT oil emulsion of Example 1 and 90 mis of a solution containing appropriate electrolytes, trace minerals and vitamins.
  • the solution is mixed by hand and is connected to an infusion pump suitable for administration into a patient.
  • the solution contains 60 gms of amino acids and a total of 1800 kcals. 65% of the nonprotein calories are hydrous dextrose and 35% of the nonprotein calories are lipid.
  • the solution may be administered to a hospitalized patient over 24 hours at a constant rate of 72 mls/hr.
  • a suitable mixing vessel approximately 1.5 kg of MCT oil and 0.5 kg of soybean oil, 120 g of purified egg phospholipids, 225 g of glycerol, USP, and a suitable quantity of water for injection, USP, are mixed to produce a coarse emulsion.
  • This emulsion is then homogenized repeatedly at high pressure to produce an emulsion of mean particle diameter of less than 0.75 ⁇ m.
  • the pH of the emulsion is adjusted to a physiological range with sodium hydroxide.
  • the final volume is adjusted, if necessary with water for injection, USP, to 10 L and the emulsion filtered into glass containers and heat sterilized by the normal procedure.
  • a 2 L container suitable for intravenous infusions of admixtures (TravamulsionTM container) is added 385 mis of a crystalline amino acid solution (Travasol® 10%; Travenol Laboratories, Inc.), 535 mis of 4% isomolar branched chain amino acid (leucine, isoleucine, and valine) solution, 430 mis of hydrous dextrose, 560 mis of 10% lipid emulsion comprised of 75% MCT oil and 25% soybean oil (Example 3) and 90 mis of a solution containing appropriate electrolytes, trace minerals and vitamins.
  • the resulting solution is mixed by hand and is connected to an infusion pump suitable for administration into a patient.
  • the solution contains 60 gms of amino acid and a total of 1800 kcals. 65% of the nonprotein calories are hydrous dextrose and 35% of the nonprotein calories are lipid in the form of a 75% MCT oil emulsion and 25% soybean oil emulsion.
  • the solution may be administered to a hospitalized patient over a 24-hour period at a constant rate of 72 mis/hour.
  • Hepatic insufficiency was induced in previously healthy Sprague-Dawley CR1:CD rats by portacaval anastomosis.
  • An end-to side portacaval anastomosis (shunt) was induced by a nonsuture method using Teflon tubing.
  • the rats were returned to stainless steel cages and allowed to consume laboratory chow, ad libitum. After that period in time, 24 animals were fasted overnight and hepatic function assessed by both static and dynamic indices. Results were compared to 20 similar animals that received only a sham operation.
  • hepatic reticuloendothelial system function was evaluated in 12 additional portacaval shunted rats and 10 sham operated rats.
  • the portacaval shunt model in the rat produced a hepatic insufficiency model which mimics in many ways the clinical conditions seen in human liver disease.
  • Sprague-Dawley CR1:CD rats underwent portacaval anastomosis and splenectomy and were returned to their metabolic units for 3 weeks. Following the recovery period, the rats were randomized to receive total parenteral nutrition for four days. All of the diets delivered 300 kcals/Kg BW/day and 12.5 g amino acid/day except for the dextrose only group ("D only") which received only 300 dextrose kcals/Kg BW/day. One group of animals received all of the nonprotein calories as dextrose (AA+D) whereas the remaining two groups received half of their nonprotein calories as lipid.
  • One of the lipid groups received its fat calories as a soybean (LCT) oil emulsion (AA+D+L) while the remaining lipid group received one-half of the fat calories as the 20% MCT oil emulsion of example 1 and the other half as a 20% soybean oil emulsion (AA+D+PM).
  • LCT soybean
  • AA+D+PM soybean oil emulsion
  • the improved liver morphology and albumin concentration in the rats given the 50:50 physical mix of soybean oil emulsion and MCT oil emulsion support the conclusion that MCTs as a component of total parenteral nutrition are an effective energy source during hepatic dysfunction.
  • the effect of MCT emulsions on reticuloendothelial system function was investigated in 24 additional portacaval shunted rats that had also undergone splenectomy. Seven weeks following portacaval anastomosis and splenectomy, all animals received diets that delivered 200 kcals/Kg BW/day and 8.3 g amino acid/Kg BW/day.
  • Lipid was given at 50% of the total nonprotein calorie intake as either a 10% soybean oil emulsion (AA+D+LCT) or a 10% MCT oil emulsion (AA+D+MCT).
  • AA+D+LCT 10% soybean oil emulsion
  • AA+D+MCT 10% MCT oil emulsion
  • This contemplated example demonstrates the use of an MCT emulsion in providing parenteral nutrition to a liver diseased patient.
  • a 47-year-old white male (62 Kg) is admitted to the hospital because of delirium and hematemesis.
  • the patient had a 25 year history of alcohol abuse and on a previous admission had biopsy proven alcoholic cirrhosis. Gastroscopy had demonstrated the presence of extensive esophageal varices.
  • Serum albumin concentration was 1.9 g/dl (normal greater than 3.5 g/dl) and total protein 4.4 g/dl (normal greater than 6 g/dl) reflecting visceral protein attrition. Abnormalities in the serum amino acid pattern were also evident with L-tyrosine being 274 nmols/ml (normal 50-100 nmols/ml) and L-phenylalanine being 332 nmols/ml (normal 50-100 nmols/ml). The serum aromatic to branched chain amino acid ratio was 2.74 with normal being less than 0.80.
  • Nutritional support for the patient was set at a total calorie intake of 30 kcals/Kg BW/day and protein (as amino acid equivalents) at 1.0g/Kg BW/day.
  • the amino acid source was a standard amino acid mixture (Travasol amino acids) supplemented with the branched chain amino acids, leucine, isoleucine, and valine so that the total branched chain proportion was 50% of the total amino acids by weight.
  • the remaining 26 kcals/Kg BW/day were administered as 65% hydrous glucose and 35% as a physical mixture of 20% MCT oil emulsion and 20% soybean oil emulsion. 75% of the lipid calories were given as the medium chain triglyceride oil emulsion and 25% of the lipid calories as a soybean oil emulsion.
  • Actual daily intake of the hydrous glucose was 3.5 mg/Kg/min, of the soybean oil emulsion was 0.174 mg/Kg/min and of the MCT oil emulsion, 0.585 mg/Kg/min. Electrolytes, trace minerals, and vitamins were adjusted daily to meet the established requirements of the patient.
  • the entire formula was administered in a course of therapy commencing with 1720 ml of fluid continuously over a 24 hour period at a rate of 72 mls/hr through the subclavian vein catheter.
  • the patient's condition was considered to have improved after treatment with the regimen of this Example.

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Abstract

Medium chain triglyceride containing lipid emulsions for the nutrition of liver diseased or septicemic patients are improved by the inclusion in the emulsions of long chain triglycerides. The emulsions may also contain amino acids in proportions desirable for the nutrition of liver diseased patients, as well as carbohydrates, drugs, vitamins and electrolytes.

Description

PARENTERAL NUTRITION WITH MEDIUM AND LONG CHAIN TRIGLYCERIDES
Background
This relates to total parenteral nutrition of patients with liver disease or septicemia. It is particularly concerned with providing such nutrition via lipid emulsions.
Lipid emulsions for parenteral nutrition are available commercially or can be manufactured in accordance with known processes. Generally, such emulsions have been made using the triglycerides of long chain fatty acids (LCTs). LCTs are obtained conventionally from soybean or safflower oil. Long chain fatty acids are fatty acids having 14 or more carbon atoms, usually 16 or 18 carbon atoms.
More recently, lipid emulsions which contain triglycerides of medium chain fatty acids (MCTs) have become available. MCTs are triglyceride esters of fatty acids which contain a preponderance of C8 and C10 fatty acids (caprylic and capric acid, respectively). Emulsions of this type are disclosed in European Patent Application 0071995 and Eckart et al., "J. Parenteral and Enteral Nutrition" 4(4):360-366 (1980). The above cited European Patent Application discloses an Isotonic LCT/MCT emulsion for parenteral use, which contains a fat content of 3 to 30%, an LCT/MCT ratio between 4/1 and 1/4, a physiologically unobjectionable polyhydric alcohol and egg phosphatide as emu!sifier. Early studies involving enteral administration of MCT emulsions to animals and man indicated that MCTs are handled by a physiological pathway other than the one known for LCTs. In-depth studies revealed that MCTs are hydrolyzed to free fatty acids in the intestinal lumen at a rate five times faster than the hydrolysis rate for LCTs. Further, these MCT-derived fatty acids are absorbed by the intestinal cell at a rate twice the absorption rate of LCT-derived fatty acids. The most striking difference between MCT and LCT was shown to be the mechanism of transport to sites of utilization and, as a result, their predominant mode of utilization. MCT-derived fatty acids pass through the intestinal epithelial cell without reesterlflcation to MCT. They then enter the portal vein, bind to albumin, and are transported in this bound form in the bloodstream. LCT-derived fatty acids, on the other hand, after absorption are reesterified in intestinal cells to form LCT and packaged with protein and phospholipids to form lipid particles (chylomicrons) that enter the lymph system and, later, the circulatory system for distribution to the tissues of utilization.
In comparison to LCTs, MCTs are much more readily utilized for caloric energy, but are less effectively incorporated into tissue lipids. MCTs, when administered orally, are believed to be metabolized primarily in the liver, while LCTs are metabolized throughout the body (Scheig, R. In: Medium Chain Triglycerides, J.R. Senior, Ed. pp 39-49 [1968]).
Liver disease as this term is used herein means a primary or secondary disorder of the liver parenchyma that results in reduced hepatic function. The etiology of the disease may include but not be limited to any one of the following common disorders: Alcoholic cirrhosis, acute hepatocellular damage secondary to drug abuse or poisoning, genetic deficiencies such as tyrosinosis, trauma to the liver, hepatitis, primary biliary cirrhosis, liver abscess, Budd-Chiarf syndrome, Wilson's disease, or primary or secondary liver neoplasms. Clinically, hepatic dysfunction is diagnosed by increases in liver function tests such as serum glutamate-oxaloacetate transaminase, serum glutamate-pyruvate transaminase and billrubin, reductions in indocyanin green or bromosulphopthalein clearance, tissue biopsy, and/or neurological manifestations such as encephalopathy. Liver disease as defined herein excludes the subclinically mild and reversible hepatic dysfunction induced by parenteral nutrition (Eckart et al. Ibid).
Patients with septicemia include patients having subclinical septicemia or susceptibility to septicemia. Patients in this group include patients recuperating from abdominal surgery, patients with respiratory diseases and those with active infections such as abcesses or infected wounds.
Intravenous calorie intake in liver diseased patients is hampered by chronic carbohydrate and fluid intolerance. In addition, current LCT emulsions, although calorically dense, are contraindicated in liver disease because liver dysfunction is frequently associated with an impaired ability to metabolize LCT. A need exists for an intravenous calorie source for liver diseased patients that does not exhibit the disadvantages of available calorie sources.
MCTs have been included in oral formulations for the nutrition of stressed (including liver diseased) patients. An example is the Travasorb® Hepatic formulation sold by Travenol Laboratories, Inc. The doses of MCT to be delivered with such formulations have been low, however, on the order of about 0.2 mg MCT/Kg body weight (BW)/min. when following the instructions for use. MCTs are added to these nutrient formulations because they are believed necessary to circumvent the maladsorption of LCTs that accompanies deficient bile secretion by diseased livers. However, the low doses were believed mandated by the prevalent belief in the art that MCTs are harmful to liver diseased patients. See, for example, N. Greenberger et al. "Ann. Intern. Med." 66(4):727-734 (1967), who state that "it will be important to withhold MCT therapy from patients with decompensated cirrhosis until more is known about the effects of MCT therapy on such patients." (Id at p.732). In part, this contraindication is based on the role of the liver as the primary site of medium chain fatty acid metabolism. The dysfunctional liver might not be expected to metabolize these fatty acids at a rate sufficient to avoid the observed effects of excess fatty acids in the blood: Somnolence, vomiting and even death. In addition, the narcotic effect of MCTs could be expected to exacerbate any tendency in liver diseased patients towards encephalopathy. Thus, MCTs have not been considered appropriate for providing a substantial percentage of the calorie needs of liver diseased patients.
We now have discovered that MCTs can be parenterally administered to recipients with liver disease or septicemia, and in dosages heretofore believed to be potentially hazardous, without toxic side effects. We have found that MCTs can supply nutritionally adequate calories to such patients without resulting in the liver fatty deposits or the reductions in the efficacy of the reticuloendothelial system (RES) noted when supplying LCTs as a significant calorie source.
Summary
The improvement herein comprises parenterally administering a composition comprising MCTs to a liver diseased patient or a patient with septicimia. It further comprises administering greater than about 0.35 mg MCTs/Kg BW/min. to such patients, preferably about from 0.5 to 2 mg MCTs/Kg BW/min., and selecting a weight proportion of MCTs to LCTs no greater than about 3 to 1.
The improvement herein also comprises compositions including (1) a composition comprising (a)lipids wherein about from 25% to 75% by weight of the lipids are MCTs and the remainder are LCTs and (b)the branched chain amino acids, valine, leucine and/or isoleucine or the keto analogues of valine, leucine and/or valine.
(2) a composition comprising MCTs and at least one branched chain amino acid, or preferably an amino acid mixture in which greater than about 35% of the mole weight of amino acids are valine, isoleucine and/or leucine or the keto analogues of valine, isoleucine and/or leucine.
Detailed Description
The MCTs to be used herein will be C6, C8, C10 and/or C12 mixtures in proportions ranging in weight percent about from 0% to 3%, 50% to 100%, 50% to 100%, and 0% to 3%, respectively. Usually only C8 and C10 fatty acids will be present, in ratios of about from 1:3 to 3:1. Preferably, the proportions C6, C8, C10 and C12 fatty acids will be < 2%, 65-80%, 20-35%, and < 2%. The MCT compositions can contain free fatty acids at up to about 0.005/mEq/g (USP), will have a saponification value of about from 325-365 (USP) and an iodine value (USP Method II) of up to about 1.0 gl2/100g. Color (Lovibond, AOCS Cc 13h.45) is preferably 1.0 R. Unsaponifiable matter (USP), hydroxyl value (USP), and heavy metals (USP Method II) should be less than about 1.0%, 10.0 and 10 ppm, respectively. The refractive index (USP) and specific gravity (USP) range from about 1.440 to 1.460 and 0.920 to 0.960, respectively. These specifications are not critical. MCT oils of this type are commercially available as lauric oils from coconut oil. The exact specifications, including the relative proportions of C6 to C12 medium chain fatty acids , will vary somewhat since the MCTs are obtained from natural sources. The MCTs are used alone or incorporated with minor proportions of LCTs into the oil phase of an oil-in-aqueous emulsion. The proportion of MCTs to LCTS is preferably no more than about 3:1 by weight. However, emulsions containing MCTs as the sole lipid source are suitable for use at physiologic nonprotein calorie intakes for the nutrition of liver diseased patients. Animals having surgically induced liver disease (disclosed in Example 5 below) have shown no tendency towards somnolence or overt encephalopathic symptoms upon administration of MCTs at substantial proportions of normal, physiologic nonprotein calorie intakes. MCT dosages of up to about 4mg MCTs/Kg/hr can be administered on a continuous basis, although the physician will need to tailor the maximum dose to the capabilities of the patient and be observant for toxicity symptoms such as vomiting and lethargy.
Studies with normal animals have disclosed that MCT toxicity can be ameliorated by supplying a proportion of non-protein calories as LCTs. A given hyperphysiological dose of MCTs may result in MCT toxicity symptoms, but the same dose accompanied by an approximately equal or minor proportion of LCTs will not produce the symptoms. Thus in the case of liver patients who exhibit various degrees of compromised MCT metabolic capacity, it is preferred that the MCT emulsions contain a proportion of LCTs, i.e., about from 15% to 50% by weight of the total lipids.
The MCT-containing emulsions may contain other substances besides LCTs. These include surfactants such as egg or soya phospholipid, tonicity adjusting agents such as glycerol, carbohydrate nutrients such as dextrose, and electrolytes, amino acids, vitamins and trace minerals. The concentration by weight of the oil in the emulsion is about from 5% to 20%, with 20% being preferred.
The amino acid compositions used in the aαueous phase of the emulsions for use with liver diseased patients preferably will have one or more of the following characteristics: (a) The total mole percent of the amino acids serine, glycine, threonine, tryptophan, glutamine and histidine will range about from 8% to 16%;
(b) The total mole proportion of valine, leucine and isoleucine, (or their keto analogues α -ketoisovaleric, ketoisocaproic and α -keto-β -methyl valeric add, respectively) to the other amino acids will be greater than about 35%, preferably about 40% to 60% and more optimally about 50%; and/or
(c) A reduced proportion of sulfur-containing amino acids, e.g. methionine, when compared to standard formulations based on proteins such as egg white.
The amino acid compositions optimally will include essential and nonessential amino acids, in the latter group especially arginine and histidine. These last two amino acids are known to be desirable in the nutrition of liver diseased patients. A representative amino acid composition is disclosed in PCT International Application published as WO 83/00085. Other representative compositions that have been urged to be useful in the nutrition of liver diseased patients are disclosed in U.S. patents 3,950,529; 4,100,293; 3,832,465; and 4,259,353; and U.K. patent 2,037,161A, all of the foregoing being incorporated by reference. The amino acids are desirably supplied in the crystalline form rather than as protein hydrolysates. The amount of amino acids included in the emulsions will be sufficient to maintain patients' nitrogen requirements at the planned rate of infusion of MCT and/or LCT calories.
The lipid particles in the emulsion will have a diameter of less than about 0.75 μm and preferably less than about 0.5 μm. The emulsions will be sterile and ordinarily are packaged in glass containers. They can be made by known methods. For example see U.S. patent 3,169,094 and European Patent Application 0071995.
The contribution of lipid to total nonprotein calories in the emulsions herein ordinarily will range about from 20% to 80%. Thus the MCTs in the emulsion will make up about from 5% to 60% of the total nonprotein calories in the emulsions, preferably about from 15% to 60%. For example in a 70 Kg man receiving 40 kcals/Kg BW/day, MCT dosage may vary about from 0.35 mg/Kg BW/min. to 2.05 mg/Kg BW/min., preferably about from 0.4 mg/Kg BW/min. to 1.00 mg/Kg BW/min. and optimally about from 0.5 to .75 mg/Kg BW/min. The remaining nonprotein calories are carbohydrates or a mixture of LCTs and carbohydrates.
A convenient method for preparing and administering the emulsion herein is for the hospital or user pharmacy to sterile mix the emulsion components using commercially available equipment. The MCT and LCT emulsions are mixed with sterile aqueous solutions of other desirable additives: Amino acids in proportions suitable for disease nutrition, vitamins, carbohydrates such as dextrose, electrolytes such as potassium and sodium chloride drugs, and trace minerals such as zinc ions. The resulting product is a sterile, emulsion of MCTs and LCTs, in an aqueous solution containing amino acids in proportions characterized above, carbohydrate and, optionally, drugs, trace minerals and vitamins. Alternatively, and less preferably, the MCTs and LCTs can be mixed as oils, then emulsified and combined with the other additives noted above. Drugs which have heretofore been conventionally administered to liver disease patients (cymeditine or steroids) or septictmia patients (antibiotics) may be included in the emulsion.
The emulsions herein are packaged and stored in hermetically sealed containers for long or short term storage. The additives to be included in the emulsions will depend upon how long the emulsions are to be stored. Long term storage is acceptable for emulsions with aqueous phases containing sugar, the amino acids and some electrolytes. Dextrose should not be included in emulsions prepared for long term storage. They are administered continuously or discontinuously by infusion into the subclavian vein as is the conventional practice in total parenteral nutrition. When LCT and MCT emulsions are combined in pharmacies or are mixed with other solutions for short-term storage as discussed above they may be stored in flexible containers now available commercially for temporary storage of LCT emulsion admixtures.
The following examples are merely illustrative and are not to be considered limiting with respect to the claims. Ordinarily the emulsions are stored in glass containers.
EXAMPLE 1
In a suitable mixing vessel, 2.0 kg of MCT oil consisting of approximately 75% octanoic acid and 25% decanoic acid, 120 g of purified egg phospholipids, 225 g of glycerol, USP, and a suitable quantity of water for injection, USP, are mixed to produce a coarse emulsion. This emulsion is then homogenized repeatedly at high pressure to produce an emulsion of mean particle diameter of less than 0.75 μm. During the process, the pH of the emulsion is adjusted to a physiological range with sodium hydroxide. The final volume is adjusted, if necessary, with water for injection, USP, to 10 L and the emulsion filtered Into glass containers and heat sterilized by the normal procedure.
EXAMPLE 2
To a 2 L plastic bag suitable for intravenous admixtures (Travamulsion™ container) is added 385 mis of a 10% crystalline amino acid solution (Travasol® 10%; Travenpl Laboratories, Inc.), 535 mis of 4% isomolar branched amino acid (leucine, isoleucine, and valine) solution, 430 mis of 70% hydrous dextrose, 63 mis of 20% soybean oil emulsion (Travamulslon™ 10%; Travenol Laboratories, Inc.), 217 mis of a 20% MCT oil emulsion of Example 1 and 90 mis of a solution containing appropriate electrolytes, trace minerals and vitamins. The solution is mixed by hand and is connected to an infusion pump suitable for administration into a patient. The solution contains 60 gms of amino acids and a total of 1800 kcals. 65% of the nonprotein calories are hydrous dextrose and 35% of the nonprotein calories are lipid.
The solution may be administered to a hospitalized patient over 24 hours at a constant rate of 72 mls/hr.
EXAMPLE 3
In a suitable mixing vessel, approximately 1.5 kg of MCT oil and 0.5 kg of soybean oil, 120 g of purified egg phospholipids, 225 g of glycerol, USP, and a suitable quantity of water for injection, USP, are mixed to produce a coarse emulsion. This emulsion is then homogenized repeatedly at high pressure to produce an emulsion of mean particle diameter of less than 0.75 μm. During the process the pH of the emulsion is adjusted to a physiological range with sodium hydroxide. The final volume is adjusted, if necessary with water for injection, USP, to 10 L and the emulsion filtered into glass containers and heat sterilized by the normal procedure.
EXAMPLE 4
To a 2 L container suitable for intravenous infusions of admixtures (Travamulsion™ container) is added 385 mis of a crystalline amino acid solution (Travasol® 10%; Travenol Laboratories, Inc.), 535 mis of 4% isomolar branched chain amino acid (leucine, isoleucine, and valine) solution, 430 mis of hydrous dextrose, 560 mis of 10% lipid emulsion comprised of 75% MCT oil and 25% soybean oil (Example 3) and 90 mis of a solution containing appropriate electrolytes, trace minerals and vitamins. The resulting solution is mixed by hand and is connected to an infusion pump suitable for administration into a patient. The solution contains 60 gms of amino acid and a total of 1800 kcals. 65% of the nonprotein calories are hydrous dextrose and 35% of the nonprotein calories are lipid in the form of a 75% MCT oil emulsion and 25% soybean oil emulsion.
The solution may be administered to a hospitalized patient over a 24-hour period at a constant rate of 72 mis/hour.
EXAMPLE 5
Hepatic insufficiency was induced in previously healthy Sprague-Dawley CR1:CD rats by portacaval anastomosis. An end-to side portacaval anastomosis (shunt) was induced by a nonsuture method using Teflon tubing. For three weeks following surgery, the rats were returned to stainless steel cages and allowed to consume laboratory chow, ad libitum. After that period in time, 24 animals were fasted overnight and hepatic function assessed by both static and dynamic indices. Results were compared to 20 similar animals that received only a sham operation.
In 12 portacaval shunted rats and 10 sham operated rats, indocyanine green clearance, an index of hepatocyte function, was evaluated.
Fifteen minutes following intravenous injection of indocyanine green, both sham operated and portacaval shunted rats were killed and results are summarized in Table 1. TABLE 1 Portocaval Shunt (PCS) Effects on Body Weight, Liver Weight, Indocyanine Green Clearance and Serum Albumin Concentrations
Indocyanine Body Weight (g) Liver Green Serum Albumin Before After Weight (g) Retention(%) (g/dl)
SHAM 274+8 351+15 8.9+0.6 9.0+3.3 3.05+0.04 PCS 277+23 301+35 6.2+0.4* 18.3+4.7* 2.68+0.16*
*p 0.05
Hepatic dysfunction was clearly evident. Liver weight in portacaval shunted rats was 42% less than in sham operated animals (p 0.05) and serum albumin concentration (a liver synthesized protein) was also significantly reduced (p 0.05). As a dynamic assessment of hepatocyte function, indocyanine green retention was almost twice as great (p 0.05) in portacaval shunted rats indicating reduced clearance.
In addition to these assessments, hepatic reticuloendothelial system function was evaluated in 12 additional portacaval shunted rats and 10 sham operated rats. The blood concentration of live Pseudomonas aeruginosa P4 in portacaval shunted rats following an intravenous challenge of
5x108 cfu of bacteria was about ten times greater (one log) than the sham operated group (Table 2) (p 0.05). Although the capacity to clear bacteria was reduced in portacaval shunted rats, the capacity of the spleens to sequester Pseudomonas was markedly increased, indicating a compensatory role by that organ. TABLE 2 Effect of PCS on Host Nonspecific Immunity and Organ Reticuloendothelial System Function
Blood Bacteremia (log cone.) Organ Sequestration (%) 0' 30' 60' Liver Spleen
SHAM 7 4.5+0.3 3.0+0.3 35+2 6+1 PCS 7 5.4+0.2* 4.2+0.2* 38+2 12+1
*p 0.05
Therefore, the portacaval shunt model in the rat produced a hepatic insufficiency model which mimics in many ways the clinical conditions seen in human liver disease.
Twenty-eight male Sprague-Dawley CR1:CD rats underwent portacaval anastomosis and splenectomy and were returned to their metabolic units for 3 weeks. Following the recovery period, the rats were randomized to receive total parenteral nutrition for four days. All of the diets delivered 300 kcals/Kg BW/day and 12.5 g amino acid/day except for the dextrose only group ("D only") which received only 300 dextrose kcals/Kg BW/day. One group of animals received all of the nonprotein calories as dextrose (AA+D) whereas the remaining two groups received half of their nonprotein calories as lipid. One of the lipid groups received its fat calories as a soybean (LCT) oil emulsion (AA+D+L) while the remaining lipid group received one-half of the fat calories as the 20% MCT oil emulsion of example 1 and the other half as a 20% soybean oil emulsion (AA+D+PM). TABLE 3 Protein Responses to Various TPN Regimens in Portocaval Shunted Rats.
Serum Albumin Fractional Synthetic Rate(%/d) N Balance (g/dl) Albumin Muscle (mg/4 days)
AA+D+PM 3.2+0.3* 85+14 5.7+2.2 61+14
AA+D+LOT 3.0+0.5 84+15 6.1+1.2 20+35
AA+D 2.6+0.3 68+5 5.9+1.0 71+32
D only 2.4+0.5 20+8* 5.6+2.8 -150+10*
*p 0.05 vs AA+D
Results summarized in Table 3 demonstrated that portacaval shunted rats given the 50:50 physical mixture (PM) of MCT emulsion and soybean oil emulsion had the highest serum level of albumin (a hepatic secretory protein), and serum albumin levels were lowest in animals given only glucose. In addition, liver histology (following hemotoxylin and eosin staining) showed marked infiltration of glycogen in the hepatocytes from rats infused with dextrose regimens (AA+D and D only). In contrast, in rats given all of their nonprotein calories as a soybean oil emulsion and glucose (Group AA+D+LCT) increased lipid sequestration in the Kupffer cells was observed. Rats given nonprotein calories as glucose and the physical mix of soybean and MCT oil emulsion (AA+D+PM) had normal hepatic physiology.
The improved liver morphology and albumin concentration in the rats given the 50:50 physical mix of soybean oil emulsion and MCT oil emulsion support the conclusion that MCTs as a component of total parenteral nutrition are an effective energy source during hepatic dysfunction. The effect of MCT emulsions on reticuloendothelial system function was investigated in 24 additional portacaval shunted rats that had also undergone splenectomy. Seven weeks following portacaval anastomosis and splenectomy, all animals received diets that delivered 200 kcals/Kg BW/day and 8.3 g amino acid/Kg BW/day. Lipid was given at 50% of the total nonprotein calorie intake as either a 10% soybean oil emulsion (AA+D+LCT) or a 10% MCT oil emulsion (AA+D+MCT). To assess reticuloendothelial system function following these courses of total parenteral nutrition, a body weight-related dose of E. coli was administered intravenously.
TABLE 4 Effect of MCT AND LCT on Reticuloendothelial System Function in PCS Rats
N Blood Organ
Balance Bacteria (log conc) Sequestration (%)
(mg/5d) 0' 30' 60' Liver Lung
SHAM + AA+D+LCT 117+15 7 4.2+0.4* 3.4+0.2 36.4+1.2 12.5+1.2
PCS + AA+D+LCT 101+38 7 5.5+0.3 4.8+0.2 42.1+2.3 15.5+2.0
PCS + AA+D+MCT 105+18 7 4.5+0.1* 3.9+0.2* 55.7+4.5* 8.4+0.7*
*p 0.05 vs PCS +AA+D+LCT
No differences in nitrogen balance were observed (Table 4). However, decreased bacterial clearance and liver uptake of E. coli indicative of hepatic reticuloendolthelial system blockade were seen in portacaval shunted and splenectomized rats given lipid calories as a soybean oil emulsion. Such results suggest that administration of LCT oil emulsions without MCTs may have adverse effects during hepatic insufficiency. In contrast, intravenous MCT emulsions support nitrogen balance equally well and may better support hepatic reticuloendothelial system function in order to improve sequestration of organisms in theliver during bacteremia.
EXAMPLE 6
This contemplated example demonstrates the use of an MCT emulsion in providing parenteral nutrition to a liver diseased patient.
A 47-year-old white male (62 Kg) is admitted to the hospital because of delirium and hematemesis. The patient had a 25 year history of alcohol abuse and on a previous admission had biopsy proven alcoholic cirrhosis. Gastroscopy had demonstrated the presence of extensive esophageal varices.
Laboratory analysis of the patient confirmed the clinical diagnosis of variceal bleeding secondary to decompensated alcoholic cirrhosis. Total bilirubin was 7 mg/dl (normal less than 1 mg/dl); serum glutamate-oxalo-acetate transaminase was 80 U/L (normal less than 15 U/L). Serum glutamate pyruvate transaminase was 155 U/L (normal less than 15 U/L) and serum gamma glutaryl transaminase was 180 U/L (normal less than 30 U/L). Hemoglobin was 7.5 g/l (normal = 14-16 g/l).
Serum albumin concentration was 1.9 g/dl (normal greater than 3.5 g/dl) and total protein 4.4 g/dl (normal greater than 6 g/dl) reflecting visceral protein attrition. Abnormalities in the serum amino acid pattern were also evident with L-tyrosine being 274 nmols/ml (normal 50-100 nmols/ml) and L-phenylalanine being 332 nmols/ml (normal 50-100 nmols/ml). The serum aromatic to branched chain amino acid ratio was 2.74 with normal being less than 0.80.
The patient's mental condition varied from Grade II to Grade III coma and the patient had severe asterixis. During the first two days of admission, 2 gms of neomycin, twice daily, and 20 mis of 10% lactolose three times daily, were administered. Due to acute alcohol withdrawal, the patient's clinical course was complicated by the presence of alcohol -induced delirium tremens.
Because of the patient's reduced visceral protein status, nutritional support was recommended. Oral intake was not recommended because of the decreased mental status and presence of delirium tremens. Use of nasogastric feeding tube was also contraindicated because of esophageal varices. The physicians recommended total intravenous nutrition and a subclavian catheter was inserted into the superior vena cava.
Nutritional support for the patient was set at a total calorie intake of 30 kcals/Kg BW/day and protein (as amino acid equivalents) at 1.0g/Kg BW/day. The amino acid source was a standard amino acid mixture (Travasol amino acids) supplemented with the branched chain amino acids, leucine, isoleucine, and valine so that the total branched chain proportion was 50% of the total amino acids by weight.
The remaining 26 kcals/Kg BW/day were administered as 65% hydrous glucose and 35% as a physical mixture of 20% MCT oil emulsion and 20% soybean oil emulsion. 75% of the lipid calories were given as the medium chain triglyceride oil emulsion and 25% of the lipid calories as a soybean oil emulsion. Actual daily intake of the hydrous glucose was 3.5 mg/Kg/min, of the soybean oil emulsion was 0.174 mg/Kg/min and of the MCT oil emulsion, 0.585 mg/Kg/min. Electrolytes, trace minerals, and vitamins were adjusted daily to meet the established requirements of the patient.
The entire formula was administered in a course of therapy commencing with 1720 ml of fluid continuously over a 24 hour period at a rate of 72 mls/hr through the subclavian vein catheter. The patient's condition was considered to have improved after treatment with the regimen of this Example.

Claims

1. A method comprising parenterally administering a composition includinq MCTs and LCTs to a patient with liver disease , the proportion of MCTs to LCTs ranging about form 1:3 to 3:1.
2. The method of claim 1 wherein the MCTs are administered as an emulsion by constant infusion at a dose of greater than about 0.35 mg MCTs/Kg BW/min.
3. The method of claim 2 wherein the dose ranges from about from 0.5 to 2 mg MCTs/Kg BW/min.
4. The method of claim 1 wherein sufficient MCTs are administered to supply about from 5% to 60% of the patient's total nonprotein calorie requirements.
5. The method of claim 1 wherein about from 15% to 60% of the patient's total nonprotein calorie requirements are supplied by MCTs.
6. The method of claim 1 wherein the MCTs are administered as an emulsion in an amino acid and carbohydrate containing aqueous solution.
7. The method of claim 6 wherein the carbohydrate is dextrose.
8. The method of claim 6 wherein the solution contains a mixture of essential and nonessential amino acids.
9. The method of claim 8 wherein the total mole percent of the amino acids serine, glycine, theonine, tryptophan, glutamine and histidine in the mixture is about from 8% to 16%.
10. The method of claim 8 wherein the total mole percent of valine, isoleucine and leucine in the mixture is greater than about 35%.
11. The method of claim 10 wherein the percent is about from 40% to 60%.
12. The method of claim 6 wherein the solution contains at least one branched chain amino acid.
13. The method of claim 1 wherein the MCTs are administered as an emulsion in an aqueous solution comprising
-ketoisovaleric acid, α-ketoisocaproic acid and/or α-keto-β -methylvaleric acid.
14. The method of claim 1 wherein the MCTs comprise the triglycerides of caprylic and capric acids.
15. The method of claim 1 wherein the MCTs consist essentially of the triglycerides of caprylic and capric acids.
16. The method of claim 14 wherein the ratio of caprylic to capric acid ranges from about 3 to 1 to about 1 to 3.
17. The method of claim 2 wherein the emulsion comprises lipid particles with a mean particle diameter of less than 1.0 μm and the LCTs and MCTs are present in separate lipid particles or each particle is a mixture of LCTs and MCTs.
18. The method of claim 12 wherein the MCTs have a saponification value between about 325 and 365, and a hydroxyl value of less than about 10.
19. A sterile composition comprising an emulsion of MCTs and LCTs in an aqueous solution containing at least one branched chain amino acid or branched chain amino acid keto analogue.
20. The composition of claim 19 further comprising a carbohydrate.
21. The composition of claim 19 wherein the solution contains a mixture of essential and nonessential amino acids.
22. The composition of claim 21 wherein the total mole percent of the amino acids serine, glycine, threonine, tryptophan, glutamine and histidine in the mixture is about from 8% to 16%.
23. The composition of claim 21 wherein the total mole percent of branched chain amino acids in the mixture is greater than about 35%.
24. The composition of claim 23 wherein the percent is about from 40% to 60%.
25. The composition of claim 19 wherein the branched chain amino acid analogue is α -ketoisovaleric acid, α-ke toisocaproic acid or α -keto- β -methyl valeric acid.
26. The composition of claim 19 wherein the LCTs and MCTs are present in separate lipid particles.
27. The composition of claim 19 wherein each particle is a mixture of LCTs and MCTs.
28. The composition of claim 19 which is hermetically sealed in a container.
29. A sterile emul sion comprising, in relative weight proportion
(a) MCTs, about from 2.5 to 187;
(b) branched chain amino acids, about from 12.25 to 105; and
(c) LCTs, about from 7.8 to 187.
30. A method which comprises infusing the emul sion of claim 29 into a patient with l iver disease.
EP19850900428 1984-01-16 1984-12-18 Parenteral nutrition with medium and long chain triglycerides. Ceased EP0168425A4 (en)

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SE8803141L (en) * 1988-09-07 1990-03-08 Kabivitrum Ab FOOD FOR FOOD AND ANIMALS
EP0537113A1 (en) * 1991-10-10 1993-04-14 SANDOZ NUTRITION Ltd. Energy supplementary food
JP2990686B2 (en) * 1994-11-17 1999-12-13 田辺製薬株式会社 Total infusion containing water-soluble vitamin B
US6835408B2 (en) 1998-11-13 2004-12-28 The Nisshin Oillio Group, Ltd. Oil or fat composition
JP5498491B2 (en) 2008-07-07 2014-05-21 ペンテック ヘルス, インコーポレイテッド Nutritional composition and method of using the nutritional composition
US20140066439A1 (en) 2010-11-10 2014-03-06 Katholieke Universiteit Leuen, K.U.Leuven R&D Osteoclast activity
EP4450090A2 (en) * 2017-08-10 2024-10-23 The Children's Medical Center Corporation Methods and compositions relating to emulsions comprising fish oil and/or omega-3 fatty acids
WO2019125913A1 (en) * 2017-12-20 2019-06-27 Michael Guarnieri Nutritional bolus for animals
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