TOTAL PARENTERAL AND ENTERAL NUTRITION COMPOSITION

Abstract: A stable fat emulsion composition for parenteral or enteral nutrition containing amino acids, fat and carbohydrates. The emulsion is stabilized by a combination of co-emulsifiers comprising a phosphatide such as egg or soybean phosphatide and a fatty acid-amino acid peptide wherein the fatty acid component of the peptide is a saturated or unsaturated fatty acid having from 16 to 22 carbon atoms.

Description: TOTAL PARENTERAL AND ENTERAL NUTRITION COMPOSITION BACKGROUND OF THE INVENTION 1. Field of the Invention This invention relates to an improved composition for total parenteral or enteral nutrition, and more particularly, to a composition containing amino acids, fat and carbohydrates and a means for emulsifying such a composition. 2. Description of the Prior Art Total parenteral nutrition (TPN) is a technique employed to sustain life and/or accelerate recovery in patients who cannot consume foods due to primary diseases. To provide TPN, aqueous solutions of amino acids, fat, carbohydrate, vitamins and electrolytes are typically admixed under an aseptic environment in the pharmacy prior to intravenous administration in patients. This practice not only increases hospital cost in terms of ordering, stocking and admixing, but also introduces a possibility of microbial contamination, thereby exposing patients to a higher risk of in ection. Furthermore, the current TPN practice requires a central vein catheter for administration. The surgical procedures for catheter place¬ ment frequently present a problem in many rural and community hospitals. Patients in these situations may be deprived of optimal medical care. Thus, the development of a TPN solution which does not require admixing and can be administered through a peripheral vein becomes a vital solution to the problems encountered in small hospitals. A typical TPN infusate should contain protein sources in the form of amino acids, together with fat and carbohydrate. Amino acids are used to synthesize body protein, while fat and carbohydrate are sources of energy for vital processes. To synthesize body proteins effectively, all of the 20 protein amino acids are required to be present in an optimal proportion in organs and tissues. Although certain of these amino acids are considered non-essential, that is they can be synthesized in the body, it is necessary to receive from an external source the essential amino acids which cannot be synthesized in the body from a TPN infusate. As fat is not water soluble, a stable oil-in-water emulsion is required for intravenous infusion. It has been found from previous laboratory work that two amino acids, lysine, which is an essential amino acid, and arginine, which is a semi-essential amino acid, destabilize fat emulsions containing other essential nutrients. Thus, it has been difficult heretofore to manu¬ facture a stable TPN infusate containing these amino acids in a fat emulsion. There are currently at least two products known to exist which include in a single emulsion, fat, amino acids and carbohydrate. These are Trieve 1000 T manufactured by Labor atoire Egic in France and Nutrifundin manufactured by B. Braun in West Germany. Both composi- tions contain soy bean oil as the fat source and use soy bean phosphatides as an emulsifier. Use of the soy bean phosphatides as the emulsifier has at least two drawbacks. First, the soy bean phosphatide can result in undesirable side effects and may be nutritionally undesirable. Further, the use of soy bean phosphatides as the sole emulsifier does not permit the inclusion of a sufficient amount of arginine and thus the amino acid composition of these two products is undesirable due to their very low concentration or total absence of arginine. A similar composition has been described in U.S. Patent No. 3,793,450 to Schnell. The composition described in this patent contains various amino acids, fat and either soy or egg yolk phosphatide as an emulsifier. Again, however, the use of only the soy or egg phosphatide is not sufficient to stabilize a solution containing arginine with fat. All of the examples described in this patent include diaminovaleric acid (ornithine), apparently as a substitute for arginine. U.S. Patent No. 3,273,720 to Suzuki, et al., teaches the use of a fatty acid (or its basic amino acid salt) as a co-emulsifier with egg-yolk phospholipids. The salt disclosed in Suzuki would dissociate in solution and is not really dif erent from the use of the fatty acid alone in an amino acid containing emulsion. However, the use of the fatty acid-amino acid peptide, as opposed to the mere salt which dissociates in solution, has been found to provide additional stabilization advantages, including increased water solubility and lower requirements for effectiveness. A combination of fatty acids together with soybean phosphatides was not able to sufficiently stabilize a at emulsion containing arginine together with other nutrients. The same considerations apply in formulating a composition for oral and enteral use. Where such a composition contains all of the essential amino acids together with fat and carbohydrate, it is necessary to provide a compatible means for stabilizing a fat/water emulsion, particularly one containing arginine with fat. BRIEF SUMMARY OF THE INVENTION It is therefore an object of this invention to provide a stable composition for total parenteral and/or enteral nutrition containing fat, amino acids and carbohydrate. It is a further object of this invention to provide such a composition which includes the emulsion destabilizing amino acids lysine and arginine. The composition of the present invention involves the use of disodium salts or other cation salts of a fatty acid-amino acid peptide alone and in combination with egg or other phosphatides as co-emulsifiers. The remainder of the fat emulsion contains fat, amino acids, including lysine and arginine, and other essential nutrients for TPN and enteral nutritional use. It has been discovered that the fatty acid-amino acid peptide may be used as an emulsification agent to provide improved stability to a fat emulsion beyond that provided by the mere salt of the fatty acid and the amino acid. This was surprising in that previous laboratory tests have indicated that fatty acid-amino acid peptides, such as linoleoyl glutamate, when administered in a saline solution can be hemolytic and toxic. However, when included in the fat emulsion of the present invention, the peptide is physiologically acceptable and combines with the phosphatide to stabilize the fat emulsion. It has further been discovered that the use of the fatty acid-amino acid peptide together with a phosphatide provides a synergistic emulsification which permits the preparation of a stable fat emulsion containing lysine and arginine. The parenteral or enteral composition of the present invention contains the following ingredients in essentially the indicated weight proportions. Ingredient Weight Proportion Fat " 3-30 Phosphatide 0.5 - 5 Fatty Acid-Amino Acid Peptide 0.05 - 0.5 L-Lysine Acetate 0.2 - 2.0 L- Arginine 0.2 - 2.0 Remaining Amino Acids * 2 - 20 Sugar Alcohols ** 3 - 30 * The amino acids used in the invention are the L-isomers and glycine which are utilized for protein synthesis or per orming biological functions in mammals. Biologically available precusors of these amino acids in the form of derivatives and peptides may also be included. ** Sugar alcohols such as giycerol and sorbitol included in the present invention are those which can be metabolized to generate biologically available energy in the mammalian species, and are chemically compatible with amino acids during heat sterilization and/or are stable during shelf life storage. The reducing sugars, such as glucose, generally result in undesir¬ able reactions with amino acids during heat sterilization. While the composition of the present invention, in order to be complete for total nutrition, pre errably contains carbohydrate as an energy source, the inclusion or exclusion of such does not affect the use of the fatty acid-amino acid peptide and egg phosphatides as co-emulsifiers in oil in water emulsions. The fatty acid-amino acid peptide useful with the present invention is a compound which contains a peptide bond linking the car boxy lie group of a long chain fatty acid with the amino group of an amino acid. Examples of long chain fatty acids useful with the present invention consist of saturated and unsaturated acids with 16 - 22 carbon atoms including palmitic acid, stearic acid, arachidic acid, lignoceric acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. Amino acids which may be used as part of the peptides may include leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. It is also contemplated that the peptides be used either as the salt or the ree acid. The novel features which are believed to be characteristic of the present invention, both as to its composition and method of preparation, together with further objectives and advantages thereof will be better understood from the following description in which presently preferred embodiments of the invention are illustrated by way of example. It is to be expressly understood, however, that the specific embodiments are for the purposes of illustration and description only, and are not intended as a definition of the limits of the invention. DETAILED DESCRIPTION OF THE INVENTION The total parenteral or enteral nutrition composition of the present invention comprises a combination of amino acids, fat and carbohydrates in a fat-water emulsion. In particular, it has been surprisingly found that a ' fatty acid-amino acid peptide may be used as an emulsifier and that a combination of co-emulsifiers can be advantageously used to provide a stable emulsion even when the amino acids lysine and arginine are included. The co-emulsifiers of the present invention comprise a combination of a fatty acid-amino acid peptide together with a phosphatide such as egg or soybean phosphatide. The use of these co-emulsifiers in combination, provides a synergistic stability to the emulsion not obtainable by using either emulsifier alone. The ability to use a fatty acid-amino acid peptide as an emulsifier in a parenteral solution is unexpected in itself. Tests involving the administra¬ tion of disodium linoleoyi glutamate, an example of a peptide pursuant to the present invention, in a saline solution to mice clearly showed the undesirable properties of such parenteral administration of a fatty acid-amino acid peptide. A saline solution containing 0.1% disodium linoleoyi glutamate was injected into the tails of laboratory mice. Hemolysis from this injectate was observed in the tails of the animals. After five days of 50 ml/kg injections, the entire tail was necrotic. The results of these tests clearly suggested that the use of a fatty acid-amino acid peptide in an aqueous parenteral solution would be undesirable. Tests using disodium linoleoyi glutamate in fat-water emulsions, however-, unexpectedly showed no adverse affects. No hemolysis was observed as with the linoleoyi glutamate in normal saline. A fat/amino acid emulsion having a composition as stated in Table 1 was prepared. The amounts of egg yolk phosphatide and disodium linoleoyi -L -glutamate were _ varied to assess the stability of the composition. TABLE 1 Comoonent g/100 ml L-Threonine 0.18 L-Serine 0.26 L-Proline 0.50 Glycine 0.63 L-Alanine 0.32 L-Valine 0.30 L-Methionine 0.24 L-Isoleucine 0.31 L-Leucine 0.41 L-Phenylalanine 0.25 L-Tryptophan 0.07 L-Lysine Acetate ' 0.46 L-Histidine 0.13 L-Arginine 0.43 L-Cysteine HC1 H2O 0.02 Soybean Oil 5.0 Egg Yolk Phosphatide 0 - 2.0 Glycerol 3.0 Sorbitol 3.0 Disodium Linoleoyl-L-Glutamate 0 - 0.4 The compositions of Table 1 were placed in vials purged with nitrogen, capped and sterilized statically at 120°C for 20 minutes. The stability of the emulsion was determined by measuring the "M-value" of each sample. The M-values were determined by diluting a 100 ml aliquot with distilled water and obtaining an absorbance reading in a 1 cm cuvette at 500 nm versus a distilled water blank. The actual M-value which is proportional to the stability of the emulsion is then computed by multiplying the absorbance reading by the dilution factor. The results of the study are set forth in Table 2. TABLE 2 Emulsion Composition M-values (XI 000) 4 month LG Cone, EYP* Pre Post storage g/100 ml g/100 ml Sterilization Sterilization (c\ 4Q Q C 0.0 1 40.6 169 Separated 0.0 2 24.6 120 Separated 0.1 0.5 39.2 64.1 66.2 0.1 1.0 37.8 53.3 51.8 0.1 1.5 38.7 46.8 45.7 0.1 2.0 38.0 40.7 42.0 0.2 0.5 30.0 44.2 44.6 tJ.2 1.0 27.6 . 33.1 31.6 0.2 1.5 33.2 33.0 32.2 0.2 2.0 35.2 34.1 35.0 0.3 0.5 17.1 39.7 42.8 0.3 1.0 18.1 20.8 22.2 0.3 1.5 19.3 18.3 18.9 0.3 2.0 16.6 18.8 ' 18.6 0.4 0.5 14.3 64.3 59.8 0.4 1.0 10.6 14.8 15.3 0.4 1.5 9.3 10.7 12.1 0.4 2.0 10.6 11.0 11.3 *EYP - Egg yolk phosphatide As can be seen from the results of the above study, the combination of the fatty acid-amino acid peptide with egg yolk phosphatide as co- emulsifiers provides a synergistic effect in stabilizing the fat/amino acid emulsion. From Table 2 it can be seen that it is desirable to use at least approximately 1.0 g/100 ml of the egg yolk phosphatide. The stability of the emulsion increases with an increasing amount of the fatty acid-amino acid peptide. The specific desired amount would depend on a number of factors including cost and the stability desired. For purposes of parenteral administration of the emulsion, it is preferred to use approximately 0.1 - 0.2 g/100 ml of the peptide. All of the components listed in Table 1 are available commercially with the exception of disodium linoleoyl-L-glutamate. The synthesis of linoleoyi glutamate is well known in the art. The particular synthetic process used is described by 1. R. Vaughn and R. L. Ostato in the Journal of the American Chemical Society, 74:676 (1952). As discussed above, a number of variations can be made in the above composition without departing from the spirit or scope of the present invention. For example, different sources of fat may be used other than soy bean oil. These may include corn oil, other vegetable oils or other nutritionally acceptable fat sources. Further, different phosphatides may be used other than those found in egg. An example is soy bean phosphatide or lecithin. Various supplemental components such as electrolytes and vitamins may also be added or complete nutrition. A number of fatty acid-amino acid peptides may be used other than linoleoyl-L-glutamate. Preferably, the group of long chain fatty acids which may be used as part of the peptide consists of saturated and unsaturated acids with 16 to 22 carbon atoms. These include palmitic acid, stearic acid, arachidic acid, lignoceric acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. Amino acids which may be used as part of the peptides may include leucine, isoieucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid,- and glycine. It is preferable to use the L-isomer of the amino acids which is biologically active and therefore will also have nutritional value. However, the D-isomer or a racemic mix may also be used while retaining the desired emulsification characteristics. It is also contemplated that the peptides may be used either as the salt or the free acid. The specific amino acid composition of the emulsion as a whole is not critical to the present invention. However, the maximum benefits are realized by the ability to include arginine and lysine in the fat emulsion. The remaining ingredients are desirable for a total nutritional formulation. However, their presence is not necessary in order to obtain the specific benefits of the present invention. The ranges of proportions of ingredients which may be used in a total parenteral or enteral nutrition composition according to the present inven¬ tion are set forth in Table 3. Since it is the interaction of the various components which provides the stability of the emulsion, it is the relative amounts of each ingredient which are Important rather than the absolute amounts present in the emulsion. In other words, the concentration of the overall comppsition may vacy within pharmaceutically acceptable ranges, provided that the relative amounts of each component remain within the ranges stated below. TABLE 3 Weight Proportion Operative Preferred Ingredients Range Range Fat 3 - 30 4 - 8 Phosphatide 0.5 - - 5.0 1 - 2 Fatty Acid-Amino Acid Peptide 0.05 - 0.5 0.1 - 0.2 L-Lysine Acetate 0.2 - - 2.0 0.40 - 0.52 L-Arginine 0.2 - - 2.0 0.37 - 0.49 Remaining Amino Acids 2 - 20 3 - 6 Sugar Alcohols 3 - 30 4 - 8 EXAMPLE 1 A total parenteral nutrition composition was prepared containing the following ingredients: Component g/100 ml L-Threonine 0.18 L-Serine 0.26 L-Proline 0.50 Glycine 0.63 L-Aianine 0.32 L-Valine 0.30 L-Methionine 0.24 L-Isoleucine 0.31 L-Leuciήe 0.41 L-Phenylalanine 0.25 L-Tryptophan 0.07 L-Lysine Acetate 0.46 L-Histidine 0.13 L-Arginine 0.43 L-Cysteine HCl H2O 0.02 Soybean Oil 5.0 Egg Yolk Phosphatide 1.0 Glycerol 3.0 Sorbitol 3.0 Disodium Linoleoyl-L-Glutamate 0.2 The egg yolk phosphatide was dissolved in soy bean oil by stirring at 600 rpm at 80°C for ten minutes. USP grade water warmed to 80°C was then added to the oil mixture under continuous agitation until all egg phosphatide was dissolved. A primary dispersion was then made by high shear mixing under nitrogen purge at 8,500 rpm at 40°C for twenty minutes. The dispersion was then subjected to high pressure homogenization at 530 kg/cm 2 and 50°C for ten cycles. An aqueous solution previously made to contain appropriate amounts of glycerol, sorbitol, amino acids, including lysine and arginine, and disodium linoleoyl-L-glutamate was then added to the primary dispersion and further homogenized under high pressure for ten cycles. After cooling to room temperature, the emulsion was adjusted to an appropriate physiological pH (from about 5 to 9) using means known in the art and filtered through a 0.8 micron filter under 0.5 kg per square centimeter nitrogen pressure. The emulsion was then placed in appropriate containers and may be sterilized using conventional techniques. This may include heat or filter sterilization. The resulting emulsion was stable, non-pyrogenic and suitable for intravenous administration to human patients. EXAMPLE 2 A composition useful for enteral nutrition may be prepared using similar processing steps to those described in Example 1 and containing the following ingredients: Component g/100 ml L-Isoleucine 0.44 L-Leucine 0.69 L-Methionine 0.69 L-Phenyialanine 0.69 L-Threonine 0.315 L-Tryptophan 0.157 L-Valine 0.504 L-Lysine Acetate 0.705 L-Histidine 0.158 Corn Oil 16.0 Lecithin 0.187 Mono- and Diglycerides 0.373 Maltodextrin 16.0 Sucrose 3.3 Disodium Linoleoyl-L-Glutamate 0.109 It should be noted that the amount of heat applied to sterilized enteral compositions is generally less than that required for parenteral compositions. Furthermore, glucose polymers such as maltodextrins and starches can be included in enteral compositions to achieve the desired nutritional effects. It is possible to sterilize enteral compositions containing glucose polymers and amino acids without adverse chemical reactions which may compromise the nutritional properties of the composition. EXAMPLE 3 Another composition suitable for enteral nutrition according to the present invention also contains a number of vitamins and electrolytes. It has the following composition: Component wt./lOOml Disodium Linoleoyi Glutamate 148 mg Corn Oil 3.0 g Medium Chain Triglycerides 2.0 g Lecithin 262 mg Polysorbate 80 39 mg Maltodextrin 18.0 g Carrageenan 190 mg Citric Acid 114 mg Egg Albumin Hydrolysate 7 -3 g L-Valine 1 .1 g L-Leucine 1.8 g L-Isoleucine 0.95 g Vitamin A 364 IU Vitamin D3 27 IU Vitamin E 4 IU Vitamin K[ 12 meg Vitamin C 13 mg Thiamine 121 meg Riboflavin 121 meg Niacinamide 1.34 mg Vitamin Bg 176 meg Folic Acid 38 ' meg Vitamin Bj^ 0.42 meg Biotin 21 meg Pantothenic Acid 791 meg Potassium Iodide 10 meg Chromium Chloride 13 meg Sodium Molybdate 20 meg Selenium Dioxide 11 meg Dicalcium Phosphate ' 113 mg Monocalcium Phosphate 64 mg Magnesium Oxide 28 mg Manganous Sulf ate H2O 245 meg Ferrous Gluconate 7 mg Copper Gluconate 111 meg Zinc Oxide 902 meg Sodium Chloride 147 mg Potassium Citrate H2O 307 mg Potassium Chloride 31 mg While a wide variety of materials and preparation procedures may be used in the present invention, it should be understood that changes can be made without departing from the spirit or scope thereof. This invention therefore, is not to be limited to the specific embodiments discussed herein.

Claims: WHAT IS CLAIMED IS: 1. A stable aqueous fat emulsion comprising a fat suitable for human nutrition, one or more nutritive amino acids and two or more co-emulsifiers wherein at least one of said co-emulsifiers is a pharmaceutically acceptable phosphatide and at least one other of said co-emulsifiers is a fatty acid-amino acid peptide or a pharmaceutically acceptable salt thereof and wherein the fatty acid component of said peptide is selected from the group consisting of saturated and unsaturated fatty acids having from 16 to 22 carbon atoms and the amino acid component of said peptide is a pharma¬ ceutically acceptable amino acid. 2. An emulsion according to Claim 1 wherein said fatty acid com¬ ponent of said peptide is selected from the group consisting of palmitic acid, stearic acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. 3. An emulsion according to Claim 1 wherein said amino acid com¬ ponent of said peptide is selected from the group consisting of leucine, "isoleucine, valine, methionine,' phenylalanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proiine, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. 4. An emulsion according to Claim 1 wherein said fatty acid com¬ ponent of said peptide is linoleic acid. 5. An emulsion according to Claim 1 wherein said amino acid com¬ ponent of said peptide is glutamic acid. 6. An emulsion according to Claim 1 wherein at least one of said co-emulsifiers is disodium linoleoyl-L-glutamate. 7. An emulsion according to Claim 1 wherein said phosphatide is selected from the group consisting of egg phosphatide and soybean phosphatide. 8. An emulsion according to Claim 1 wherein one of said nutritive amino acids is L-arginine. 9. An emulsion according to Claim 1 wherein one of said nutritive amino acids is L-lysine. 10. An emulsion according to Claim 1 wherein said fat is a vegetable oil. 11. An emulsion according to Claim 1 wherein said emulsion is non-pyrogenic, has a pH range of about 5 to 9, and is suitable for intravenous administration to humans. 12. An emulsion according to Claim 1 wherein said fat, said peptide, said phosphatide, and said amino acids are present in approximately the following relative weight proportions: Ingredient Weight Proportion Fat - 3 - 30 Fatty acid-amino acid peptide 0.05 - 0.5 Phosphatide 0.5 - 5.0 Amino acids 2 - 24 13. An emulsion according to Claim 12 wherein said relative weight proportions are: Ingredient Weight Proportion Fat 4 - 8 Fatty acid-amino acid peptide 0.1 - 0.2 Phosphatide 1 - 2 Amino acids 3.7 - 7 14. A stable aqueous fat emulsion suitable for human nutrition comprising 3-30 w/v% based on the emulsion of a fat suitable for human nutrition, 0.05-0.5 w/v% of a fatty acid-amino acid peptide or a pharma¬ ceutically acceptable salt thereof, 0.5-5.0 w/v% of a phosphatide and 2-24 w/v% of one or more nutritive amino acids. 15. An emulsion according to Claim 14 wherein the fatty acid com¬ ponent of said peptide is selected from the group of saturated and unsaturated fatty acids having from 16 to 22 carbon atoms. 16. An emulsion according to Claim 15 wherein said fatty acid component is selected from the group consisting of palmitic acid, stearic acid, arachidic acid, lignoceric acid, palmitoleric acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. 17. An emulsion according to Claim 14 wherein the amino acid com¬ ponent of said peptide is selected from the group consisting of leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. 18. An emulsion according to Claim 14 wherein said fatty acid com¬ ponent of said peptide is linoleic acid. 19. An emulsion according to Claim 14 wherein said amino acid com¬ ponent of said peptide is glutamic acid. 20. An emulsion according to Claim 14 wherein said peptide is disoldium linoleoyl-L-glutamate. 21. An emulsion according to Claim 14 wherein said phosphatide is selected from the group consisting of egg phosphatide and soybean phosphatide. 22. An emulsion according to Claim 14 wherein one of said nutritive amino acids is L -arginine. 23. An emulsion according to Claim 14 wherein one of said nutritive amino acids is L-lysine. 24. An emulsion according to Claim 14 wherein said fat is a vegetable oil. 25. An emulsion according to Claim 14 wherein said emulsion is non-pyrogenic and is suitable for intravenous administration to humans. 26. A stable, non-pyrogenic aqueous fat emulsion suitable for parent¬ eral administration to humans comprising 3-30 w/v% based on the emulsion of a fat suitable for human nutrition, 0.05-0.5 w/v% of a fatty acid-amino acid peptide or a pharmaceutically acceptable salt thereof, 0.5-5.0 w/v% of a phosphatide and 2-24 w/v% of one or more nutritive amino acids. 27. An emulsion according to Claim 26 wherein the fatty acid com¬ ponent of said peptide is. selected from the group of saturated and unsaturated fatty acids having from 16 to 22 carbon atoms. 28. An emulsion according to Claim 26 wherein said fatty acid component is selected from the group consisting of palmitic acid, stearie acid, arachidic acid, lignoceric acid, palmitolerie acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. 29. An emulsion according to Claim 26 wherein the amino acid com¬ ponent of said peptide is selected from the group consisting of leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. 30. An emulsion according to Claim 26 wherein said fatty acid com¬ ponent of said peptide is linoleic acid. 31. An emulsion according to Claim 26 wherein said amino acid com¬ ponent of said peptide is glutamic acid. 32. An emulsion according to Claim 26 wherein said peptide is disoldiu linoleoyl-L-glutamate. 33. An emulsion according to Claim 26 wherein said phosphatide is selected from the group consisting of egg phosphatide and soybean phosphatide. 34. An emulsion according to Claim 26 wherein one of said nutritive amino acids is L -arginine. 35. An emulsion according to Claim 26 wherein one of said nutritive amino acids is L-lysine. 36. An emulsion according to Claim 26 wherein said fat is a vegetable oil. 37. A method of stabilizing an aqueous fat emulsion containing nutritive amino acids and suitable for human nutrition comprising including in said emulsion two or more co-emulsifiers in ef ective amounts wherein at least one of said co-emulsifiers is a phosphatide and at least one other of said co-emulsifiers is a fatty acid-amino acid peptide or a pharmaceutically acceptable salt thereof and the fatty acid component of said peptide is selected from the group consisting of saturated and unsaturated fatty acids having from 16 to 22 carbon atoms and the amino acid component of said peptide is a pharmaceutically acceptable amino acid. 38. A method according to Claim 37 wherein said fatty acid com¬ ponent of said peptide is selected from the group consisting of palmitic acid, stearie acid, arachidic acid, lignoceric acid, palmitolerie acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. 39. A method according to Claim 37 wherein said amino acid com¬ ponent of said peptide is selected from the group consisting of leucine, isoleucine, valine, methionine, phenylalanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. 40. A method according to Claim 37 wherein said fatty acid com¬ ponent of said peptide is linoleic acid. 41. A method according to Claim 37 wherein said amino acid com¬ ponent of said peptide is glutamic acid. 42. A method according to Claim 37 wherein at least one of said co-emulsifiers is disodium linoleoyl-L-glutamate. 43. A method according to Claim 37 wherein said phosphatide is selected from the group consisting of egg phosphatide and soybean phosphatide. 44. A method according to Claim 37 wherein one of said nutritive amino acids is L-arginine. 45. A method according to Claim 37 wherein one other of said nutritive amino acids is L-lysine. 46. A method according to Claim 37 wherein said fat is a vegetable oil. 47. A method according to Claim 37 wherein said emulsion is non-pyrogenic and is suitable for intravenous administration to humans. 48. A method according to Claim 37 wherein said fatty acid-amino acid peptide is present in an amount of from 0.05 to 0.5 w/v% based on the emulsion. 49. A method according to Claim 48 wherein said phosphatide is present in an amount of from 0.5 to 5.0 w/v% based on the emulsion. 50. A method according to Claim 48 wherein said nutritive amino acids are present in amount of from 2 to 24 w/v% based on the emulsion. 51. A stable aqueous fat emulsion comprising a fat suitable for human nutrition, and an emulsifier comprising a fatty acid-amino acid peptide or a pharmaceutically acceptable salt thereof wherein the fatty acid component of said peptide is selected from the group consisting of saturated and unsaturated fatty acids having from 16 to 22 carbon atoms and the amino acid component of said peptide is a pharmaceutically acceptable amino acid. 52. An emulsion according to Claim 51 wherein said fatty acid component of said peptide is selected from the group consisting of palmitic acid, stearie acid, arachidic acid, lignoceric acid, palmitolerie acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. 53. An emulsion according to Claim 51 wherein said amino acid component of said peptide is selected from the group consisting of leucine, isoleucine, valine, methionine, phenyiaianine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, crysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. 54. An emulsion according to Claim 51 wherein said fatty acid component of said peptide is linoleic acid. 55. An emulsion according to Claim 51 wherein said amino acid component of said peptide is glutamic acid. 56. An emulsion according to Claim 51 wherein said emulsifier is disodium linoleoyl-L-glutamate. 57. An emulsion according to Claim 51 further comprising one or more nutritive amino acids, 58. A method of stabilizing an aqueous fat emulsion suitable for human nutrition comprising including in said emulsion an emulsifier in an effective amount wherein said emulsifier is a fatty acid-amino acid peptide or a pharmaceutically acceptable salt thereof and the fatty acid component of said peptide is selected from the group consisting of saturated and unsaturated fatty acids having from 16 to 22 carbon atoms and the amino acid component of said peptide is a pharmaceutically acceptable amino acid. 59. A method according to Claim 58 wherein said fatty acid component of said peptide is selected from the group consisting of palmitic acid, stearie acid, arachidic acid, lignoceric acid, palmitolerie acid, oleic acid, linoleic acid, linolenic acid, arachidonic acid, and clupanodonic acid. 60. A method according to Claim 58 wherein said amino acid component of said peptide is selected from the group consisting of leucine, isoleucine, valine, methionine, phenyialanine, tryptophan, threonine, lysine, arginine, histidine, alanine, proline, serine, cysteine, cystine, tyrosine, aspartic acid, glutamic acid, and glycine. 61. A method according to Claim 58 wherein said fatty acid component of said peptide is linoleic acid. 62. A method according to Claim 58 wherein said amino acid component of said peptide is glutamic acid. 63. A method according to Claim 58 wherein at least one of said co- emulsifiers is disodium linoleoyl-L-glutamate. 64. A method according to Claim 58 wherein said fatty acid-amino acid peptide is present in an amount of from 0.05 to 0.5 w/v% based on the emulsion. 65. A method according to Claim . 58 wherein said emulsion further comprises one or more nutritive amino acids.

Inventors: PARK JOHN YOL, PARK, JOHN, YOL
Applicants: AMERICAN HOSPITAL SUPPLY CORP, AMERICAN HOSPITAL SUPPLY CORPORATION
Application year: 1985
Main classification: A61K37
IPC codes: A61K9, A61K31, A61K38