MXPA99007737A - Use of polyunsaturated fatty acids forreducing the incidence of necrotizing enterocolitis - Google Patents

Abstract

Enteral formulas that contain long-chain polyunsaturated fatty acids (PUFAs), e.g. arachidonic acid (AA) and docosahexaenoic acid (DHA) essentially free of cholesterol, and a process for making such enteral compositions are described. More particularly, the invention relates to methods for reducing the incidence of necrotizing enterocolitis by administering compositions which provide n-6 and n-3 long chain PUFAs;phospholipids and/or choline. Compositions from egg yolk lipids are presently preferred as they contain n-6 and n-3 long chain PUFAs and are predominantly in a phosphtidylcholine form. This is believed to provide a synergistic effect. Also disclosed is a process of making such a composition that provides improved organoleptic and stability properties.

Description

METHODS AND COMPOSITIONS TO REDUCE THE INCIDENCE OF NECROTIZING ENTEROCOLITIS FIELD OF THE INVENTION The present invention relates in general terms to enteric formulas containing polyunsaturated fatty acids (PUFAs) of long chain and to processes for the preparation of said compositions, and to methods for reducing the incidence of necrotising enterocolitis. More specifically, the present invention relates to enteric compositions that provide PUFAs such as arachidonic acid (AA) and docosahexaenoic acid (ADH), essentially free of cholesterol, which can be obtained from the lipids of the egg yolk. The PUFAs supplied by the egg yolk are predominantly in the form of phospholipids. The process of making such compositions offer improved organoleptic and stability properties. Enteral administration of such compositions may reduce the incidence of necrotising enterocolitis.

Background of the Invention Long-chain PUFAs in formulas or in enteric compositions have been the subject of numerous and diverse articles in the literature. For example, the US Patent. No. 4,670,285 ("Clandinin" patent) discloses a specific fat blend suitable for use in formulas for infant feeding. More specifically, the fat blend of Clandinin contains at least one C20 or C22 n-6 fatty acid and a C20 or C22 n-3 fatty acid. It has been revealed that said fatty acids, at certain and defined quantities, prevent the occurrence of harmful effects in the feeding of the infants who are fed with said fatty mixture. The C2o or C22 n-6 fatty acids are also present in a total amount of approx. 0.13 to 5.6% by weight of all the fatty acids in said product. The fatty acid C20 or C22 n-3, if present, is included in a total amount of approx. 0.01.3 - 3.33% by weight of all fatty acids of the product. Clandinin reveals the use of egg lipids in order to supply n-6 and n-3 fatty acids; however, the egg lipids used by Clandinin also contain high levels of cholesterol. Furthermore, said patent discloses the use of 75-95 parts by weight of lipids of the egg yolk wherein the remaining oil portion corresponds to coconut oil or soybean oil. The nomenclature used by Clandinin for fatty acids will also be used in this document. WO 93/20717 discloses a formula for infants which contains only slightly lower proportions than the irritant amounts of free long chain fatty acids (C16 or C22) and triglycerides. Said patent application also discloses that by providing short chain alkyl esters such as ethyl esters, of said fatty acids in infant formulas, the tendency of the fatty acid to injure the intestinal epithelium of the infant is essentially eliminated, although it allows absorption and the processing of the fatty acid portion. U.S. Patent No. 4,913,063 issued to Lichtenberg discloses compositions containing exclusive blends of phospholipids and neutral lipids for the prevention or treatment of ulcers and inflammatory bowel disease. Said patent discloses mixtures of saturated or unsaturated phospholipids, together with saturated or unsaturated triglycerides and / or sterols, necessary to provide protective efficacy against ulcers in study models with animal experiments. This patent also discloses the inclusion of polyvalent cations or antioxidants in the mixture of lipids in order to intensify said activity. International Patent Publication WO 96/10922 issued Konn et al., Discloses a mixture of fats for infant formula characterized in that arachidonic acid and docosahexaenoic acid are present in the mixture of fats in the form of phospholipids. European Patent Application No. 0 376 628 B1 issued to Tomarelli, reveals a fat composition of vegetable oils which uses oils from randomized palm oil (with distribution to, randomness of unsaturation) or randomized palm olein oil as the only source of palmitic acid oils. It is also disclosed that all fat compositions based on vegetable oils are particularly suitable for use in formulas for infants or for infants born before term -premature- (also for infants with low birth weight). The fat compositions for preterm infants of the patent application issued to Tomarelli include medium chain triglycerides (MCT) with a randomized palmitic acid oil, lauric acid oil, or an oleic acid oil and a linoleic acid oil. Although the references discussed above correspond to important contributions in this field, the need for formulas for infants containing egg phospholipids as a source of long chain PUFAs at concentrations appropriate for human nutrition still remains. Another need that remains to be met are methods for the preparation of enteric formulas containing egg phospholipids wherein said formulas possess acceptable organoleptic properties. Such compositions have a particular application in formulas for infants in both premature and full term infants, for which minimum requirements have been established for the consumption of long chain PUFAs for appropriate neural development and for the development of visual acuity. On the other hand, they may have a protective effect on the intestine. Necrotizing enterocolitis (NEC) corresponds to a serious problem in infants with birth weights less than 1,500 grams Despite having more than three decades of study, the etiology and pathophysiology of the NEC still remain unclear. NEC is a disease with lethal prognosis characterized by ischemic necrosis of the structures of the alimentary tract involved and by intestinal neuromatosis, which results in the perforation of the intestine. A premature baby with NEC presents a clinical picture of thermal instability, lethargy, gastric retention, vomiting, abdominal distension, blood in thick or hidden clots, blood in the stool, and radiographic evidence of pneumatosis intestinalis, air in the portal veins or in the neuroperitoneum. Frequent apnea spelis, shoc and sclerema, and even death occur frequently. Numerous researchers have made several observations and established factors that influence this disease. (Nue, Pediatr. Clin. North Am. April, 1996, 43 (2): 409-32). As an example, the following observations and factors are mentioned: • Flageóle et. al., Necrotizing Enterocolitis of the Newborn, Review for the Clinician. Union-Med-Can 1991 Sep-Oct; 120 (5): 334-8, suggests that the pathogenesis of NEC includes mesenteric schema, intestinal immaturity, enteric feeds and possibly even infection; • Caplan et. al., Role of Platelet Activating Factor and Tumor Necrosis Factor-Alpha in Neonatal Necrotiz? Ng Enterocolitis, Journal of Pediatrics, June, 1990, 960-964, reports that counts of platelet-activating factor and factor-alpha of tumor necrosis are elevated in patients with NEC; • Kliegman et al Clostridia as Pathogens m Neonatal Necrotizing Enterocolitis, Journal of Pediatrics, August, 1979, 287-289, reports the isolation of Clostridia perfringens in infants with neonatal NEC; • Ostertag et al., Early Enteral Feeding Does Not Affect the Incidence of Necrotizing Enterocolitis, Journal of Pediatrics, Vol. 77, No. 3, March 1986, 275-280, describes how the early intake of calories by enteral route, diluted, does not adversely affect the incidence of NEC; • Bell et al., Neonatal Necrotizing Enterocolitis, Annals of Surgery, Vol. 187, January 1978, No. 1, 1-7, suggests the use of an antimicrobial combination therapy in the treatment of infants with NEC; • Eyal et al., Necrotizing Enterocolitis in the Very Low Birth Weight Infant: Expressed Breast Milk Feeding Compared with Parenteral Feeding, Archives of Disease in Childhood, 1982, 57, 274-276 reports that the incidence of NEC in low birth weight infants birth was reduced by the delay of initiation of enteric feeding. • Finer et al., Vitamin E and Necrotizing Enterocolitis, Pediatrics, Vol. 73, No. 3, March 1984 suggests that administration of vitamin E reduces the incidence of severe sequelae of retrolental fibroplasia may be associated with an increase in incidence of NEC. • Brown et al., Preventing Necrotizing Enterocolitis in Neonates, JAMA, Nov. 24, 1978. Vol. 240. No. 22. 2452-2454 reports that ECN can be virtually eliminated through the use of a slowly progressive diet regimen. Kosloske, Pathogenesis and Prevention of Necrotizing Enterocolitis: A Hypothesis Based on Personal Observation and a Review of the Literature, Pediatrics, Vol. 74, No. 6, Dec. 1984, 1086-1092, hypothesizes that ECN occurs through coincidence of two of three pathological events: (1) intestinal ischemia; (2) colonization by pathogenic bacteria and (3) excess protein substrate in the intestinal lumen.

Kisloske, supra, also reports that NEC is rare in infants who are fed only breast milk. In humans, breast milk plays an important role in passive immunization of the neonate's intestine and contains factors that promote the growth of Bifidobacterium in the intestinal flora. It has also been reported that the beneficial content of human milk can be adversely affected by freezing, pasteurization, or simple storage. As can be seen, there is a lot of debate about the etiology and treatment of NEC, leaving then the need to have compositions and methods that are better able to cure and / or reduce the incidence of this devastating and frequently fatal condition.

Compendium of the Invention The present invention has several aspects. In a first aspect. The invention contemplates a method for reducing the incidence of necrotizing enterocolitis in an infant susceptible to developing this disease, wherein said method comprises administering an effective amount of at least one long-chain PUFA selected from the group consisting of C20 fatty acid n -6, fatty acid C22 n-6, fatty acid C20 n-3, and fatty acid C20 @ -3. For example, the administration of arachidonic acid, an n-6 acid, has been found to be effective. The administration can be done enterically or parenterally. Better still, a combination of n-6 fatty acids and n-3 fatty acids, for example, arachidonic acid and docosahexaenoic acid, can be used. Enteric administration is performed at a level of at least 1.0 mg of n-6 fatty acids per kilogram of baby's body weight per day. A more preferred practice uses a combination of n-6 and n-3 fatty acids and weight ratios therefrom from ca. 2: 1 to approx. 4: 1; and administer at least 5.0 mg of long chain n-6 fatty acids per day. The method can be carried out by supplying by feeding a sufficient amount of an enteric composition containing arachidonic acid and docosahexaenoic acid in order to supply said infant from ca. 1.0 to ca. 60 mg per day of arachidonic acid and approx. 0.25 - 35 mg per day of docosahexaenoic acid. The most typical amounts are between approx. 5.0 - 40 mg of arachidonic acid and from approx. 1.5 to approx. 20 mg of docosahexaenoic acid kg / day. Preferably, the weight ratio of arachidonic acid to docosahexaenoic acid ranges from ca. 2 to approx. 4. Preferably, the long-chain polyunsaturated fatty acids are in the form of phospholipids, especially in the form of phosphatidylcholine. Such phospholipids are present in high concentrations in egg lecithin and in egg phosphatides. Accordingly, in a further aspect, the invention provides a method for decreasing the incidence of necrotizing enterocolitis in an infant, wherein said method comprises feeding said infant with a sufficient amount of an enteral nutritional composition containing protein, carbohydrate and phospholipids. so as to provide at least 1.0 mg of long chain n-6 polyunsaturated fatty acids per day. Preferably, the feed additionally provides at least 0.5 mg of n-3 long-chain polyunsaturated fatty acids per day, in the form of arachidonic acid and docosahexaenoic acid, respectively. In another aspect, the invention provides a method for decreasing the occurrence of necrotizing enterocolitis in a human infant, wherein said method comprises administering to the infant phospholipids in an effective amount in order to reduce the incidence of necrotising enterocolitis. Typically said phospholipids are administered in order to provide between approx. 60 and approx. 2 400 μmol, preferably between approx. 200 and approx. 1 500 μmol, better still between approx. 400 and approx. 1 000 pmol of phospholipids per kg / day. The source of phospholipids is not crucial. Phospholipids obtained from egg lecithin are suitable for the purposes of the present invention. Phospholipids are easily available from the animal membrane, including the milk fat globule membrane. Other sources rich in phospholipids are the oils of soybeans and other seeds. When the egg lecithin phospholipids are used, the preferred amount to be administered enterically should be sufficient to provide at least 1.0 mg of n-6 long chain fatty acids per day. Preferably, the egg phospholipids supply arachidonic acid in the manner of a significant portion of n-6 fatty acids and preferably also provide docosahexaenoic acid and / or long chain n-3 fatty acids in the aforementioned proportions. These can have a synergistic effect. However, it should be noted that the length and saturation of the fatty acids linked to the main molecular spine glycerol in the "phospholipid" aspect of the present invention are not crucial and can be used for the effect of fatty acids other than chain PUFAs. long In still another aspect, the invention provides a method for decreasing the occurrence of necrotizing enterocolitis in a human infant, wherein said method comprises administering to the infant choline in an amount effective to reduce the incidence of necrotising enterocolitis. Typically, said hill is administered to provide approx. between 60 and 1 800 μmoles; better still between approx. 150 and 1 200 μmoles of choline kg / day. The source of choline is not crucial: phosphatidylcholine may be preferred and phosphatidylcholine obtained from egg lecithin for the purposes of this invention may be appropriate. Other sources rich in choline or phosphatidylcholine include soybean oils and other seeds. When egg lecithin choline is used, it is preferred that it be administered in combination with n-6 and / or n-3 fatty acids in order to provide at least 1.0 mg of long-chain fatty acids n- 6 per day. Preferably, the egg lecithin supplies arachidonic acid as a significant portion of n-6 fatty acids and preferably also supplies docosahexaenoic acid and / or other long chain n-3 in the above-mentioned proportions. This may produce a synergistic effect. . However, as regards the appearance of the phospholipid, the length and saturation of the fatty acids linked to the main molecular spine glycerol and any phosphatidylcholine used in the invention are not crucial and the fatty acids other than the long chain PUFAs can also be used . Alternatively, choline from sources other than phospholipids can be used.

Additionally, due to the beneficial effects observed in infants susceptible to developing enterocolitis, it may well be the case that the beneficial effects are also observed in adults. Therefore, a further aspect of the present invention consists in the use of any of the above compositions in the treatment or prevention of ulcerative colitis and related intestinal pathological conditions, in adults. Of course, the dosage should be adjusted based on the increased weight of the adult patient and on other known factors in this field of medicine. Other aspects of the invention, including the enteric formulations and the processes of their preparation, are described in other sections of the present application. For example, in yet another aspect of the present invention, there is disclosed a process for the preparation of an enteric formula comprising egg yolk phospholipids, a process comprising the steps of: (a) Delivery of dehydrated egg phosphatides, in powder, essentially free of cholesterol; (b) Dispersing said phospholipid fraction in an aqueous phase to form a phospholipid dispersion; and Ce) Combination of said phospholipid dispersion with mixtures of the other components of said enteric formula. Preferably and according to the process, the dispersion in the aqueous phase provides egg phosphatides approx. between 2% and 15% by weight; and preferably the egg phosphatide powder is added to the water at a temperature between 20-50 ° C. This aspect can be used to produce a formula for human infants containing arachidonic acid and docosahexaenoic acid in the form of phospholipids, wherein said enteric formula is produced through said process. In yet another aspect, the invention provides an appropriate formula for infant feeding, comprising protein, carbohydrates and lipids, and wherein the improvement is characterized in that the lipid mixture comprises medium chain triglycerides, and egg phospholipids, in where said egg phospholipids are present in a proportion from ca. 1% - 40% of the lipid mixture, and wherein said egg phospholipids are essentially free of cholesterol. Typically the egg phospholipid is present at a level of 5-30% by weight of the mixture of lipids and arachidonic acid of the formula in a concentration of ca. 10 - 31 mg per 100 kcal. Better still, the formula includes docosahexaenoic acid, at a concentration between 3 -16 mg per 100 kcal, and the arachidonic and docosahexaenoic acids are present in a ratio that can range from 4: 1 to approx. 2: 1 Detailed description of the invention General Terminology The fatty acids are hydrocarbon chains of various lengths, which have a carboxylic acid at one end, which makes them to some degree polar and hydrophilic in this place, while on the contrary they are hydrophobic to varying degrees depending on the length of the hydrocarbon chain. Fatty acids are classified based on the length of the hydrocarbon chain. For example, chains with less than 6 carbon atoms are considered "short", "chains of 6-18 are considered" medium "and chains of 20 or more carbons are" long. "Fatty acids also have one or more doubles. links which correspond to points of "unsaturation" in the hydrocarbon chain As used herein, the term "long chain PUFA" refers to a fatty acid of twenty carbon atoms or more that has at least one two carbon-carbon (polyunsaturated) double bonds The number and position of double bonds in fatty acid is designated by conventional nomenclature, for example, arachidonic acid ("AA" or "ARA") has a chain length of 20 carbon atoms and four double bonds starting at the sixth carbon counted from the methyl terminal., will be referred to as a "C20.4 n-6" fatty acid. Likewise, docosahexaenoic acid ("ADH") has a chain length of 22 carbon atoms with 6 double bonds starting from the third carbon atom counted from the terminal methylene and designated as "C22: 6 n- 3". Also known in nature are PUFAs with less prevalent chain lengths (with less occurrence) and some of them are listed in Tables I and IV (below the solid dividing line). "Glycerides" are complex lipids that possess a glycerol spine esterified with fatty acids. A "Triglyceride" (eg, triacylglycerol) has three esterified fatty acids, one at each hydroxyl site of the glycerol spine.The di- and monoglycerides possess, respectively, two and one esterified fatty acid.A phosphoglyceride (eg, "phospholipid") or "phosphatide" - [interchangeable terms]) differ from a triglyceride in that they have a maximum of two esterified fatty acids, while the third position of the glycerol spine is esterified with phosphoric acid, becoming a "phosphatidic acid" "In nature, phosphatidic acid is usually associated with an alcohol which contributes to the presence of a strongly polar head." Two such alcohols commonly found in nature are choline and entanolamine.A "lecithin" is a Phosphatidic acid associated with the aminoalcohol "choline" and is also known as "phosphatidylcholine." Lecithin can vary in the content of the compound of fatty acid and can be obtained from sources such as for example. the eggs and soy. The cephalin (phosphatid? Letanolamine), phosphatidylserine and phosphatidylinositol correspond to other phosphoglycerides. Phospholipids are commonly found in the cell membranes of all living beings. The traditional sources of phospholipids are egg yolk and soybean oil. Phospholipids can also be obtained from the brain, kidney, heart and lungs of mammals; or the membrane of the milk fat globule. On the other hand, sources of microbial origin, (oils from unicellular organisms) such as algae oils and fungal oils can be used, particularly as regards the fatty acid components AA and ADH of the phospholipids. Chicken eggs correspond to a relatively abundant source of lipids. Approx. 33% of the yolk of a chicken egg is lipid, of which approx. 67% corresponds to triglycerides, 28% is a phospholipid, and the remaining percentage is mainly cholesterol (the percentages are by weight). These figures are approximate and will vary to some degree, depending on the diet, diet and general conditions of the hens. Of the fraction of phospholipids approx. 75% is phosphatidyl choline, and approx. 20% is phosphatidylethanolamine. The hill half makes approx. 15 to 30% of each molecule of phospholipids depending on the particular type of bound fatty acids. Therefore, the choline content of the egg phospholipids can vary from ca. 10% up to approx. 25% by weight; or based on the total content of egg lipids, from approx. 3% up to approx. 7% by weight.

Compositions The compositions useful in the present invention comprise n-6 and / or n-3 long chain PUFAs. The source of long chain PUFAs is not critical. Known sources of long chain PUFAs include fish or oil from marine products, lipids and phospholipids from the egg yolk, oil from unicellular microorganisms (e.g., algae oil and fungal oils). It can be understood that some sources are better than others in this field of industry in achieving high and specific amounts of long chain PUFAs. It is evident to those skilled in the art that there are other edible, semi-purified or purified sources of long-chain PUFAs. New sources of long-chain PUFAs can be developed through the genetic manipulation of plants and / or plants containing oils, and it is intended that the use of said recombinant products be contemplated within the scope of the present invention. The long chain PUFA can be provided in the composition in the form of free fatty acid esters; mono-, di- and triglycerides, phosphoglycerides, including lecithins; and / or mixtures thereof. It may be preferable to provide long chain AGPls in the form of phospholipids, especially phosphatidylcholine. A currently preferred source, at least when it is processed in such a way that the organoleptic properties and the cholesterol level are acceptable, are evidently the phospholipids of the egg yolk, perhaps due to the high content of phospholipids and / or phosphatidyl choline associated with the PUFAs obtained from the eggs. The long-chain PUFAs n-6 or n-3 can be administered in the form of an intravenous (e.g., parenteral) solution, as can choline and phosphatidylcholine. An intravenous solution will preferably contain effective amounts of PUFA, phospholipid and / or choline, at a reasonable daily intake of parenteral solution. The exact concentration, therefore, is highly variable depending on the volume of anticipated intake and is significantly more concentrated in a bolus or parenteral solution of small volume than in a parenteral nutritional or moisturizing product. Parenteral compositions will generally include pharmaceutically acceptable carriers and excipients, such as buffers, preservatives and the like. The long-chain PUFA n-6 and / or n-3 and choline, and the phospho-lipid can alternatively be administered in the form of an enteric administration composition. The enteric compositions containing the long chain PUFA, the choline or the phospholipid may be in the form of a solution or an emulsion or as the active ingredient; or in a nutritional matrix that contains protein, carbohydrates, other fats, minerals and vitamins. Enteral compositions containing active components can provide either a complete nutritional support or one as a supplement. The concentration of the long chain PUFA in the enteral composition can range from nearly 100% (as in the case of a bolus administration emulsion) to 0.5% by weight (as in the case of a complete nutritional formula) in weight of the composition, depending on the mode of administration and the intended purpose. In complete nutritional formulas the concentration may even be lower if a sufficient amount of formula is supplied in order to provide effective amounts of the long-chain PUFA. A particularly preferred practice of the present invention is that relating to a nutritionally complete formula for the feeding of infants, including premature infants. Such a preferred composition comprises proteins, carbohydrates and lipids, wherein from ca. 6 up to approx. 40% by weight of total lipids correspond to egg phospholipids essentially free of cholesterol. The term "essentially free" means that the content of co -terol in the egg phospholipids is less than 0, 1% by weight and preferably less than 0.05% by weight of total lipids. Those experts in this field of industry will easily understand what formula means for infants. When they are diluted or reconstituted, if initially they are in the form of concentrates or a powder, in order to obtain a form ready to be administered as a food, a typical infant formula contains approx. 10 - 35 g of protein per liter of formula; 20-50 g of lipid per liter of formula: 60-110 g of carbohydrates per liter of formula together with the other diverse components such as vitamins, minerals, fibers, emulsifiers and the like. For purposes of a better understanding of the components of a formula for infant feeding and the methods of their production, the following patents are cited below as reference only: 1) US Patent No. 5,492,899 issued to Masor et al; 2) U.S. Patent No. 5 021 245 issued to Borschel et al .; 3) U.S. Patent No. 5,234,702 issued to Katz et al .; 4) US Patent No. 5 602 109 issued to Masor et al .; and 5) U.S. Patent No. 4,670,268 issued to Mahmoud. More specifically, this practice of the invention comprises an infant formula containing approx. 40-50 g of lipid per liter of formula wherein the lipid comprises a mixture of medium chain triglycerides and egg pholipids essentially free of cholesterol. Typically, the lipid mixture comprises from approx. 1 - 40% by weight, better still between approx. 5 to approx. 30% by weight of egg pholipids. This practice is specifically designed to provide long-chain PUFAs selected from n-3 fatty acid and n-6 fatty acid, pholipids and / or choline in amounts beneficial to infants.

Elaboration process Because the egg yolks include both triglycerides and phosphatides, it may be preferable to process the egg yolks using organic solvents in a manner that separates the phosphatides from the triglycerides, from the sterols (e.g., cholesterol) and from other components. Several methods found in the literature are appropriate for this separation, at least on a laboratory scale. Alternatively, such egg phosphatides essentially free of cholesterol are commercially available in the form of dehydrated powders, for example those produced by Pfanstiehl, Inc. (Waukegan, IL) with Catalog Number P-123. The egg phosphatide is then incorporated into the enteral composition of the present invention. Due to the lipid content, the incorporation of egg phosphatides into an enteral formula would be expected to be easy in an oil phase. However, it has surprisingly been found that these lipid-lipid dispersions are unacceptable and that the preparation of an aqueous dispersion of the egg phosphatide results in an improved product. The aqueous dispersions from approx. 2 - 15% by weight, preferably 3-8% by weight, should be carried out cold and up to the ambient water temperature (20-25 ° C) in order to obtain better results. Higher temperatures result in less acceptable organoleptic properties. Pasty mixtures corresponding to carbohydrate, protein and lipids comprising the source of macronutrients are prepared separately, in the manner known in this field of industry, and these pasty mixtures are combined by mixing between ca. 130 to 140 ° C. Just before homogenization, the dispersion of phosphatides is mixed with the rest of the ingredients of the formula. In a particularly preferred variation, before the addition of the phosphatide dispersion to the final product mixture (just before homogenization) the phosphatide dispersion is de-aerated (the air is removed) using a moderate vacuum. The deaeration can be carried out by any mechanism but a spray deaerator of approx. 15 inches of Hg (38.1 mm Hg) provides satisfactory results. This additional step has been shown to improve the organoleptic and olfactory properties of the final product, even more than can be achieved with the filtration on activated charcoal or by combination of the two methods (see Example III). To make the parenteral compositions useful for the purposes of the present invention, conventional sterile parenteral product production technology can be used. It may be preferable in this case to avoid the use of the egg phosphatides and instead use triglyceride oils or fatty acid esters, such as those which can be found in recombinant sources or in the oils of unicellular organisms.

Industrial Utility The compositions of the present invention are useful in the nutritional sustenance of infants or adults The addition of long chain PUFAs, especially n-6 and n-3 fatty acids, and more specifically AA and ADH, has generally been considered as beneficial for neural development and visual acuity of infants, although there is a conflict in some studies reported in the literature. The compositions useful in the present invention include one or all of the following constituents: (a) Long chain PUFAs selected from n-6 and n-3 fatty acids, typically in the form of phospholipids 6 of phosphatidylcholine; (b) polar phospholipids, regardless of the nature or length of the bound fatty acids; (c) choline, preferably phosphatidylcholine. For example, the fortified formula in egg phospholipids described in detail in the Examples, provide higher levels of each of the specific components, and surprisingly it was found that they substantially reduce the incidence of NEC in child populations susceptible to developing this disease. In a more specific practice, the method for reducing the incidence of NEC is carried out through the administration of arachidonic acid (AA, 20: 4 n-6) or, better still, AA in combination with docosahexaenoic acid (ADH, 22: 6 n-3). In broader terms, this aspect of the invention contemplates a method for reducing the incidence of necrotizing enterocolitis in an infant which is susceptible to contracting necrotizing enterocolitis, wherein said method comprises the administration of an effective amount of at least one PUFAs. of long chain selected from the group consisting of C2o n-6 fatty acids, C22 n-6 fatty acids, C2o n-3 fatty acids and C22 n-3 fatty acids. The administration is carried out at a level of at least 1.0 mg of n-3 fatty acid per kilogram of infant body weight / day. A more preferred practice is one which uses a combination of n-6 and n-3 fatty acids in weight proportions ranging from ca. 2: 1 to about 4: 1. A further method for decreasing the occurrence of necrotizing enterocolitis in a human infant is also disclosed, wherein said method comprises administering to the infant phospholipid from the egg in an amount that results in the administration of at least 1.0 mg. of long chain fatty acid n-6 per day. Preferably, the egg phospholipids supply AA as a significant portion of n-6 fatty acids and preferably also provide ADH and other long chain n-3 fatty acids in the aforementioned proportions. A further aspect of the present invention of the present invention relates to administration by whole route! to humans of phospholipids, especially phospholipids containing AA and / or ADH which easily increase serum blood levels of AA and ADH fatty acids in humans, compared to compositions having triglycerides of AA and ADH. A more appropriate measure of the administration of compositions according to the present invention corresponds to the daily intake in mg per kg of body weight of the infant. The following table A provides the guidelines on preferred ideal target ranges provided for each of the useful compositions of the present invention.

Table A - Guidelines for Recommended Daily Intake (based on infant weight in kg) Preferred minimum component most preferred ideal goal AA, mg 1 2 - 60 50 - 40 10 - 30 ADH, mg 0.25 0.5 - 35 1.5 - 20 3 - 15 ratio AA / ADH 0.25 0.5 - 10 1 - 8 2 - 4 phospholipid, μmol 50 60 - 2400 200 - 1500 400 - 1000 hill, μmol 50 60 - 1800 150 - 1200 300 - 900 There is a wide variation in ranges due largely to the fact that not all infants that are likely to benefit from the compositions of the present invention will consume equal volumes of formula. Those who consume less will, of course, receive less of each ingredient. It is assumed that for the case of ideal target ranges, approx. 100 kilocalories. Also, there is controversy about methods for estimating choline content. As can be seen in Table A, it is most preferable that there is 2-4 times more AA than ADH. It can also be observed that the minimum levels of phospholipids and hills are almost identical. This can be achieved by supplying all phospholipids as a phosphatidylcholine. To the extent that other nitrogen alcohols replace choline, (e.g., ethanolamine, serine or inositol) the relative amount of choline relative to total phospholipids decreases. The AA and / or the ADH can be administered individually, in the form of separate or combined components, or together, or in combination with other ingredients such as proteins, lipids, vitamins, and carbohydrates. Nutritional support for infants with low birth weight can be treated either from a parenteral (intravenous feeding) or an enteral feeding. Accordingly, appropriate levels of long chain PUFA can be incorporated into the parenteral nutrition solution or added to an enteral formula according to birth weight. Better still, the method of the present invention is accomplished through the administration of an enteric solution of an infant formula designed for low birth weight infants containing AA and ADH. Such formula for infants also includes appropriate levels of carbohydrates and proteins and an appropriate combination of minerals and vitamins. An infant formula that serves as an example for the purposes of the methods of the present invention corresponds to the modified Similac Special Care® formula (Ross Products Division of Abbott Laboratories, Columbus, Ohio), which will be discussed in more detail in Example II. In yet another aspect of the present invention, there is provided a method for increasing blood serum levels of arachidonic acid and docosahexaenoic acid in human blood serum, wherein said method comprises the step of administering to said human an enteral formula containing AA and ADH in the form of phospholipids. Recent studies carried out by the applicants of the present invention have indicated that the administration of long chain PUFAs to infants susceptible to contract NEC will reduce the incidence rate of NEC and may also reduce the level of severity of said disease. Applicants have also discovered that such administration of phospholipids obtained from plant or animal sources, also be effective in reducing the incidence of NEC in populations of infants susceptible to developing NEC.

EXAMPLE I Phosphatide from the egg yolk was obtained from Pfanstiehl, Inc. (Waukegan, IL) with Catalog Number P-123, which was used in the following Examples. The fatty acid and cholesterol profile of this egg phosphatide is shown in Table I. The totals of all the "long chain" AGPls n-3 and n-6 are also given in the Table.

TABLE 1: Fatty Acid Profile and Cholesterol Content of Egg Yolk Lecithin.

Fatty acid g / 1 Sample OOg C14: 0 0.08 C16: 0 18.83 C16: 1 n-7 0.82 C16: 4 0.21 C18: 0. 6.72 C18: 1 n-9 17, 36 C18: 2 n-6 9.8 C20: 1 n-9 0.11 C20: 2 n-6 0.24 C20: 3 n-6 0.3 C20: 4 n-6 Arachidonic 4.93 C22: 0 0.07 C22: 4 n-6 0.3 C22: 5 n-6 1.45 C22: 5 n-3 0 09 C22: 6 n-6 docosahexaenoic 1 24 Colest erol < 0.05 Total? Long-chain GPIs n-6 7.22 Total long-chain GPIs n-3 1 33 Those experts in this field of industry will appreciate that specific levels of the different fatty acids contained in the yolk lipid will vary depending on the diet, diet, and age of the hen. On the other hand, the extraction procedure used by Pfanstiehl to prepare the phosphatide used in the Examples, results in a material containing extremely low cholesterol levels, while at the same time possessing a fatty acid profile which is highly useful in the field of nutritional products.

EXAMPLE II In this example, the formulas "Experimental" and "Control" for feeding infants were prepared respectively with and without the egg phosphatide of Example I. The Control composition corresponded to the formula Similac Special Care® (Ross Products Division of Abbott Laboratories , Columbus Ohio) and was prepared using the following list of ingredients which resulted in the formula having the composition set forth in Tables ll-IV, which are presented below: Water (Kosher), fat-free milk, starch, hydrolyzed corn, lactose, fractionated coconut oil (medium chain triglycerides), whey protein concentrate, soybean oil, coconut oil, tribasic calcium phosphate, potassium citrate, sodium citrate, magnesium chloride, ascorbic acid, mono- and diglycerides, soy lecithin, calcium carbonate, carragaen gum, choline chloride, ferrous sulfate, m-inositol, taurine, niacinamide, L-carnitine. alpha-tocopherol acetate, zinc sulfate, calcium pantothenate, potassium chloride, cupric sulfate, riboflavin, and vitamin A palmitate, thiamine chloride hydrochloride, pyridoxine hydrochloride, biotin, folic acid, manganese sulfate, phyloquinone, Vitamin D3l sodium selenite and cyanocobalamin. Generally, pasty mixtures of the protein, carbohydrate, lipid, vitamins and minerals are prepared separately, and then these are mixed in turn before homogenization, as is generally disclosed in the aforementioned patents in the manner of reference, in relation to the manufacture of formulas for infants. In the Experimental formula, the egg phosphatide, of Example I, was incorporated into this formula during its manufacture. First, the egg phosphatide was dispersed in water at 25 ° C in order to prepare an 8% dispersion. Just before homogenization, the dispersion of the phosphatide was combined with the mixtures of protein, carbohydrate, vitamin, mineral and other mixtures of lipids, whereby the "Experimental" formula having the composition illustrated in Table II-IV was obtained. , presented later. The quantities of each component are expressed both "per liter" and "per kilocalories" because it is known in this industry field the preparation of formulas for infants with higher or lower caloric densities than the norm or standard of 20 kilocalories per fluid ounce. (0.677 kcal / ml, 677 kcal / liter).

TABLE II: Components of the "Control" and "Experimental" Formulas A contribution of 24 kcal per fluid ounce is assumed (approximately 812 kcal / liter) Table III establishes the lipid content (the only variable) used in the Control products. and Experimental. It can be seen that the two formulas have the same amount of total lipids but differ mainly in the change of egg phospholipids by a portion of medium chain triglycerides. Substitution leads significantly to higher levels of phospholipids and choline as well as the presence of additional long chain PUFAs.

TABLE III: Lipids in the "Control" and "Experimental" Formulas TCM = fractionated medium chain triglycerides ND = not detected Table IV establishes the composition of the fatty acid profile for the Control and Experimental formulas. This represents the sum of the fatty acid components of egg lecithin and the Similac Special Care® formula.

TABLE IV: Average Profiles of Fatty Acids (% by weight) Fatty acid Formula Control Formula Ex. 6: 0 - caproic 0.71 0.27 8: 0 - caprylic 30.56 23.11 10: 0 - capric 19.61 16.44 12: 0 - lauric 9.69 10.24 14: 0 - myristic 3 , 85 4.08 15: 0 and 14: 1 0.04 0.01 16: 0 - palmitoleic 5.51 7.65 16: 1 - palmitoleic 0.03 0.12 16: 2 - - 17: 0 - margaric 0.04 0.09 16; 3 - - 16: 4 - - 18: 0 - stearic 2.68 3.89 18: 1 n-9-oleic 8.31 11, 25 18: 2 n-6-linoleic 16 , 36 18.87 18: 3 n-6 - linoleic 2,3 - 18: 3 n-3 2,24, 2,45 18: 4 n-6 - 0,02 : 0 - arachidic 0.12 0.14 20: 1 n-9 0.04 0.09 20: 2 n-9 0.02 0.02 20: 3 n-9 - 0.05 20: 4 n- 6 - AA - 0.41 : 4 n-3 - - 20: 5 n-3 - - 20: 0 - behenic 0.07 0.12 22: 5 n-6 - 0.07 22: 5 n-3 - 0.07 22: 6 n-3 - ADH - 0.14 24: 0 0.04 0.07 Total Long chain PUFAs n-3 0.21 Total long chain PUFAs n- 6 0 0,48 Total n-3 2,24 2,66 Total n-6 18,66 19,37 The inclusion of the egg phosphatide gave 0.21% by weight of the total lipid mixture, as long-chain fatty acids n-3; and 0.48% by weight as long chain acids n-6. More specifically, 0.14 weight percent of the total fat blend was ADH and 0.41 of the total lipid mixture was AA. Based on the administration of 100 kcal / kg / day for an infant weighing 1 kg, this formula provides approx. 22 mg of AA and approx. 7 mg of ADH per day. Of course, this is hardly a possible practice of the proportions that may fit within the present invention.

EXAMPLE III In this experiment, the process variables were evaluated in an effort to reduce the obstacles or organoleptic impediments associated with the use of egg phospholipids. The isolation of the egg phospholipids useful in the present invention often results in an egg phosphatide which possesses certain organoleptic properties in some way susceptible to objections in a formula for use by infants. These can be solved, however, by providing a product that is not objectionable both by the infant and by the person in charge of caring for the baby. The process to improve the final product in this regard is described below. A number of nutritional formulas similar to that of Example II were prepared except that 6% by weight of the fat mixture corresponded to the egg phospholipid which was subjected to pre-treatment using various methods. The egg phospholipid was dispersed in a portion of the oil mixture described in Example II or in a portion of the water. Oily dispersions were unacceptable and could not be used even after heating to approx. 95 ° C. The dispersion of the phospholipid within the water at a temperature from room temperature to the heating temperature was easily performed and is the preferred means for forming the dispersion in water. A master batch of a dispersion of phospholipids from the egg 3% by weight was prepared by mixing them in water at 90 ° C for approx. 1 hour. A portion of this dispersion was passed through: (1) a single deaerator; (2) a filter unit on activated carbon alone; (3) a combined deaerator and filtration unit on activated carbon; or (4) without treatment. The activated carbon filtration unit contained 80 g of activated carbon and the deaeration unit was operated at a moderate vacuum (15 inches Hg [38.10 mm Hg]). Lot portions were passed through the filtration unit three times, and only once through the deaerator. When both techniques were used, said portion was first passed through the filter, and then through the deaerator. The treated portions were then added to the respective nutritional formulas just before the homogenization and packing of the samples.

Samples were initially evaluated in terms of "flavor appreciations" (organoleptic properties) by a panel of trained assessors. The results of the panel are presented, in Table V: Table V: Formula for Infants with Egg Yolk Phospholipids Results of Organoleptic Quality Appreciations of the aroma 'Treatment of AA Initial Dispersion AAL at three months Single Deaeration AA 1 -2, 5 AAL 2.5 Single Carbon Filter AA 1.5-2 AAL 2.5 Deaeration + Carbon filtration AA 2 AAL 2,5 No treatment AA 2,5-3 AAL 3 * Appreciations of aroma: AA = a arachidonic acid AAL = permanence of the aroma of arachidonic acid + Scale: 0.5 = very slight; 1 = mild; 1,5 = from mild to moderate; 2 = moderate; 2.5 from moderate to strong; 3 strong. Surprisingly, the least aromatic sample was that containing the dispersion that was passed only through the deaerator. The dispersion that passed through the deaerator and the carbon filter was rated with a bad score, with the exception of the control (No treatment of the phospholipid dispersion).

EXAMPLE IV Formulas were prepared according to the procedure of Examples II and III which were delivered to infants in a study conducted at the Neonatal Nursery of the University of Tennessee Newborn Center under the direction of Dr. Susan E. Carlson with financial support from Ross Products Division. of Abbott Laboratories (Study AE78), assignment of the NICHD: R01-HD31329, and assignment of the National Eye Institute: R01.-EY08770. The investigative parameters included growth, neural development, and visual acuity. It is believed that long-chain PUFAs are physiologically important for brain development and sense of sight, and rapidly accumulate in fetal tissues by the last trimester of pregnancy. Therefore, premature infants fail to accumulate normal levels of such long-chain PUFAs compared to infants born at term. Inclusion Criteria: The criteria for inclusion in this clinical study were based on a "low" birth weight of less than 1500 g (range: 750-1375) with no evidence of heart, respiratory, gastrointestinal or other systemic disease. The infant should also not exhibit a history of asphyxia or clinical complications related to blood group incompatibility at the time of birth. Mothers of children accepted in the study should not have a medical history of prenatal infections with proven adverse effects on the fetus.

Substance abuse by the mother was also an exclusion criterion. All infants were given oral feeding by day seven after birth. During the clinical study, a total of 120 infants with ages within the first seven days of birth were accepted. With the exception of one infant who was transferred to another hospital shortly after being included in the study (Control), all other infants (n = 119) were cared for within the same hospital. Infants were divided (blind, randomized) into groups, where two of these groups received the Control formula during their hospitalization and the other group received the Experimental formula (see Example II). Infants lost during hospitalization were replaced by others who were assigned to the same treatment group. Due to the design characteristics of the study, more infants were fed the Control formula. The total number of fed with the Control formula was more than double the number of fed with the Experimental formula. Findings: One finding, not anticipated, was the observation of a very high incidence of necrotizing enterocolitis (NEC) in the Control Groups compared to the Experimental Group. Table VI groups the total number of neonates according to treatment (Control Vs Experimental) and shows that the number of neonates in each group that developed NEC. The presence or signs of NEC were considered when the signs and symptoms consistent with this disease, such as abdominal distension, gastric debris, bilious vomit, hemopositive fecal material, presence of mucus in the stool, and the presence of C-reactive protein with a value >0.5 mg / dL (Pourcyrous et al., "Significance of Serial C-reactive Protein Responses in Neonatal Infection and Other Diseases", Pediatr., 1993, 92: 431-435). The ECN was confirmed in 15 of the Control infants and only in 1 of the Experimental group.

TABLE VI: Results of the Clinical Study Experimental Control ECN * 15 1 without ECN 70 33 TOTAL 85 34 or with ECN indications Statistical analysis of these data, using Fisher's exact test (two-tailed), shows that the number of infants with confirmed NEC in the Control treatment groups was significantly higher (p = 0.039) than the number of infants in the group of Experimental treatment that presented ECN.

EXAMPLE V The inclusion of AA and ADH within the administration of parenteral nutrition (intravenous feeding) is evaluated in this experiment. The parenteral solution may contain the various components known in the art, wherein AA and ADH are supplied in the form of phospholipids, triglycerides or methyl esters. AA and ADH may be the only active ingredients blended with conventional parenteral vehicles or excipients or, better yet, AA and ADH are included in a parenteral formula designed to supplement the infant's total nutritional support. . Typical parenteral solutions contain lipid levels that provide approx. 2 g / kg / day. The level of AA and ADH in the lipid mixture should preferably result in the administration of 10-30 mg / kg / day of AA and 3-15 mg / kg / day of ADH EXAMPLE VI In this experiment, the egg lecithin of the experimental formula of Example II was replaced by soy lecithin at approx. ten times higher than those found in the Control formula. Soy lecithin, like other phospholipids obtained from natural sources, does not contain long-chain polyunsaturated acids, however, the polar nature of the phospholipids and their ability to be easily incorporated into the intestinal mucosa, can produce an effect protector on the intestinal lining, in this way to produce results comparable to those exhibited by the experimental formula of Example II. Additionally, soy lecithin contains linoleic acid (18: 2n-6 - a precursor of essential fatty acids in the diet, and of course AA precursor) and linolenic acid (18: 3n-3 - a precursor of essential fatty acids in diet, and ADH).

EXAMPLE VII In this experiment, the use of phospholipids containing AA and ADH in an infant formula was compared with the use of triglycerides containing AA and ADH. The formula of Example II was compared to a similar formula for infants wherein the egg phospholipid is replaced by a mixture of triglycerides obtained from unicellular organisms containing comparable levels of AA and ADH. Healthy infants born at term were included in a clinical evaluation to measure blood serum levels of AA and ADH after enteric administration. It is expected that infants fed the formula with phospholipids reach blood serum levels of AA and ADH as closely as those infants fed with breast milk, compared to those that can be achieved with the Control formula containing AA and ADH in the form of triglycerides. This experiment could demonstrate that phospholipids containing AA and ADH correspond to a preferred form of administration, versus triglycerides containing AA and ADH. Accordingly, improved enteral formulas and methods for increasing blood serum levels of AA and ADH are contemplated within the scope of the present invention. Those skilled in the field of industry can observe how, through the above-described description of the invention, modifications and alternative practices of the compositions and methods of the present invention can be made. Consequently, this description should only be considered as illustrative and has the purpose of revealing to experts in this field how to carry them out. In the claims that are set forth below, the scope of the present invention will be defined.

Claims (39)

1. A method for reducing the incidence of necrotizing enterocolitis in an infant, wherein said method comprises administering to an infant susceptible to contracting necrotizing enterocolitis an effective amount of at least one n-6 polyunsaturated fatty acid.

2. The method according to claim 1, wherein said n-6 polyunsaturated fatty acid includes arachidonic acid.

3. The method according to claim 2, wherein said administration is carried out enterally.

4. The method according to claim 2, wherein said administration is carried out parenterai.

The method according to claim 1, wherein said n-6 polyunsaturated fatty acid is administered in combination with at least one n-3 polyunsaturated fatty acid.

6. The method according to claim 5, wherein said n-3 polyunsaturated fatty acid comprises docosahexaenoic acid.

The method according to claim 5, wherein said n-6 polyunsaturated fatty acid comprises arachidonic acid and said n-3 polyunsaturated fatty acid comprises docosahexaenoic acid.

The method according to claim 7, wherein said administration is carried out by feeding the infant with a sufficient amount of an enteric composition containing arachidonic acid and docosahexaenoic acid in order to provide said infant approximately from 1.0 and 60 mg per kg body weight / day of arachidonic acid, and from ca. 0.25 to 35 mg per kg of body weight / day of docosahexaenoic acid.

9. The method according to claim 8, wherein the weight ratio between arachidonic and docosahexaenoic acid ranges from about 2 to 4.

The method according to claim 5, wherein said n-6 polyunsaturated fatty acid comprises arachidonic acid. and said n-3 polyunsaturated fatty acid correspond to long chain fatty acids independently selected from one or more sources selected from the group consisting of egg lecithin, oils extracted from fungi, oils extracted from algae and oils extracted from marine products.

The method according to claim 5, wherein said n-6 polyunsaturated fatty acid and said n-3 polyunsaturated fatty acid are in the form of phospholipids.

The method according to claim 4, wherein said parenteral solution comprises at least 20 mg of arachidonic acid per liter and at least 10 mg of docosahexaenoic acid per liter.

The method according to claim 12, wherein said solution comprises approximately 20-200 mg of arachidonic acid per liter and approx. of 10 - 50 mg of docosahexaenoic acid per liter.

The method according to claim 1, which comprises feeding said infant with a sufficient amount of an enteral nutrition composition containing protein, carbohydrate and phospholipids to provide at least 2.0 mg of polyunsaturated fatty acids n- 6 per kg of body weight per day.

The method according to claim 14, wherein said feed additionally provides at least 0.5 mg of n-3 polyunsaturated fatty acids per kg of body weight per day.

16. The method according to claim 15, wherein said feed additionally provides at least 2.0 mg of arachidonic acid and at least 0.5 mg of docosahexaenoic acid.

17. The method according to claim 16, wherein said enteric composition comprises egg phospholipids.

18. A method for reducing the incidence of necrotizing enterocolitis in an infant, wherein said method comprises administering an effective daily amount of phospholipids to an infant susceptible to contracting necrotizing enterocolitis.

19. The method according to claim 18, which comprises administering a sufficient amount of said nutritional composition in order to provide approximately 60-2,400 pmoles of phospholipids per kg of body weight per day.

20. The method according to claim 19, which comprises the administration of a sufficient amount of said nutritional composition in order to provide approximately 200-1,500 μmol of phospholipids per kg of body weight per day.

21. The method according to claim 18, wherein said phospholipids are obtained from egg lecithin.

22. The method according to claim 19, wherein said phospholipids are administered in combination with one or more polyunsaturated fatty acids selected from the group consisting of arachidonic acid and docosahexaenoic acid.

23. The method according to claim 22, wherein said phospholipids are administered in combination with arachidonic acid and docosahexaenoic acid in order to provide approximately between 200 and 1500 pmol of phospholipid.; from approx. 5.0 mg to 40 mg of arachidonic acid; and from approx. 1.5 mg - 20 mg of docosahexaenoic acid per kg of body weight per day.

24. A method for reducing the incidence of necrotising enterocolitis in an infant, wherein said method comprises administering an effective daily amount of choline to an infant susceptible to contracting necrotizing enterocolitis.

25. The method according to claim 24, which comprises the administration of a nutritional composition containing choline in an amount sufficient to provide approx. between 60 and 1800 mole of choline per kg of body weight per day.

26. The method according to claim 25, which comprises the administration of a sufficient amount of said nutritional composition so as to provide approximately 150-1,200 mole of choline per kg of body weight per day.

27. The method according to claim 24, wherein said choline is in the form of phosphatidylcholine.

28. The method according to claim 27, wherein said phosphatidylcholine is obtained from egg lecithin.

29. The method according to claim 25, wherein said choline is administered in combination with one or more polyunsaturated fatty acids selected from the group consisting of arachidonic acid and docosahexaenoic acid.

30. The method according to claim 29, wherein said choline is administered in combination with arachidonic acid and docosahexaenoic acid in order to provide approximately between 150 and 1200 μmol of choline; from approx. 5.0 mg to 40 mg of arachidonic acid; and from approx. 1.5 mg - 20 mg of docosahexaenoic acid per kg of body weight per day.

31. A process for the production of a formula for enteral feeding comprising egg phospholipids, wherein said process comprises the steps of: (a) supplying powder of the dehydrated egg phosphatide essentially free of cholesterol, (b) dispersion of said fraction of phospholipids in an aqueous phase so as to form a phospholipid dispersion; and (c) combining said phospholipid dispersion with the pasty mixtures of the other components of said formula for enteral feeding.

32. The process according to claim 31, wherein said aqueous phase dispersion provides egg phosphatides in a weight percent approx. between 2 and 15%.

33. The process according to claim 32, wherein the preparation of said dispersion in aqueous phase comprises the addition of the egg phosphatide powder to the water at approx. 20 - 50 ° C.

34. An improved formula for enteral feeding containing arachidonic acid and docosahexaenoic acid, wherein said arachidonic and docosahexaenoic acids are in the form of phospholipids, wherein said enteral feeding formula is prepared through a process comprising the steps of (a) formation of an aqueous dispersion at 2 - 15% by weight with said phospholipids; (b) subjecting said dispersion to a deaeration process; (c) combining said deaerated dispersion with at least one component selected from the group consisting of protein, carbohydrate, vitamins and minerals, in order to form said enteric formula; (d) homogenization of said enteric formula.

35. An improved formula suitable for infant feeding, which comprises protein, carbohydrates and lipids, wherein the improvement is characterized in that the lipid mixture comprises medium chain triglycerides and egg phospholipids, wherein said egg phospholipids are they find in a proportion located between approx. 1-40% by weight of the lipid mixture, and wherein said egg phospholipids are essentially free of cholesterol.

36. The formula according to claim 35, wherein the egg phospholipids are present in a proportion between 5 - 30% or of the lipid mixture.

37. The formula according to claim 35, which additionally comprises arachidonic acid in a concentration situated between ca. 10 - 31 mg per 100 kcal.

38. The formula according to claim 37, which additionally comprises docosahexaenoic acid in a concentration situated between ca. 3 - 16 mg per 100 kcal.

39. The formula according to claim 38, wherein said arachidonic acid and said docosahexaenoic acid are present in a weight ratio between 4: 1 and 2: 1.