HK1189461A - Compositions and methods for nutrient delivery - Google Patents

Description

Compositions and methods for nutrient delivery

Technical Field

The present disclosure relates to improved enteral nutritional compositions comprising docosahexaenoic acid (DHA) and arachidonic acid (ARA), and methods for providing nutritional support in the form of a stabilized emulsion to a population of subjects suffering from nutritional deficiencies, such as preterm infants and/or low birth weight infants. The liquid nutritional compositions of the present disclosure may contain a lipid component containing an emulsion of DHA and/or arachidonic acid (ARA) dispersed in an aqueous component comprising nutrients such as amino acids, vitamins, minerals, and other nutrients or combinations of the foregoing. The nutritional composition may be suitable for enteral delivery by nasogastric tube, intragastric feeding, transpyloric administration, and/or any other mode of administration that results in direct introduction of the nutritional composition into the digestive tract of a subject. In certain embodiments, the nutritional composition is a fortifier suitable for addition to human milk or infant formula for oral feeding.

Background

The present disclosure relates to improved enteral nutritional compositions that address nutritional deficiencies in diseased populations as well as physiological and other consequences often caused by such deficiencies. In particular, the present disclosure addresses nutritional deficiencies that may occur in premature and/or low birth weight infants.

Nutritional support for preterm infants is important because short term survival, long term growth, and development are problematic. When providing nutritional support to preterm infants, important goals include increasing growth rates and adding nutrients to the extent that they are achieved during fetal development, thereby optimizing neurological development outcomes and establishing a firm foundation for long-term health. These goals cannot be readily achieved because severely ill, low birth weight premature infants often cannot tolerate traditional enteral feeding due to concomitant pathological conditions or immaturity of the gut and other organ systems. Therefore, complete parenteral nutrition (TPN) is indicated to be the only or preferred method of providing nutritional support. While TPN can save lives, it is not a perfect way of nutritional support. TPN lacks many key nutrients and its limitations can have long-lasting physiological and developmental consequences for infants.

Low and very low birth weight infants are particularly susceptible to both postnatal growth deficiency and nutrient deficiency. However, TPN does not provide an adequate supply of valuable nutrients such as docosahexaenoic acid and/or arachidonic acid. Thus, many preterm infants are not adequately supplied with DHA and/or ARA.

In healthy subjects consuming a normal diet, which would provide sufficient DHA and ARA, DHA or ARA supplementation is generally not required, as large amounts of ARA and DHA are stored in the human brain and other tissues during intrauterine and postnatal growth (Clandin MT et al, "requisitions of new bones for long chain fermented fruits". Acta Paediata Scan 1989; 351 suppl: 63-71). In fact, the fetus accumulates long-chain polyunsaturated Fatty Acids (LCPUFAs) such as DHA and ARA during the third month after pregnancy because the placenta provides DHA and ARA to the fetus (A. Lapitlone et al, "evaluation of the DHA requirement for the characterization information", prostagladins, Leukotrienes and Essential Fatty Acids 81 (2009) 143-. However, in the case of preterm birth, the infant faces a sudden loss of placental LCPUFA supply. Premature infants are often severely ill and face numerous physiological stresses that can rapidly deplete their available LCPUFA storage, and the resulting LCPUFA deficiency can increase the infant's more immaturity.

Meeting the nutritional needs of preterm infants is problematic due to their gastrointestinal immaturity, poor nutrient storage, and high demand for nutrients to support growth (L.G. Smithers et al, "Effect of two doses of docosahexanoic acid (DHA) in the di et of present in-fant in fant acid status, solutions, Leuktrienes and Essential fant Acids 79 (2008) 141-. However, in severely diseased premature infants, inadequate supply of essential fatty acids and their derivatives appears to cause long-term impairment in visual function and in neurodevelopment (d. Driscoll et al, "Pharmaceutical and Clinical applications of partial lipid accumulation in neurology", Clinical Nutrition (2008) 27, 497-503). The absence of long chain polyunsaturated acids (such as DHA and ARA) in parenteral nutrition and TPN solutions exacerbates these problems.

Indeed, TPN and other parenteral nutritional supplements currently on the market provide only negligible amounts of preformed DHA and ARA at best. DHA is an omega-3-fatty acid and is the most abundant long chain polyunsaturated fatty acid in the brain and retina, which is considered essential for proper brain and vision development in infants. Although there is a metabolic pathway of linolenic acid biosynthesis from the diet, this pathway is bioenergetically unfavorable, and mammals obtain most of their DHA from preformed DHA provided via dietary sources. For infants, the source of DHA is typically human milk; however, DHA is often absent from parenteral formulations provided to preterm infants.

Parenteral preparations also generally do not provide sufficient levels of arachidonic acid. ARA is an omega-6 LCPUFA that plays a major role as a structural lipid associated with phospholipids in blood, liver, muscle, and other major organ systems. ARA is synthesized by elongation and desaturation of linoleic acid. However, most ARA must be provided in the diet. ARA is particularly important in the fast body growth phase and is therefore an important component of infant nutrition.

Many studies have indicated that unfulfilled preterm milk provided to infants will provide insufficient amounts of several nutrients needed to meet the needs of preterm infants (Davis, d.p., "acquired of expressed breast milk for early growth of preterm intants", Archives of diseases in Childhood, 52, page 296, 301, 1997). Although the exact needs vary from infant to infant due to differences in activity, energy expenditure, nutrient absorption efficiency, disease, and the ability to utilize energy for tissue synthesis, currently available parenteral nutrition sources are inadequate.

Furthermore, preterm infants often do not tolerate a feeding volume well and nutrients must be provided in acceptable volumes, often by enteral administration. Suitable methods for enteral feeding of preterm infants are based on gestational age, birth weight, clinical condition and the opinion of the attending medical staff. Specific feeding decisions are made based on the infant's ability to coordinate sucking, swallowing, and breathing. Often, premature or immature, weak or badly ill infants need to be fed through tubes to avoid the risk of aspiration and to conserve energy.

Nasal feeding is commonly used in neonatal intensive care units and can be accomplished by bolus or continuous infusion of fortified human milk or other nutritional supplements. Continuous feeding can be better tolerated by very low birth weight infants as well as infants that previously did not tolerate bolus feeding; however, as discussed previously, reduced or starved nutrient delivery is a problem associated with continuous feeding methods known in the art.

Thus, there is a need for stable nutritional compositions that are well tolerated by preterm infants and which can be readily administered to subjects suffering from nutritional deficiencies in a form and manner that is readily accepted by the subject and by caregivers.

Populations such as premature infants are often subject to nutritional deficiencies because they are provided a diet lacking the above-mentioned key nutrients. Accordingly, there is a need in the art to provide nutritional compositions comprising valuable nutrients (such as DHA and ARA) that support infant development. Thus, the nutritional compositions and methods of the present disclosure provide enteral nutritional support to subjects suffering from nutritional deficiencies in order to promote optimal health and development by delivering important nutrients that are either not present in parenteral nutrition and other infant formulas or are provided in insufficient amounts.

Disclosure of Invention

Thus, briefly, the present disclosure relates to stable nutritional compositions for addressing the problem of nutritional deficiencies in subjects requiring low volume nutritional support (such as preterm infants), and methods of promoting healthy development in those subjects. The present disclosure provides compositions for administering fatty acids (such as DHA and/or ARA) and other nutrients to a subject in order to prevent the development of a nutritional deficiency and/or correct an existing nutritional deficiency by increasing the intake of nutrients (such as omega-3 or omega-6 long chain polyunsaturated acids) by the subject.

In one embodiment, the present disclosure includes a nutritional composition comprising an emulsion of docosahexaenoic acid and/or arachidonic acid.

In another embodiment, the present disclosure includes a method for providing nutritional support to a subject, the method comprising: administering to the subject a nutritional composition comprising an emulsion of docosahexaenoic acid and/or arachidonic acid.

Another embodiment includes a nutritional supplement for fortifying human milk or infant formula suitable for oral administration.

It is to be understood that both the foregoing general description and the following detailed description present embodiments of the disclosure, and are intended to provide an overview or framework for understanding the nature and character of the disclosure as it is claimed. This description is made for the purpose of illustrating the principles and operation of the claimed subject matter. Other and further features and advantages of the present disclosure will be readily apparent to those skilled in the art upon review of the following disclosure.

Detailed Description

The present disclosure provides nutritional compositions and methods for providing nutritional support. The nutritional composition includes a lipid component comprising DHA and ARA, and is suitable for delivery to a subject suffering from a nutritional deficiency, such as a preterm infant. The present disclosure additionally provides improved fortifiers for addition to human milk or infant formulas. The enhancer comprises a stable emulsion of DHA and ARA. The present disclosure additionally provides methods for providing nutritional support to a subject (such as a preterm infant). In the following description, the present disclosure, in its entirety and implementations, are set forth, including their best mode for one of ordinary skill in the art.

Hereinafter, "enteral administration" includes, but is not limited to: feeding via nasogastric tube, orogastric feeding, intragastric feeding, or transpyloric administration. "enteral administration" may also include any other method known in the art for introducing a nutritional composition directly into the digestive tract (other than via oral feeding).

The phrase "nutritional composition" includes nutritional supplements, human milk fortifiers, infant formula fortifiers, and the like, but is not limited thereto. The nutritional compositions of the present disclosure may be suitable for enteral or oral administration.

By "preterm infant" is meant a subject born before 37 weeks gestational age. The phrase "premature infant" is used interchangeably with the phrase "immature infant".

By "low birth weight infant" is meant an infant with a birth weight of less than 2500 grams (about 5 pounds, 8 ounces).

By "very low birth weight infant" is meant an infant with a birth weight of less than 1500 grams (about 3 pounds, 4 ounces).

By "ultra-low birth weight infant" is meant an infant with a birth weight of less than 1000 grams (about 2 pounds, 3 ounces).

"infant" refers to human subjects ranging in age from birth to no more than about 1 year old, including infants from 0 to about 12 months of corrected age. The phrase "corrected age" refers to the chronological age of the infant minus the amount of time the infant was born prematurely. Thus, the corrected age is the age of the infant assumed to be delivered at term. The term infant includes low birth weight infants, very low birth weight infants, ultra low birth weight infants and premature infants.

"emulsion" refers to a mixture of two or more immiscible liquids comprising a dispersed phase and a continuous phase. In an emulsion, one liquid, known as the dispersed phase, is dispersed in another liquid, known as the continuous phase, the bulk phase, or the aqueous component.

By "unit dose" is meant a single package of nutritional composition.

All percentages, parts and ratios used herein are by weight of the total composition, unless otherwise indicated.

The nutritional compositions of the present disclosure may also be substantially free of any optional or selected ingredients described herein, provided that the remaining nutritional composition still contains all of the desired ingredients or features described herein. In this context, and unless otherwise indicated, the term "substantially free" means that the selected composition contains less than a functional amount of the optional ingredient, typically less than 0.1% by weight, and also includes 0% by weight of such optional or selected ingredient.

All references to a single feature or limitation of the disclosure are to include the corresponding plural feature or limitation and vice versa unless otherwise indicated herein or clearly contradicted by context in which the reference is made.

All combinations of methods or method steps used herein can be performed in any order, unless otherwise indicated, or otherwise clearly contradicted by context in which the combination is made.

The methods and compositions of the present disclosure (including components thereof) can comprise, consist of, or consist essentially of the essential elements and limitations of the present disclosure described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in nutritional compositions.

The term "about" as used herein should be interpreted to mean any numerical value specified in a range. Any reference to a range should be taken as providing support to any subset within the range.

The nutritional compositions of the present disclosure may provide nutritional support to preterm and/or low birth weight infants or any other patient with an unmet nutritional need. In certain embodiments, the nutritional compositions are designed to meet the specific nutritional needs of an individual subject (such as an infant or preterm infant) in the form of a stable unit dose liquid composition standardized to a specified enthalpy, and/or as a concentrate to meet the specific nutritional needs of the subject.

In addition, the present disclosure provides a nutritional composition that can be used to combat nutrient deficiencies when providing nutrients to those subjects that rely on partial or complete parenteral nutrition, thereby promoting healthy development of the subject. In fact, the nutritional composition will provide an effective amount of nutrients, such as DHA and/or ARA, which will promote, for example, visual and neurological development in infants.

The present disclosure also provides methods for enteral delivery of nutrients to subjects in need of administration of very small volumes of nutrients. Enteral administration as used herein includes: nasogastric tube feeding, orogastric feeding, intragastric feeding, transpyloric administration, or any other method known in the art to introduce a nutritional composition directly into the digestive tract.

Thus, the present disclosure satisfies the need for any population that may require small volume enteral nutritional support, including, but not limited to, perioperative subjects, subjects with short bowel syndrome, pediatric intensive care subjects, and/or any population of any age that cannot be fully orally fed or is receiving minimal enteral nutritional support or TPN.

In particular, the nutritional compositions of the present disclosure may provide beneficial nutrients to infants that would otherwise be deficient due to various conditions (such as premature birth or trauma). Such nutrients include, but are not limited to, docosahexaenoic acid, arachidonic acid, and any other water soluble or fat soluble nutrient.

In at least one embodiment, the present disclosure relates to a nutritional composition that delivers a small volume of a particular set of nutrients to a subject. The resulting nutritional compositions may be commercially viable and practically useful in critical care settings, including, but not limited to, Neonatal Intensive Care Unit (NICU). In certain embodiments, the nutritional compositions of the present disclosure comprise an enteral nutrient delivery system by which small, precise volumes of the nutritional composition are introduced into the digestive tract of a subject. In certain embodiments, the nutritional composition is delivered in a volumetric dose of at least 0.5 mL. In certain embodiments, the nutritional composition is delivered in a volumetric dose of about 0.7 to about 1.3 mL. In certain embodiments, the nutritional composition is delivered in a volume of about 1 mL. In another embodiment, the nutritional composition may be delivered in a volume of up to about 1.5mL, or up to about 2 mL.

In certain embodiments, the nutritional composition delivers valuable nutrients to preterm infants or infants in a small volume liquid dose of about 1 mL. Although preterm infants are often ill unable to tolerate complete enteral feeding, the nutritional compositions of the present disclosure are designed to be administered as a small volume nutritional supplement that can be administered directly to the infant, for example, via a nasogastric tube in an infant placed within the NICU. Thus, administration of the nutritional compositions of the present disclosure may begin on the first day of post-partum.

Furthermore, the nutritional composition may be administered 1 or 2 times per day or more frequently as determined by a medical professional. Indeed, the nutritional composition may be administered 3 times per day, 4 times per day, or even more frequently as determined by a medical professional. Administration may begin immediately after birth and may continue as long as the subject has nutritional needs. In certain embodiments, the nutritional composition is administered daily to preterm infants up to a time equal to term pregnancy. In other embodiments, the nutritional composition is administered to the subject for an amount of time equal to the time that the patient receives full or partial parenteral nutrition.

The nutritional compositions of the present disclosure may comprise a nutritional supplement, a human milk fortifier, an infant formula fortifier, or any other ingestible nutritional product. Furthermore, the disclosed nutritional compositions may be provided in any form known in the art, such as a powder, gel, suspension, paste, solid, liquid concentrate, reconstitutable milk powder substitute, or ready-to-use product. In certain embodiments, the nutritional composition is a liquid nutritional supplement suitable for enteral administration. In other embodiments, the nutritional composition is a liquid fortifier that can be readily mixed with human milk or infant formula.

The nutritional composition may include a lipid component containing a fat or a combination of fats to deliver a desired blend of fatty acids to a subject. The fat or lipid source suitable for practicing the present disclosure may comprise any lipid source known in the art, including, but not limited to, animal sources, e.g., milk fat (milk fat), butter, milk fat (butter fat), egg yolk lipids; marine sources such as fish oil, marine oil, single cell oil; vegetable and vegetable oils such as corn oil, canola oil, sunflower oil, soybean oil, palm olein (palmolein), coconut oil, high oleic sunflower oil, evening primrose oil, rapeseed oil, olive oil, linseed oil, cottonseed oil, high oleic safflower oil, palm stearin, soybean lecithin, palm kernel oil, wheat germ oil, medium chain triglyceride oil.

In certain embodiments, the lipid component of the nutritional composition comprises a single fatty acid, such as a long chain polyunsaturated fatty acid (LCPUFA), or a combination of LCPUFAs. LCPUFAs typically have a carbon chain length of at least 18. LCPUFAs suitable for inclusion in the nutritional compositions include, but are not limited to, omega-3 or omega-6 long chain polyunsaturated acids such as arachidonic acid (20: 4 n-6) and docosahexaenoic acid (22: 6 n-3). In one embodiment, the lipid component comprises DHA. In other embodiments, the lipid component of the nutritional composition comprises DHA and ARA. Preferred forms of DHA and ARA incorporated in the nutritional composition are free, unesterified DHA and ARA.

All or part of the lipid component may constitute a lipid emulsion. In certain embodiments, the lipid component may comprise from about 2.5 to about 5 g/100 mL of the nutritional composition. In certain embodiments, the nutritional composition may comprise from about 5 to about 20% w/w lipid component.

The present disclosure describes such compositions and methods: it is used to deliver lipid emulsions with different oil compositions to preterm infants in order to meet their essential fatty acid requirements and energy needs. The general illness and immature organs of premature infants, as well as the reduced endogenous supply of essential fatty acids, require the administration of lipid emulsions immediately after birth. In certain embodiments, the present disclosure teaches a non-pharmaceutical nutritional composition comprising LCPUFA delivered in a lipid emulsion, preferably preformed DHA and ARA. Thus, the nutritional composition meets unmet nutritional needs and will support optimal growth and development of preterm infants.

In certain embodiments, the lipid component of the nutritional composition may comprise DHA in an amount of about 0.3w/w% to about 5 w/w%. In a specific embodiment, the lipid component comprises at least about 0.32% DHA. In other embodiments, the lipid component comprises at least about 0.5% DHA. In certain embodiments, the lipid component comprises at least about 1% DHA. In other embodiments, the lipid component comprises at least about 1.5% DHA. In other embodiments, the lipid component of the nutritional composition comprises at least about 2% DHA. The source of DHA can be any source known in the art, for example, marine oils, fish oils, single cell bio-oils, egg yolk lipids, and brain lipids. The DHA may be in a natural or purified form. Furthermore, in an embodiment, the nutritional composition comprises a source of DHA comprising DHASCO @and/or a fungal oil blend.

Likewise, in certain embodiments, the nutritional composition may be formulated to deliver at least about 25 mg/kg/day of docosahexaenoic acid to the subject. In certain embodiments, the nutritional composition may be formulated to deliver at least about 50 mg/kg/day of DHA. In other embodiments, the nutritional composition may deliver at least about 60 mg/kg/day of DHA to the subject. And in certain embodiments, the nutritional composition may be formulated to deliver at least about 75 mg/kg/day of docosahexaenoic acid to the subject. In other embodiments, the nutritional composition is formulated to deliver at least about 100 mg/kg/day of DHA. Thus, then, since many preterm infants weigh between about 500 g and 2000 g, the nutritional composition may be formulated to deliver, for example, about 12 mg to 200 mg DHA per day. In certain embodiments, the nutritional composition comprises from about 12 to about 200 mg DHA/100 mL.

The lipid component of the nutritional composition may comprise about 0.5w/w% to about 5w/w% ARA. In one embodiment, the lipid component comprises at least about 0.64% ARA. In other embodiments, the lipid component comprises at least about 0.5% ARA. In certain embodiments, the lipid component comprises at least about 1% ARA. In other embodiments, the lipid component comprises at least about 1.5% ARA. In other embodiments, the lipid component of the nutritional composition comprises at least about 2% ARA. The ARA source may be any ARA source known in the art. In certain embodiments, the nutritional composition comprises a source of ARA comprising ARASCO @and/or a blend of fungal oil. In certain embodiments, the ARA component of the nutritional supplement comprises about 30% of the fungal oil blend.

The nutritional composition may be formulated to deliver at least about 10 mg/kg/day arachidonic acid to a subject. In certain embodiments, the nutritional composition may be formulated to deliver at least about 15 mg/kg/day of arachidonic acid to a subject. In certain embodiments, the nutritional composition may be formulated to deliver at least about 25 mg/kg/day arachidonic acid to a subject. In certain embodiments, the nutritional composition may be formulated to deliver at least about 40 mg/kg/day of ARA. In other embodiments, the nutritional composition may deliver at least about 50 mg/kg/day of ARA to the subject. And in certain embodiments, the nutritional composition may be formulated to deliver at least about 60 mg/kg/day of ARA to the subject. Thus, then, since many preterm infants weigh between about 500 g and 2000 g, the nutritional composition may be formulated to deliver, for example, about 12 mg to 120 mg ARA per day.

The nutritional composition may be supplemented with DHA and ARA as part of the lipid component. In certain embodiments, the ratio of DHA to ARA is between about 1:6 and 6: 1. In other embodiments, the ratio of DHA to ARA is between about 1:2 and 2: 1. In other embodiments, the ratio of DHA to ARA is about 1: 1. In other embodiments, the ratio of DHA to ARA may be from about 3:1 to about 1: 9.

In certain embodiments, the nutritional composition further comprises a protein component. The protein component may include, but is not limited to, milk protein powder, milk protein concentrate, milk protein isolate, skim milk solids, skim milk powder, whey protein isolate, whey protein concentrate, sweet whey, acid whey, casein, acid casein, caseinate (e.g., sodium caseinate, sodium calcium caseinate, calcium caseinate), and any combination thereof.

In one embodiment, the protein is provided as an intact protein. In other embodiments, the protein is provided as a combination of both intact protein and partially hydrolyzed protein (degree of hydrolysis between about 4% and 10%). In certain other embodiments, the protein is more completely hydrolyzed. In another embodiment, the protein source may be supplemented with a glutamine-containing peptide.

In certain embodiments, the nutritional composition comprises a carbohydrate component. Depending on the usage, the carbohydrate used in the nutritional composition may be any digestible carbohydrate, such as glucose, fructose, sucrose, maltose, maltodextrin, corn syrup solids, or mixtures thereof. Hydrolysed or partially hydrolysed proteins and/or carbohydrates may be desirable due to their easy digestibility. Furthermore, the nutritional composition may contain other nitrogen sources in addition to the identified amino acids and proteins.

The nutritional composition may include vitamins and mineral components. The vitamins and mineral components may optionally include, but are not limited to, one or more of the following minerals or derivatives thereof: boron, calcium acetate, calcium gluconate, calcium chloride, calcium lactate, calcium phosphate, calcium sulfate, chloride, Chromium chloride, Chromium picolinate (Chromium picolinate), copper sulfate (copper sulfate), copper gluconate, copper sulfate (copper sulfate), fluoride, iron, carbonyl iron, ferric iron, ferrous fumarate, ferric orthophosphate, iron triturate, polysaccharide iron, iodide, iodine, magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium stearate, magnesium sulfate, manganese, molybdenum, phosphorus, potassium phosphate, potassium iodide, potassium chloride, potassium acetate, selenium, sulfur, sodium, docusate sodium, sodium chloride, sodium selenate, sodium molybdate, zinc oxide, zinc sulfate, and mixtures thereof. Non-limiting exemplary derivatives of the mineral compound include salts, basic salts, esters, and chelates of any mineral compound.

The minerals may be added to the nutritional product in the form of salts such as: calcium phosphate, calcium glycerophosphate, sodium citrate, potassium chloride, potassium phosphate, magnesium phosphate, ferrous sulfate, zinc sulfate, copper sulfate, manganese sulfate, and sodium selenite. Other vitamins and minerals may be added as is known in the art.

The vitamin component of the nutritional composition may optionally include, but is not limited to, one or more of the following vitamins or derivatives thereof: vitamin B₁(thiamine, thiamine pyrophosphate, TPP, thiamine triphosphate, TTP, thiamine hydrochloride, thiamine mononitrate), vitamin B₂(riboflavin, flavin mononucleotide, FMN, flavin adenine dinucleotide, FAD, lactoflavin (lactoflavin), Ovoflavin (Ovoflavin)), vitamin B₃(nicotinic acid, nicotinamide (nicotinamide), nicotinamide (niacinamide), nicotinamide adenine dinucleotide, NAD, nicotinic acid mononucleotide, NicMN, pyridine-3-carboxylic acid), vitamin B₃Precursor tryptophan, vitamin B₆(pyridoxine, pyridoxal, pyridoxamine, pyridoxine hydrochloride), pantothenic acid (pantothenate, panthenol), folate (folic acid, folate analogue (folacin), pteroylglutamic acid), vitamin B₁₂(cobalamin, methylcobalamin, desoxyadenosylcobalamin, cyanocobalamin, hydroxycobalamin, adenosylcobalamin), biotin, vitamin C (ascorbic acid), vitamin A (retinol, retinol acetate, retinyl palmitate, retinyl esters with other long chain fatty acids, retinal, retinoic acid, retinol esters), vitamin D (ergocalciferol, cholecalciferol, vitamin D)₃1, 25-dihydroxyvitamin D), vitamin E (alpha-tocopherol, alpha-tocopherol acetate, alpha-tocopherol succinate, alpha-tocopherol nicotinate, gamma-tocopherol), vitamin K (vitamin K)₁Phylloquinone, naphthoquinone, vitamin K₂Menaquinone-7, vitamin K₃Menaquinone-4, menaquinone-8H, menaquinone-9H, menaquinone-10, menaquinone-11, menaquinone-12, menaquinone-13), choline, inositol, beta-carotene and any combination thereof.

In certain embodiments, the nutritional compositions of the present disclosure may comprise at least one prebiotic. In this embodiment, any prebiotic known in the art may be added. In a particular embodiment, the prebiotic may be selected from the group consisting of: fructo-oligosaccharide, glucose oligosaccharide, galacto-oligosaccharide, polydextrose, isomalto-oligosaccharide, xylo-oligosaccharide and lactulose.

In certain embodiments of the present disclosure, the nutritional composition may contain one or more probiotics. Any probiotic known in the art is acceptable in this embodiment, provided that it will achieve the intended results. In a particular embodiment, the probiotic may be selected from any of the genera lactobacillus (lactobacillus: (a), (b), (c), (d), and (d)Lactobacillus) Lactobacillus rhamnosus GG (GG)Lactobacillus rhamnosusGG) (American type culture Collection accession number ATCC 53103), Bifidobacterium (II)Bifidobacterium) Species Bifidobacterium longum: (Bifidobacterium longum) And Bifidobacterium animalis subsp lactis BB-12 (Bifidobacterium animalis subsp. lactisBB-12) (DSM number 10140) or a combination thereof.

In one embodiment, the one or more probiotics may be live or non-live. The term "live" as used herein means a living microorganism. The term "non-living" or "non-living probiotic" refers to non-living probiotic microorganisms, their cellular components and/or metabolites thereof. Such non-live probiotics may have been heat inactivated or otherwise inactivated, but they retain the ability to favorably affect the health of the host. Probiotics useful in the present disclosure may be naturally occurring, synthetic, or developed by genetic manipulation of organisms, whether such new sources are now known or later developed.

Many formulations known in the art tend to be physically unstable due to syneresis and the formation of non-dispersible precipitates. Instability is caused by high levels of protein, fat and minerals that are included in known nutritional formulas to provide adequate nutrition in a reasonable volume. Notably, acidification of traditional enteral formulas can also cause protein precipitation and phase separation. Often the precipitated nutrients cannot be returned to solution by shaking and they do not provide the nutritional benefits needed to promote the health of the subject.

However, the nutritional compositions of the present disclosure include stable emulsions that additionally contain an emulsifier. The emulsifier may comprise microencapsulating agents (microcapsules), surfactants, emulsion stabilizers, or combinations thereof. In certain embodiments, the emulsifier may comprise, for example, lecithin, one or more monoglycerides, or one or more diglycerides. In certain embodiments, the lipid component of the nutritional composition provides one or more fatty acids in a stable emulsion. In other embodiments, the nutritional composition may comprise a stabilizer, such as carrageenan, instead of or in addition to an emulsifier.

In certain embodiments, the emulsifying step may be accomplished by mechanical agitation, ultrasonic vibration, heat, or a combination thereof. Emulsification may be achieved using any emulsification method known in the art. In one embodiment, emulsification may comprise homogenization. In certain embodiments, multiple homogenization steps may be applied to produce the emulsified lipid component of the nutritional composition.

In certain embodiments of stabilizing the emulsion, the protein may act as a surfactant. Protein surfactants have the ability to spread at the lipid-water interface, thereby reducing droplet coalescence. Indeed, protein surfactants can reduce the interfacial tension between two liquids, thereby causing miscibility of the two liquids. The nutritional composition may comprise any emulsifier that is water soluble. In certain embodiments, the nutritional composition may comprise more than one emulsifier and/or stabilizer.

In one embodiment, the composition comprises an emulsion of at least one LCPUFA stabilized by a protein substrate comprising alpha-lactalbumin. The emulsified LCPUFA may comprise DHA. The alpha-lactalbumin acts as a stabiliser, in particular a surfactant. Other surfactants, emulsion stabilizers, and microencapsulating agents can be used in the lipid component, but are not necessary to prepare a stable emulsion of the nutritional compositions of the present disclosure. In certain embodiments, the lipid emulsion of the nutritional composition contains oil/lipid droplets having a diameter between about 0.070 μm to about 1 μm.

Furthermore, certain embodiments of the nutritional compositions, such as those optimized for preterm or severely diseased infants, may mimic certain characteristics of human breast milk. Indeed, the nutritional formula may comprise alpha-lactalbumin, which is the predominant whey protein in human breast milk. The addition of alpha-lactalbumin to compositions for premature infants may provide several physiological and nutritional benefits. However, to meet the specific DHA requirements of preterm infants, the nutritional composition comprises a higher DHA content than human milk. The increased level of DHA of the nutritional composition compensates for any DHA deficiency in the preterm infant, and/or prevents the occurrence of DHA deficiency.

Other nutrients and ingredients, such as amino acids, vitamins and minerals, may be incorporated into the liquid phase or aqueous components of the emulsion. It may be advantageous to add such other ingredients directly by mixing in the emulsion after homogenization. In effect, the stabilized emulsion allows for the incorporation of other nutrients in the aqueous component without desorbing, breaking or coalescing the lipid droplets.

Furthermore, in certain embodiments, the nutritional composition containing the emulsion is nutritionally complete, containing lipids, carbohydrates, proteins, vitamins, and minerals in appropriate types and amounts as the sole source of nutrition for the subject. Indeed, the nutritional composition may optionally include any number of proteins, peptides, amino acids, fatty acids, probiotics and/or their metabolic byproducts, prebiotics, carbohydrates, and any other nutrients or other compounds that may provide a number of nutritional and physiological benefits to a subject. In addition, the nutritional compositions of the present disclosure may include flavors, enhancers, sweeteners, pigments, vitamins, minerals, therapeutic ingredients, functional food ingredients, processing ingredients, or combinations thereof.

The present disclosure additionally provides a method for providing nutritional support to a subject (such as a preterm infant) who is receiving partial or complete parenteral nutrition. The method comprises the following steps: administering to the subject an effective amount of a nutritional composition of the present disclosure. The duration of administration may vary, but the nutritional composition should be administered when the infant is not fully fed and/or is receiving full or partial full parenteral nutrition.

The nutritional composition of the present disclosure may be commercially packaged such that it may be directly connected to enteral nutrition devices including, but not limited to, nasogastric tubes, percutaneous endoscopic gastrectomy (gastronomy), percutaneous endoscopic jejunostomy, transpyloric intubation, and the like. Also, the packaging should be incompatible with intravenous feeding lines in order to minimize the risk of intravenous administration. Such a design is convenient in terms of ensuring complete delivery of the package contents, minimizing the risk of contamination and improving compliance. Additionally, in certain embodiments, the nutritional composition may be packaged in a single unit dose delivery package of about a total volume of 1 mL, about a total volume of 1.5mL, or about a total volume of 2 mL. Unit dose packaging systems are preferred in order to minimize dosing errors and reduce the risk of contamination.

The nutritional composition may be directly excreted into the intestinal tract of a subject. In certain embodiments, the nutritional composition is placed directly into the intestinal tract. In certain embodiments, the compositions may be formulated for enteral use or administration under the supervision of a physician, and may be used for specific dietary adjustments of a disease or condition whose unique nutritional needs are established by medical evaluation based on accepted scientific principles.

The nutritional compositions of the present disclosure are not limited to compositions comprising the nutrients specifically enumerated herein. Any nutrients may be delivered as part of the composition for the purpose of meeting nutritional needs, and/or to optimize the nutritional status of the subject.

In certain embodiments, the nutritional composition may be delivered to an infant from birth until a time matching a full term pregnancy. In certain embodiments, the nutritional composition may be delivered to an infant until at least about 3 months corrected for age. In another embodiment, the nutritional composition may be delivered to the subject whenever necessary to correct the nutritional deficiency. In another embodiment, the nutritional composition may be delivered to the infant from birth until at least about 1 year of age corrected.

The nutritional compositions of the present disclosure may be standardized to a particular enthalpy, may be provided as a ready-to-use product, or may be provided in a concentrated form.

The present disclosure provides a nutritional supplement for enteral administration comprising a lipid component of an emulsion containing at least one fatty acid, wherein the nutritional supplement is designed to correct the nutritional deficiency of a subject (such as a preterm infant) by increasing the intake of nutrients (such as omega-3 or omega-6 long chain polyunsaturated acids) by the subject.

In certain embodiments, the nutritional composition is a human milk fortifier and/or an infant formula fortifier. In such embodiments, the nutritional composition comprises DHA and ARA in the form of a stabilized emulsion that can be readily mixed with human milk or infant formula. As the infant transitions from parenteral nutrition support to oral feeding (infant formula or human milk) in combination with partial parenteral nutrition support, the nutritional composition in the form of a fortifier may be added to the oral feed in order to ensure that appropriate levels of DHA and ARA are available to support optimal growth and neurodevelopment in the subject.

By addressing and correcting the nutritional deficiencies of currently available products, the nutritional compositions and methods of the present disclosure provide significant benefits over the prior art. In addition, the nutritional compositions of the present disclosure provide valuable nutrients to preterm infants that would not otherwise acquire such nutrients when relying on existing sources of TPN.

The following examples are provided to illustrate some embodiments of the nutritional compositions of the present disclosure, but should not be construed as limiting the nutritional compositions in any way. Other embodiments within the scope of the claims herein will be apparent to those skilled in the art from consideration of the specification or practice of the nutritional compositions or methods disclosed herein. It is intended that the specification, together with the examples, be considered to be exemplary only, with the scope and spirit of the disclosure being indicated by the claims which follow the examples.

Examples

In one embodiment, the nutritional compositions of the present disclosure may be formulated for administration to an infant of about 1 kg body weight 2 times per day. The infant may receive 2 deliveries of 1.5mL of the nutritional composition. The nutritional composition may be formulated to deliver about 25.5 mg DHA per day and about 17 mg ARA per day to the infant. An example of a nutritional composition suitable for use in this embodiment is as follows:

nutritional composition 1

Composition (I)	Measurement of
		DATEM (diacetyltartaric acid monoglyceride)	0.165 g
Citric acid	0.40 g
		DHASCO	4.25 g
ARASCO	2.84 g
		Water (W)	92.0 mL

Furthermore, in another embodiment, the nutritional composition may be administered to the infant 4 times per day in an amount of about 1.5 mL/delivery. The nutritional composition may be formulated to deliver about 25.5 mg DHA per day and about 17 mg ARA per day to the infant. An example of a nutritional composition suitable for use in this embodiment is as follows:

nutritional composition 2

Composition (I)	Measurement of
		DATEM (diacetyltartaric acid monoglyceride)	0.083 g
Citric acid	0.40 g
		DHASCO	2.12 g
ARASCO	1.42 g
		Water (W)	92.0 mL

All references cited in this specification, including but not limited to all papers, publications, patents, patent applications, statements, texts, reports, manuscripts, brochures, books, internet postings, journal articles, periodicals, and the like, are hereby incorporated by reference in their entirety. The discussion of references herein is intended merely to summarize the assertions made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pertinency of the cited references.

Although embodiments of the present disclosure have been described using specific terms, devices, and methods, such description is for illustrative purposes only. The language used is intended to be descriptive, not limiting. It is to be understood that changes and variations may be made by those of ordinary skill in the art without departing from the spirit or scope of the present disclosure, which is set forth in the following claims. Additionally, it should be understood that aspects of the various embodiments may be interchanged both in whole or in part. For example, while methods of preparing commercial sterile liquid nutritional supplements prepared according to those methods have been enumerated, other applications are contemplated. Therefore, the spirit and scope of the appended claims should not be limited to the description of the preferred versions contained therein.

Claims (20)

1. A nutritional supplement for enteral administration to preterm infants, comprising:

a lipid component, wherein the lipid component comprises at least about 0.64% arachidonic acid and at least about 0.32% docosahexaenoic acid, wherein the arachidonic acid and the docosahexaenoic acid are provided in an emulsified form.

2. The nutritional supplement of claim 1, wherein the lipid component comprises at least about 1% docosahexaenoic acid.

3. The nutritional supplement of claim 1, wherein the lipid component comprises at least about 2% docosahexaenoic acid.

4. The nutritional supplement of claim 1, wherein the nutritional supplement is formulated to deliver at least about 50 mg/kg/day of docosahexaenoic acid.

5. The nutritional supplement of claim 1, wherein the nutritional supplement is formulated to deliver at least about 60 mg/kg/day of docosahexaenoic acid.

6. The nutritional supplement fortifier of claim 1, further comprising a protein component.

7. The nutritional supplement of claim 1, further comprising a carbohydrate component.

8. The nutritional supplement of claim 1, further comprising a vitamin and mineral component.

9. The nutritional supplement of claim 1, further comprising at least one probiotic.

10. The nutritional supplement of claim 1, further comprising at least one prebiotic.

11. An enhancer for oral administration to a premature infant, comprising:

a lipid component, wherein the lipid component comprises at least about 0.64% arachidonic acid and at least about 0.32% docosahexaenoic acid, wherein the arachidonic acid and the docosahexaenoic acid are provided in an emulsified form.

12. The enhancer of claim 11 wherein the lipid component comprises at least about 1% docosahexaenoic acid.

13. The enhancer of claim 11 wherein the lipid component comprises at least about 2% docosahexaenoic acid.

14. The enhancer of claim 11, wherein the enhancer is formulated to deliver at least about 50 mg/kg/day of docosahexaenoic acid.

15. A method for providing nutritional support to a preterm infant receiving parenteral nutrition, the method comprising:

enterally administering to the infant a nutritional composition comprising a lipid component, wherein the lipid component comprises at least about 0.64% arachidonic acid and at least about 0.32% docosahexaenoic acid, wherein the arachidonic acid and the docosahexaenoic acid are provided in an emulsified form.

16. The method of claim 16, wherein the lipid component comprises at least about 1% docosahexaenoic acid.

17. The method of claim 16, wherein the lipid component comprises at least about 2% docosahexaenoic acid.

18. The method of claim 16, wherein the nutritional composition is administered to the infant in an amount sufficient to deliver at least about 50 mg/kg/day of docosahexaenoic acid.

19. The method of claim 16, wherein the nutritional composition is administered to the infant in an amount sufficient to deliver at least about 60 mg/kg/day of docosahexaenoic acid.

20. The method of claim 16, wherein the nutritional composition is administered to the infant in an amount sufficient to deliver at least about 40 mg/kg/day of arachidonic acid.