# Patent

## Title
Dietary supplement containing phospholipid-DHA derived from eggs

## Abstract

Described herein are manufactured dietary supplements that contain a phospholipid extract, folic acid, vitamin D, vitamin B6, vitamin B12, Vitamin E, Vitamin C, iodine, iron, and magnesium.
Described herein are manufactured dietary supplements that contain a phospholipid extract that contain phospholipid-DHA.

## Background
CROSS-REFERENCE TO RELATED APPLICATION
This application is a continuation of nonprovisional U.S. application Ser. No. 14/562,650 filed Dec. 5, 2014, which claims priority to Provisional U.S. Application No. 62/088,528 filed on Dec. 5, 2014 and Provisional U.S. Application No. 61/912,205 filed on Dec. 5, 2013, which are hereby incorporated by reference in its entirety.


FIELD
The present disclosure generally relates to a nutritional supplements providing phospholipid-docosahexaenoic acid derived from eggs.
BACKGROUND
Polyunsaturated fatty acids have numerous crucial biological functions in mammals. Moreover, in adult humans, certain polyunsaturated fatty acids have been linked to potentially promoting improved cognitive ability and have been theorized as potential treatments for arthritis, cancer, diabetes, lupus, and psoriasis. Also, certain polyunsaturated fatty acids have been linked to promoting retinal and brain development in fetuses and newborns.
SUMMARY
A manufactured dietary supplement that contains a phospholipid extract, folate, vitamin D, vitamin B6, vitamin B12, vitamin C, calcium, iron, iodine, and magnesium.
A manufactured dietary supplement that contains a phospholipid extract containing phospholipid-DHA.



DESCRIPTION OF THE FIGURES
These and other features, aspects and advantages of the present disclosure are better understood when the following detailed description of the disclosure is read with reference to the accompanying drawing, in which:
FIG. 1 is a schematic depiction of docosahexaenoic acid metabolism in a subject.
FIG. 2 is a schematic depiction of phosphatidylcholine-docosahexaenoic acid.
FIG. 3 is a schematic depiction of phosphatidylethanolamine-docosahexaenoic acid.



DETAILED DESCRIPTION
Before the present compounds, compositions, and/or methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific compounds, synthetic methods, or uses as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.
In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings:
It must be noted that, as used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a microparticle” includes one or more microparticles.
“Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.
As used herein, “subject” refers to a mammal, including a human that is in need of supplementation and/or benefits from the compositions and methods described herein.
As used herein, “organic” refers to a food that complies with U.S.D.A regulations set out herein below.
As used herein, the term “rounded” means that an outer periphery of a structure is substantially free of angularity. For example, the outer periphery of microparticles can have spherical shapes and oval shapes that are free of angularity and have rounded shapes.
As used herein, the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “slightly above” or “slightly below” the endpoint without affecting the desired result.
The disclosure provides various teachings on nutritional supplements. The ingredients, compounds, chemicals that make up the elements of the nutritional supplements may contain vitamins, foods, or other organic matter that is prone to degradation after formulation in a finished nutritional supplement. It is common practice to formulate a nutritional supplement to include an “overage” or an additional amount of ingredient. Any amount of ingredient, compound, or chemicals that is within an “overage” of the ranges and amounts claimed and exemplified in this disclosure would be considered equivalent.
As used herein, a plurality of items, structural elements, compositional elements, and/or materials may be presented in a common list for convenience. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
Concentrations, amounts, and other numerical data may be expressed or presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and thus should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. As an illustration, a numerical range of “about 1 to about 5” should be interpreted to include not only the explicitly recited values of about 1 to about 5, but also include individual values and sub-ranges within the indicated range. Thus, included in this numerical range are individual values such as 2, 3, and 4 and sub-ranges such as from 1-3, from 2-4, and from 3-5, etc., as well as 1, 2, 3, 4, and 5, individually. This same principle applies to ranges reciting only one numerical value as a minimum or a maximum. Furthermore, such an interpretation should apply regardless of the breadth of the range or the characteristics being described.
The nutritional compositions and methods described herein can comprise, consist of, or consist essentially of the essential elements and limitations described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in nutritional formula applications.
The present compositions and methods will now be described more fully hereinafter with reference to the accompanying drawings in which exemplary embodiments of the disclosure are shown. However, these compositions and methods may be embodied in many different forms and should not be construed as limited to the representative embodiments set forth herein. The exemplary embodiments are provided so that this disclosure will be both thorough and complete, and will fully convey the scope of the disclosure and enable one of ordinary skill in the art to make, use and practice the teachings of the present disclosure.
Polyunsaturated fatty acids have numerous crucial biological functions in mammals. For example, in humans, numerous polyunsaturated fatty acids have been linked to cell membrane synthesis, metabolism, and maintenance. Moreover, in adult humans, certain polyunsaturated fatty acids have been linked to potentially promoting improved cognitive ability and have been theorized as potential treatments for arthritis, cancer, diabetes, lupus, and psoriasis. Also, certain polyunsaturated fatty acids have been linked to promoting retinal and brain development in fetuses and newborns.
For example, docosahexaenoic acid (“DHA”) is one such polyunsaturated fatty acid that has been implicated in playing a role in fetus and newborn development as well as potentially playing a role in maintaining and/or promoting improved human cognitive ability. DHA is a long chain omega-3 fatty acid derived from alpha-linolenic acid having double bonds at its 4, 7, 10, 13, 16, and 19 positions. In humans, DHA is primarily found in the brain's grey matter where it functions as a building block for membrane glycerophospholipids.
Although polyunsaturated fatty acids such as DHA are known to play an important role in human cognitive ability, fetus development, and newborn development, Western diets are often deficient in adequate amounts of these polyunsaturated fatty acids, and individuals often resort to polyunsaturated fatty acid supplementation to obtain adequate nutritional amounts of these polyunsaturated fatty acids to potentially avoid problems associated with polyunsaturated fatty acid deficiencies. For example, pregnant women and health conscious individuals often supplement their diets with fish oil and algae extracts in an attempt to obtain adequate amounts of polyunsaturated fatty acids. Moreover, infant formulas are often supplemented with polyunsaturated fatty acids derived from either of these sources.
Although fish oil and algae extracts may be a source of polyunsaturated fatty acids, numerous problems exist. For example, fish oil often has an undesirable smell and taste. Due to this problem, numerous fish oil formulations often include taste and smell masking agents. However, most taste and smell masking agents never completely mask the “fishy” taste and smell of these oils. Moreover, these taste and smell masking agents increase production costs and the amount of time required to manufacture formulations having fish oil extracts. Thus, in many regards, fish oil supplementation and production of supplements having these substances remains undesirable due to these problems. Additionally, fish oil and algal oil extracts do not have high quantities of DHA in the phospholipid form. And fish oil extracts also contain higher levels of triglycerides and free fatty acids. The higher levels of triglycerides and free fatty acids are one of the reasons for the undesirable smell and taste.
In addition, numerous problems exist for DHA derived from these sources and other commonly used forms of DHA. For example, DHA derived from fish oil and algae are primarily covalently bonded to triglycerides, and other types of pharmaceutical grade DHA are ethyl ester forms of DHA. Additionally, these extraction techniques increase the amount of free fatty acids and triglycerides. In humans, these forms of DHA require multiple steps of metabolic processing to be useful for certain biological functions. Thus, these forms of DHA are energetically disfavored due to the amount of metabolic processing required by a subject's body.
Furthermore, when included in nutritional supplements and formulations, these forms of DHA are susceptible to oxidation, which leads to instability, decreased efficacy, decreased potency, and potentially increased toxicity when using these forms of DHA. The oxidation is also what contributes to the “fishy smell.” In addition to the problems mentioned above, the triglyceride and ethyl ester forms of DHA often cause gastrointestinal problems. Therefore, triglyceride and ethyl ester forms of DHA are often enterically coated in an attempt to reduce DHA oxidation and gastrointestinal problems associated with these forms of DHA, which further increases production costs and the time required to manufacture compositions having these substances.
DHA from algae or fish oxidizes (stinks) because it must be broken down to free fatty acid DHA, which is then transported via albumin into the blood. Then the supplement must provide high dosages of DHA to “force” it or push it into blood-brain-barrier (“BBB”) or must be converted in the liver to lipid form DHA (only a small amount do this). It takes a high dosages of PC-DHA to cross the blood brain barrier, which is why companies put so much in. Ultimately, the DHA must be metabolized into PC-DHA in order to be circulating and then go into the BBB. PC-DHA is the only form that can cross the BBB in significant numbers.
Therefore, it is an object of the disclosure to provide nutritional compositions including a stable source of DHA that avoids or reduces the problems associated with conventional polyunsaturated fatty acid supplementation. The forms of DHA that are most beneficial for nutritional supplementation for cognitive functions are in the phospholipid form, namely phosphatidylcholine docosahexaenoic acid (“PC-DHA”), phosphatidylethanolamine docosahexaenoic acid (“PE-DHA”), phosphatidylethanolamine-docosahexaenoic acid (“PE-DHA”) and phosphatidylserine docosahexaenoic acid (“PS-DHA”). These phospholipids are conjugated with a docosahexaenoic acid.
Described herein are nutritional compositions containing phospholipids and DHA conjugated phospholipids derived from eggs and methods of making such nutritional compositions. These nutritional compositions can be administered to a subject to promote numerous health benefits, which include, but are not limited to, promoting improved cognitive ability, retinal health, decrease inflammation, and neuronal health. Furthermore, these nutritional compositions can be administered to pregnant women and/or newborns to further promote brain and retinal development in fetuses and newborn children.
Eggs contain many phospholipids and the amount of phospholipids in eggs may be increased by supplementing the hen's diet with polyunsaturated fatty acids, particularly omega-3 oils. Eggs contain various omega-3 fatty acids. Some of the phospholipids contained in eggs include: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, lysophosphatidyl choline, sphingomyelin, lysophosphtidyl ethanolamine, and combinations thereof.
Various phospholipids may be extracted from eggs. This “phospholipid extract” derived from eggs may also be referred to as the raw material or ingredient for a nutritional supplement. Reference to phospholipid extracts claimed by this disclosure will always be phospholipid extracts derived from eggs. The phospholipids contained in the phospholipid extract include phospholipid-docosahexaenoic acid and other phospholipids. One form of phospholipid-docosahexaenoic acid is phosphatidylcholine-docosahexaenoic acid, and another form of phospholipid-docosahexaenoic acid is phosphatidylethanolamine-docosahexaenoic acid, and another form of phospholipid-docosahexaenoic acid is phosphatidylserine-docosahexaenoic acid. The phospholipid extract may also have some free fatty acids and triglycerides, however, the extract should preferably have less minimal free triglycerides and free fatty acids. The extract or raw material may also include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, lysophosphatidyl choline, sphingomyelin, lysophosphtidyl ethanolamine, and combinations thereof.
The phospholipid extract may sometimes be semi-solid and sticky. It can be difficult to use in tablet or hard capsule products. The raw material is often not soluble in oil, and using the material may be impractical in use in softgel, as it may stick on the mill surface during grinding.
In certain aspects, these nutritional compositions include a body that encapsulates iron, folate, and an additive, wherein the additive can include microparticles. In certain aspects, the microparticles have a substantially rounded shape and include a core. The core contains the raw material or phospholipid extract, which effectively and efficiently delivers the phospholipid extract to the subject. The core of the microparticle may be coated. These microparticles can be incorporated into the nutritional composition to improve efficacy of phospholipid delivery.
In addition, these microparticles can be made by providing a microparticle core made from a pharmaceutically acceptable material and a or phospholipid extract, then coating the microparticle core with a first layer, and drying the coated microparticle core, thereby forming the microparticle for the nutritional composition.
In other aspects the nutritional supplement contains the phospholipid extract without the use of microparticles.
Additional features, aspects and advantages of the disclosure will be set forth in the detailed description which follows, and in part will be readily apparent to those skilled in the art from that description or recognized by practicing the teachings of the disclosure as described herein. It is to be understood that both the foregoing general description and the following detailed description present various 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. The accompanying drawings are included to provide a further understanding of the disclosure, and are incorporated in and constitute a part of this specification.
Nutritional Compositions
Described herein are nutritional compositions that include a body encapsulating iron, folate, and an additive, wherein the additive includes a microparticle having a core that includes a phospholipid extract and a coating. The body in the nutritional compositions described herein can include, but is not limited to, a tablet, an enteric coated tablet, a capsule, an enteric coated capsule, a softgel capsule, or an enteric coated softgel capsule encapsulating iron, folate, and the additives, for example the microparticles, described herein.
Docosahexaenoic Acid (DHA)
The nutritional compositions described herein include a pharmaceutically acceptable phospholipid-DHA derived from eggs and more preferably include organic DHA or DHA derived from organic eggs.
The docosahexaenoic acid described herein generally includes the following formula:




In certain aspects, X can include a phospholipid that is preferably covalently bonded either directly to the DHA shown in Formula 2 or indirectly (via a saturated or unsaturated lower alkyl linker having C1-C8) to the DHA shown in Formula 2. For example, X can include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, or combinations thereof.
Formula 2 further illustrates the phospholipid being covalently bonded to DHA. In Formula 2, Y can include a primary amine group, a secondary amine group, a tertiary amine group, a trimethyl amine group, or a combination thereof, and R1 can include a hydrogen, a hydroxyl group, a saturated or unsaturated alkyl group, an alkoxy group, an omega-3 fatty acid, or any combination thereof. In certain aspects, Y is NH3+ or N(CH3)3.




In certain aspects, phospholipid-DHA of the nutritional composition may include 1-palmitoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine or 1-hexadecanoyl-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine or phosphatidylcholine-docosahexaenoic acid (“PC-DHA”), 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphoethanolamine or 1-octadecanoyl-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphoethanolamine or phosphatidylethanolamine-docosahexaenoic acid (“PE-DHA”), or combinations thereof. For example, Formula 3 depicts one representative example of phosphatidylcholine docosahexaenoic acid.




The docosahexaenoic acids shown in Formulas 1-3 above are preferred over fish oil and algae derived forms of DHA because these docosahexaenoic acids are in the phospholipid form, which aid in docosahexaenoic stability and potency. Furthermore, these forms of DHA are more palatable to subjects than those derived from fish oil and algae extracts. Without wishing to be bound by theory, it is thought that these forms of DHA are more easily metabolized by a subject and more easily cross the blood brain barrier.
FIG. 1 further illustrates this concept. For example, as shown in FIG. 1, linolenic acid (i.e., “LNA”) and most forms of docosahexaenoic acid are metabolized in the liver in order to cross the blood brain barrier before being used in various metabolic functions in the brain. For example, linolenic acid is converted into DHA, and DHA is further bonded to phosphatidylcholine to generate PC-DHA. After synthesizing PC-DHA, liver phospholipase A1 (PLase A1) hydrolyzes PC-DHA to form LysoPC-DHA, which can subsequently pass the blood brain barrier and can be used in various metabolic functions in the brain such as maintaining neuronal membrane glycerophospholipids and potentially preventing or reducing apoptosis of glial cells and neurons. As also shown in FIG. 1, if free PC-DHA is present, endothelial lipase can also hydrolyze this free PC-DHA to form LysoPC-DHA, which can also subsequently pass the blood brain barrier and be used in various metabolic functions in the brain such as maintaining neuronal membrane glycerophospholipids and potentially preventing or reducing apoptosis glial cells and neurons.
FIG. 2 is an illustration of PC-DHA.
FIG. 3 is an illustration of PE-DHA.
When DHA is covalently linked to phosphatidylethanolamine, these forms of DHA can also similarly be easily converted to DHA forms that can cross the blood brain barrier. For example, without wishing to be bound by theory, PE-DHA can be converted into LysoPC-DHA by various metabolic processes and eventually cross the blood brain barrier.
In addition to crossing the blood brain barrier, PC-DHA and PE-DHA can be used as a polyunsaturated fatty acid nutritional source that crosses the placental barrier in pregnant mothers and provides a fetus with sufficient DHA amounts for adequate brain and retinal development.
In contrast to the PC-DHA and PE-DHA derived from eggs discussed above, DHA derived from fish oil and algae are primarily covalently bonded to triglycerides that do not include phosphate groups and/or phospholipids. Furthermore, the DHA derived from fish oil and algae often require far more metabolic steps to be converted into a useful form of DHA that can cross the blood brain barrier and/or the placental barrier.
In certain aspects, the phospholipid extract described herein is present in a nutritional composition in an amount ranging from 50 mcg to 1000 mg.
In certain aspects, the phospholipid extract includes PC-DHA and PE-DHA. In this aspect, the combination of PC-DHA and PE-DHA provided in a microparticle or a nutritional supplement can be 5% to 15% (by weight) of the overall amount of phospholipid extract in the nutritional composition. In one aspect, PC-DHA can be 50% to 95% of the overall amount of phospholipid DHA in the nutritional composition, and PE-DHA can be 5% to 45% of the overall amount of DHA in the nutritional composition. The PC-DHA and PE-DHA may also be used in a nutritional supplement without the microencapsulation. In one aspect, the at least 7.5% the phospholipid extract by weight is phosphatidylcholine-docosahexaenoic acid. And in another aspect, at least 8% the phospholipid extract by weight is phosphatidylethanolamine-docosahexaenoic acid. Preferably the amount of triglycerides is low. In one aspect the amount of triglycerides is less than 5% of the phospholipid extract, and in another aspect the amount of triglycerides is less than 3% of the phospholipid extract.
In certain aspects, the DHA described herein includes a ratio of PC-DHA to PE-DHA ranging from 20:1 to 1:1. In another embodiment, the DHA described herein includes a ratio of PC-DHA to PE-DHA ranging from 5:1.
DHA From Eggs
Eggs naturally contain a relatively high about of phospholipids and phospholipid conjugated DHA. Additionally, to increase the amount of phospholipids and phospholipid conjugated DHA in eggs, chicken feed may be supplemented with a source of Omega-3 fatty acids like flax seeds, or other sources high in Omega-3. Omega-3 enriched eggs have been shown to have 39% less Arachidonic Acid, an inflammatory Omega-6 fatty acid that most people eat too much of. It has also been shown that Omega-3 enriched eggs had 5 times as much Omega-3 as conventional eggs.
Hens that are fed organic chicken feed potentially will be able to produce DHA, including PC-DHA to PE-DHA, derived from eggs that may be labeled as Organic DHA.
Between 200 mg to 300 mg of usable phospholipid extract for nutritional supplementation can be extracted from one egg.
In certain aspects and as discussed further below, the DHA is only included in the microparticles of the nutritional composition. In other aspects, a portion of the DHA can be included in the microparticles and another portion of the DHA can be included in a portion of the encapsulating body (e.g., tablets, softgels, capsules, or chewable) that is not the microparticle. For example, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of the DHA can be in the microparticles and the remainder of DHA can included in a portion of the encapsulating body that is not the microparticle.
Microparticles
Microparticles can be included in the disclosed nutritional compositions, and more specifically, the microparticles described herein are preferably included within a tablet, an enteric coated tablet, a capsule, an enteric coated capsule, a softgel capsule, or an enteric coated softgel capsule.
The microparticles described herein generally include a microparticle core and a layer or a plurality of layers coated on an outermost surface of the microparticle core. The microparticle core is preferably made from a pharmaceutically acceptable material that includes, but is not limited to, tartaric acid, sugar, calcium carbonate, mannitol, microcrystalline cellulose, silica, starch or any combination thereof. These materials are mixed with the phospholipid extract. The egg DHA may be PC-DHA, PE-DHA, or a mixture. DHA and other omega-3 fatty acids may also be incorporated in the microparticle core.
It is preferable that the microparticle cores have a substantially rounded shape such that the microparticle cores do not aggregate during the production of the microparticles. In addition, because non-rounded shaped microparticle cores tend to aggregate and slow the production process, it is preferable that the microparticle cores have a rounded shape to facilitate production of rounded microparticles.
The microparticle cores described herein can be generally produced with any known extrusion and spheronization techniques that can obtain the desired microparticle diameters described below. For example, the microparticle core material can be subjected to radial extruding process, axial extruding process, cone extruding process, dome extruding process, die roller extruding process, or basket extruding process. These materials can be generally extruded through a die or mesh having variable sizes. For example, the die and mesh sizes associated with these extruding techniques can include 200 μm to 8000 μm, 300 μm to 7500 μm, 300 μm to 4000 μm, 300 μm to 2000 μm, 400 μm to 2000 μm, 400 μm to 1000 μm, and 500 μm to 800 μm to produce microparticle cores having a desired particle diameter. After extrusion, the microparticle core materials can be further subjected to any known spheronization treatment to further ensure sufficient microparticle core roundness.
In certain aspects, the microparticle cores can be further subjected to flow cytometry and separated based on desired microparticle core roundness. For example, in certain aspects, the desired microparticle core diameter ranges from 180 μm to 425 μm. In exemplary embodiments, the microparticles may have an accumulated volume average particle diameter D50 of from approximately 250 μm to approximately 425 μm to meet 40-60 mesh requirements. Or the microparticles may have an accumulated volume average particle diameter D70 of from approximately 180 μm to approximately 250 μm to meet 60-80 mesh requirements. Or the microparticles may have an accumulated volume average particle diameter D90 of from approximately 150 μm to approximately 180 μm to meet 80-100 mesh requirements.
In an exemplary embodiment, the microparticle cores may have a volume average particle size distribution index GSDv of approximately 1.30 or less. When GSDv is approximately 1.30 or less, little microparticle core aggregation occurs and sufficient microparticle roundness can be obtained.
The accumulated volume average particle diameter D50 and the average particle size distribution index of the microparticle cores may be measured, for example, in the following manner. Based on a particle size distribution measured with such a measuring device as Coulter Counter TA II (available from Beckman Coulter, Inc.) or Multisizer II (available from Beckman Coulter, Inc.), accumulated distributions of volume and number are each drawn from the small diameter side with respect to the divided particle size ranges. The particle diameters where the accumulated value is 16% are designated as volume D16V and number D16P, the particle diameters where the accumulated value is 50% are designated as volume D50V and number D50P, and the particle diameters where the accumulated value is 84% are designated as volume D84V and number D84P. By using these values, the volume average particle size distribution index (GSDv) is calculated as (D84V/D16V)1/2, and the number average particle size distribution index (GSDp) is calculated as (D84P/D16P)1/2. The microparticles may have a shape factor SF1 of from approximately 110 to approximately 140, and preferably from approximately 120 to approximately 140, which results in microparticle cores having little shape irregularity and having sufficient roundness (e.g., spherical shape).
SF1 is a shape factor that shows the extent of unevenness on the surface of the microparticle cores, and is calculated as follows. An optical micrograph of the microparticle cores scattered on a glass slide is acquired to a Luzex image analyzer through a video cam, and SF1 is calculated according to the following expression from the value obtained by dividing square of the maximum length of the toner particles by the projected area ((ML)2/A) for 50 toner particles, and the average value thereof is designated as SF1.

SF1=(ML)2/a×n/4×100

wherein ML represents the maximum length of the toner particles, and A represents the projected area of the particles.

After obtaining microparticle cores having desirable roundness and diameter, the microparticle cores are then subjected to a coating process in which one or more coating layers are coated on an outermost surface of the microparticle cores. For example, in certain aspects, an outermost layer of the microparticle cores are coated with a solution, dispersion, or suspension. In some aspects, the coating may also contain additional DHA derived from eggs described above. In certain aspects, this coating can contain additional components that include, but are not limited to, excipients.
This coating can partially or completely coat the outermost layer of the microparticle core. In certain aspects, it is preferable that the coating completely coats the outermost layer of the microparticle core, and this combination of microparticle core and coating forms the microparticle. Depending on the type of material used for the microparticle core, it may be desirable to form an intermediary layer disposed between the outermost surface of the microparticle core. In one aspect the coating is pH dependent and may be used for targeting the absorption at specific locations in the GI tract. In this aspect, the intermediary layer may reduce or prevent the docosahexaenoic acid from interacting and potentially blocking absorption.
In certain aspects, a plurality of coatings can be provided on the microparticle core in order to form the desired microparticle. In this aspect, the microparticle core can be coated with a coating containing DHA derived from eggs on the outermost surface of the microparticle core. In certain aspects, this coating is allowed to dry at a desired temperature and for a desired time period. Next, a second coating can be applied. In certain aspects, this second coating can include time release agents and additional excipients to more slowly and controllably administer, for example, the docosahexaenoic acid derived from eggs to a subject. These time release coatings are described in greater detail further below. In further embodiments, additional coating layers can be provided on the microparticle cores.
In certain aspects, it is desirable that the microparticles do not exceed 500 μm in diameter because adverse effects such as gastrointestinal irritation may occur. It is also desirable that the microparticles have a substantially uniform shape and particle diameter to ensure efficient delivery to the subject. For example, in certain aspects, the microparticles described herein are monodisperse and have a polydispersity index (PDI) ranging from about 1.5 to 1, from about 1.3 to 1, and more preferably from about 1.2 to 1.
Organic DHA
The National Organic Program (NOP) under the direction of the Agricultural Marketing Service (AMS), an arm of the United States Department of Agriculture (USDA) is a national program that establishes national standards for the production and handling of organically produced products, including a National List of substances approved for and prohibited from use in organic production and handling. NOP is codified in 7 CFR Part 205, which is incorporated by reference herein.
The final regulation declared that “Producers and handlers of agricultural products used as ingredients in cosmetics, body care products, and dietary supplements could be certified as organic operations. The ultimate labeling of cosmetics, body care products, and dietary supplements, however, has yet to be addressed.”
The USDA has stated that “There are agricultural products, including personal care products, that, by virtue of their organic agricultural product content, may meet the NOP standards and be labeled as “100 percent organic,” “organic” or “made with organic” pursuant to the NOP regulations. Businesses that manufacture and distribute such products may be certified under the NOP, and such products may be labeled as “100 percent organic,” “organic” or “made with organic” so long as they meet NOP requirements. Additionally, products that may be labeled “100 percent organic” or “organic” may also carry the USDA organic seal.”
Except for exempt and excluded operations, each production or handling operation or specified portion of a production or handling operation that produces or handles crops, livestock, livestock products, or other agricultural products that are intended to be sold, labeled, or represented as “100 percent organic,” “organic,” or “made with organic (specified ingredients or food group(s))” must be certified. This means that the organic egg farm, the manufacturer of the organic egg DHA material, the intermediate manufacturer, and the final product manufacturer would need to be certified.
A certified operation must only use allowed substances, methods, and ingredients for the production and handling of agricultural products that are sold, labeled, or represented as “100 percent organic,” or “organic,” for these products to be in compliance with the Act and the NOP regulations. Use of ionizing radiation, sewage sludge, and excluded methods are prohibited in the production and handling of organic agricultural products.
The National List identifies synthetic substances, materials and ingredients that may be used in organic farming and production operations. The List also highlights non-synthetic substances, materials and ingredients that cannot be used. Notably, microcrystalline cellulose and methyl cellulose, which are ubiquitous excipients in dietary supplements, are prohibited ingredients. This limitation clearly affects finished product manufacturers.
Most DHA and omega fatty acids used in nutritional and dietary supplements are derived from algae and fish sources. The extraction processes are not processes that are eligible to be certified as “organic.” Additionally, some algae sources are genetically modified which also prevent products derived from the algae as certified “organic.” The present disclosure is the only source of dietary supplementation of DHA that is able to be certified as “organic” by the USDA.
Organic egg production is the production of eggs through organic means. There are three main requirements for organic egg production:

    
    
        Poultry can be exposed to antibiotics only during infectious outbreak.
        Poultry must be fed organic feed (no animal byproducts or genetically-modified crops).
        Poultry must have access to outdoors. It cannot be raised in cages.
    
    


Organic production is also regulated by animal welfare audit system. Mistreatment of the chickens could potentially lead a farmer to losing his organic certification.
Requirements of Phospholipid Extract Intermediate Manufacturers
Phospholipid extract intermediate manufacturers would need to be certified as organic operations.

    (a) Mechanical or biological methods, including but not limited to cooking, baking, curing, heating, drying, mixing, grinding, churning, separating, distilling, extracting, slaughtering, cutting, fermenting, eviscerating, preserving, dehydrating, freezing, chilling, or otherwise manufacturing, and the packaging, canning, jarring, or otherwise enclosing food in a container may be used to process an organically produced agricultural product for the purpose of retarding spoilage or otherwise preparing the agricultural product for market.
    (b) Nonagricultural substances allowed under §205.605 and non-organically produced agricultural products allowed under §205.606 may be used:
    
        (1) In or on a processed agricultural product intended to be sold, labeled, or represented as “organic,” pursuant to §205.301(b), if not commercially available in organic form.
        (2) In or on a processed agricultural product intended to be sold, labeled, or represented as “made with organic (specified ingredients or food group(s)),” pursuant to §205.301(c).
    
    
    (c) The handler of an organic handling operation must not use in or on agricultural products intended to be sold, labeled, or represented as “100 percent organic,” “organic,” or “made with organic (specified ingredients or food group(s)),” or in or on any ingredients labeled as organic:
    
        (1) Practices prohibited under paragraphs (e) and (f) of §205.105.
        (2) A volatile synthetic solvent or other synthetic processing aid not allowed under §205.605: Except, That, nonorganic ingredients in products labeled “made with organic (specified ingredients or food group(s))” are not subject to this requirement.
    
    


The types of DHA in nutritional supplements currently available are not able to be certified as “organic.” This is because DHA comes from either hill and fish, and the extraction processes are not certified as organic, or it comes from genetically modified algae, which is also prohibited from being “organic”.
In one embodiment, this disclosure provide for phospholipids to be used in a nutritional supplement that may be labeled “organic” according to the USDA guidelines. In one embodiment, this disclosure provide for DHA to be used in a nutritional supplement that may be labeled “organic” according to the USDA guidelines. In one embodiment, this disclosure provide for phospholipid-DHA to be used in a nutritional supplement that may be labeled “organic” according to the USDA guidelines. “DHA” as labeled in nutritional supplements oftentimes referred to “DHA” as a genus of various forms of DHA.
Eggs may be farmed following the USDA guidelines for “organic” foods. The phospholipids from the eggs from organically raised and fed hens are then extracted to be “Organic Phospholipid-DHA,” “Organic DHA,” or “Organic Phospholipids.” Then the Organic phospholipid extract may be included in a nutritional supplement in the form of a tablet, capsule, softgel, or chewable tablet.
Folic Acid and Folate
A pharmaceutically acceptable form of folic acid, folic acid derivatives, folate, reduced folate, or any combination thereof is included within the nutritional compositions. Folate has been shown to play a role in nucleotide synthesis in mammals. Specifically, folic acid is known to play a role in various methylation processes in humans and more specifically in the synthesis of thymine from uracil (i.e., dUMP, deoxyuracil monophosphate). In adult humans, folic acid supplementation has been implicated in reducing megaloblastic anemia often associated with folate deficiency and/or side effects associated with various medical treatments (e.g., chemotherapy).
In addition, folic acid has been shown to play a role in preventing neural tube defects that occur during pregnancy. For example, although the molecular and physiological mechanisms are currently unknown, folic acid supplementation has been theorized to reduce the occurrence of spina bifida by up to 70%. Thus, for at least these reasons, it is desirable to include a pharmaceutically acceptable form of folic acid and folic acid derivatives in the disclosed nutritional compositions.
Various forms of folic acid are present in high concentrations in eggs. For example, folic acid, reduced folate, dihydrofolate, tetrahydrofolate, 10-formyl folic acid, 5-formyl tetrahydrofolate, and 5-methyl tetrahydrofolate are present in egg yolks. Therefore, in certain aspects and to potentially lower production costs of the disclosed nutritional compositions, it is desirable to extract folate from eggs while obtaining the phospholipid derived from eggs.
In certain aspects, folic acid derivatives having substituents at its N5 or N10 position have increased stability and are less prone to cleavage and oxidation. Thus, these folic acid derivatives may be favored in the disclosed nutritional composition. For example, in certain aspects, it is preferable that at least one of folic acid, 10-formyl folic acid, 5-formyl tetrahydrofolate, 5-methyl tetrahydrofolate, or any combination thereof is present at a higher concentration in the nutritional composition than dihydrofolate and tetrahydrofolate, and in certain aspects, dihydrofolate and/or tetrahydrofolate are not present in the nutritional composition.
The total biologically active amount of folate: folic acid and derivatives thereof present in the nutritional composition ranges from 100 μg to 15 mg. Total biologically active amounts of folic acid and derivatives thereof below 100 μg are potentially inadequate to prevent or reduce problems associated with folate deficiencies (e.g., megaloblastic anemia, neural tube defects in fetuses, etc.). Pregnant mothers are recommended to take between 400 mcg and 1 mg of folate. High dosages of folate have been shown to improve a number of human ailments and conditions including impaired cognitive function, memory loss, diabetic peripheral neuropathy, and depression. Therefore, in certain aspects, the total biologically active amount of folic acid and derivatives thereof present in the nutritional composition ranges from 100 μg to 15 mg, 400 μg to 800 μg, 400 μg to 1000 μg, 800 μg to 1000 μg, 1 mg to 3 mg, 3 mg to 6 mg, 7.5 mg to 15 mg, or any range having endpoints falling within any of the preceding ranges.
In certain aspects, the total amount of folate, folic acid, and reduced folate derivatives present in the nutritional composition ranges from 0.1 mg to 20 mg based on the total weight of the nutritional composition.
In certain aspects, the folic acid and folic acid derivatives are not included in the microparticles of the nutritional composition. In other aspects, a portion of the folic acid and folic acid derivatives are included in any of the coated layers of the microparticles and another portion of the folic acid and folic acid derivatives are included in the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of the folic acid and folic acid derivatives are not in the microparticles, and in this aspect, the remainder of the folic acid and folic acid derivatives can included in the microparticle.
Iron
A pharmaceutically acceptable form of iron is also included within the disclosed nutritional compositions. In the human body, iron is a key component, which is often complexed with various porphyrin rings to facilitate numerous metabolic and biological processes. More specifically, iron is often complexed with heme groups to form hemoglobin, and iron is also often complexed with various cytochromes (e.g., Cytochrome C in the mitochondria) to carry out electron transport during the production of adenosine tri-phosphate (i.e., ATP) in the mitochondria.
In humans, iron deficiency is usually associated with various anemias, thrombocytosis, decreased immunity, increased susceptibility to sepsis, increased maternal mortality, and atrophy of mucous membranes (e.g., Plummer-Vinson syndrome). Furthermore, iron deficiency in pregnant mothers, can potentially lead to low birth weights, preterm birth, and under development in a newborn child. Thus, for at least these reasons, it is desirable to include a pharmaceutically acceptable form of iron in the disclosed nutritional compositions.
In the disclosed nutritional composition, it is preferable to include iron in the total amount of about 0.1 mg/kg to 6 mg/kg, 2.5 mg/kg to 5.5 mg/kg, 3 mg/kg to 5 mg/kg, 3.5 mg/kg to 4.5 mg/kg, or any range having endpoints falling within any of the preceding ranges of a subject's body mass. For example, if the subject has a body mass of 100 kg (i.e., 220 lbs), it is preferable to orally administer 10 mg to 600 mg of iron to this subject when using the 2 mg/kg to 6 mg/kg range. Total amounts of iron in the nutritional composition falling below 1 mg/kg are potentially inadequate to prevent or reduce problems associated with iron deficiency. Furthermore, total amounts of iron exceeding 6 mg/kg may be associated with unwanted side effects associated such as iron poisoning if administered for an extended period of time. Therefore, in certain aspects, the total amount of iron thereof present in the nutritional composition ranges from 10 mg to 600 mg, 10 mg to 500 mg, 10 mg to 400 mg, 10 mg to 300 mg, 10 mg to 200 mg, 10 mg to 100 mg, 50 mg to 500 mg, 50 mg to 400 mg, 50 mg to 300 mg, 50 mg to 200 mg, 50 mg to 100 mg, 100 mg to 500 mg, 100 mg to 450 mg, 100 mg to 400 mg, 100 mg to 350 mg, 100 mg to 300 mg, 100 mg to 250 mg, 100 mg to 200 mg, 100 mg to 150 mg, 200 mg to 400 mg, 200 mg to 350 mg, 200 mg to 300 mg, 200 mg to 250 mg, 300 mg to 500 mg, 300 mg to 450 mg, 300 mg to 400 mg, 300 mg to 350 mg, or any range having endpoints falling within any of the preceding ranges.
Iron may be provided through many different pharmaceutically acceptable salts or chelates and one skilled in the art would know of these salts and chelates. Some pharmaceutically acceptable forms of iron supplementation may be through carbonyl, ferrous gluconate, ferrous fumerate, iron amino acid complexes, ferronyl carbonate, iron chelates, among others not listed.
In certain aspects, the total amount of Iron present in the nutritional composition is about 27.5 mg. In certain aspects, the total amount of iron present in the nutritional composition ranges from 0.5 mg to 100 mg based on the total weight of the nutritional composition.
In certain aspects, iron is not included in the microparticles of the nutritional composition. In other aspects, a portion of iron is included in any of the coated layers of the microparticles and another portion of iron is included in the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of iron is not in the microparticles, and in this aspect, the remainder of the iron can be included the microparticle.
Other Ingredients
In certain embodiments and as discussed further below, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin B6, Vitamin B12, N-Acetyl-Cysteine (NAC), Coenzyme Q10 (CoQ 10) or any combination thereof.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin B6. Vitamin B6, and more specifically pyridoxal-5-phosphate, is involved in numerous biological reactions occurring in a subject including amino acid metabolism, hemoglobin synthesis, neurotransmitter synthesis, lipid metabolism, and gluconeogenesis (e.g., glycogenolysis). Vitamin B6 may also be supplemented as pyridoxine HCl. Other forms of Vitamin B6 are known and one skilled in the art would be aware of the various forms. Thus, to further complement the effects of DHA, folic acid and derivatives thereof, and iron mentioned above, Vitamin B6 can be added to the nutritional composition. In certain aspects, the total amount of Vitamin B6 present in the nutritional composition ranges from 0.1 mg to 100 mg, 0.1 mg to 75 mg, 0.1 mg to 50 mg, 0.1 mg to 25 mg, 0.1 mg to 10 mg, 0.1 mg to 7.5 mg, 0.1 mg to 5 mg, 0.1 mg to 3 mg, 0.1 mg to 2.5 mg, 0.1 mg to 2 mg, 0.1 mg to 1 mg, 0.1 mg to 0.5 mg, 0.2 mg to 10 mg, 0.2 mg to 7.5 mg, 0.2 mg to 5 mg, 0.2 mg to 2.5 mg, 0.2 mg to 2.0 mg, 0.2 mg to 1.5 mg, 0.2 mg to 1 mg, 0.3 mg to 10 mg, 0.3 mg to 7.5 mg, 0.3 mg to 5 mg, 0.3 mg to 2.5 mg, 0.3 mg to 2.0 mg, 0.3 mg to 1.5 mg, 0.3 mg to 1 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg, 0.5 mg to 3 mg, 0.5 mg to 2.5 mg, 0.5 mg to 2.0 mg, 0.5 mg to 1.5 mg, 0.5 mg to 1 mg, 0.75 mg to 3 mg, 0.75 mg to 2.5 mg, 0.75 mg to 2.0 mg, 0.75 mg to 1.5 mg, 0.75 mg to 1 mg, 1 mg to 2 mg, 1 mg to 1.5 mg or any range having endpoints falling within any of the preceding ranges.
In certain aspects, the total amount of Vitamin B6 present in the nutritional composition ranges from 0.5 mg to 55 mg based on the total weight of the nutritional composition. In one aspect, the total amount of Vitamin B6 is 26 mg. In another aspect, the total amount of Vitamin B6 is 35 mg. In one aspect, the total amount of Vitamin B6 is 25 mg.
In certain aspects, Vitamin B6 is not included in the microparticles of the nutritional composition. In other aspects, a portion of Vitamin B6 is included in any of the coated layers of the microparticles and another portion of Vitamin B6 is included in the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Vitamin B6 is not in the microparticles, and in this aspect, the remainder of Vitamin B6 can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin B12. Vitamin B12 plays a role in DNA synthesis, regulation of DNA synthesis, and fatty acid synthesis. Vitamin B12 has been implicated in playing a key role in maintaining normal brain function and regulating the nervous system. In humans, Vitamin B12 deficiency can cause severe and irreversible damage to the brain and nervous system, which may manifest with symptoms of mania and psychosis. Thus, to potentially prevent Vitamin B12 deficiency and to further complement the effects of DHA, folic acid and derivatives thereof, and iron discussed above, Vitamin B12 can be added to the nutritional composition. Vitamin B12 may also be supplemented as cyanocobalamin, or preferably methylcobalamin. Other forms of Vitamin B12 are known and one skilled in the art would be aware of the various forms.
In certain aspects, the total amount of Vitamin B12 present in the nutritional composition ranges from 0.1 μg to 5 μg, 0.1 μg to 4 μg, 0.1 μg to 3 μg, 0.1 μg to 2 μg, 0.1 μg to 1 μg, 0.3 μg to 4.5 μg, 0.3 μg to 3.5 μg, 0.3 μg to 2.5 μg, 0.3 μg to 2 μg, 0.3 μg to 1 μg, 0.4 μg to 3.5 μg, 0.4 μg to 3 μg, 0.4 μg to 2.5 μg, 0.4 μg to 2 μg, 0.4 μg to 1 μg, 0.5 μg to 3 μg, 0.5 μg to 2.5 μg, 0.5 μg to 2 μg, 0.5 μg to 2 μg, 0.5 μg to 0.9 μg, or any range having endpoints falling within any of the preceding ranges. In certain aspects, the total amount of Vitamin B12 present in the nutritional composition ranges from 10 μg to 5 mg based on the total weight of the nutritional composition. In one aspect, the total amount of Vitamin B12 is 12 mcg. In another aspect, the total amount of Vitamin B12 is 2 mg.
In certain aspects, Vitamin B 12 is not included in the microparticles of the nutritional composition. In other aspects, a portion of Vitamin B12 is included in any of the coated layers of the microparticles and another portion of Vitamin B12 is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Vitamin B12 is not in the microparticles, and in this aspect, the remainder of Vitamin B12 can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable N-Acetyl-Cysteine in the range of from 100 mg to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 100 mg to 400 mg, 100 mg to 300 mg, 100 mg to 200 mg, 200 mg to 800 mg, 200 mg to 650 mg, 200 mg to 500 mg, 200 mg to 450 mg, 200 mg to 300 mg, 300 mg to 750 mg, 300 mg to 600 mg, 300 mg to 500 mg, 300 mg to 450 mg, 300 mg to 400 mg, 400 mg to 650 mg, 400 mg to 600 mg, 400 mg to 550 mg, 400 mg to 500 mg, 400 mg to 450 mg, or any range having endpoints falling within any of the preceding ranges.
In certain aspects, the total amount of N-Acetyl-Cysteine present in the nutritional composition ranges from 1 mg 1 g based on the total weight of the nutritional composition.
In certain aspects, N-Acetyl-Cysteine is not included in the microparticles of the nutritional composition. In other aspects, a portion of N-Acetyl-Cysteine is included in any of the coated layers of the microparticles and another portion of N-Acetyl-Cysteine is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of N-Acetyl-Cysteine is not in the microparticles, and in this aspect, the remainder of N-Acetyl-Cysteine can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Coenzyme Q10 (CoQ 10). CoQ 10 is a vitamin-like substance that is present primarily in mammalian mitochondria. In humans, CoQ10 has been implicated in oxidative phosphorylation and electron chain transport in the mitochondria, which ultimately results in the production of ATP. Furthermore, CoQ10 has an antioxidant function that reduces or prevents lipid peroxidation. Therefore, in certain aspects, CoQ10 may act synergistically with the DHA described herein as well as Vitamin B6 and/or Vitamin B12 to promote cognitive function by promoting lipid synthesis and lipid maintenance occurring, for example, in the brain while concurrently reducing lipid damage occurring from lipid peroxidation.
In certain aspects, the total amount of CoQ10 present in the nutritional composition ranges from 0.5 mg to 7 mg, 0.5 mg to 6 mg, 0.5 mg to 5 mg, 0.5 mg to 4 mg, 0.5 mg to 3 mg, 0.5 mg to 2 mg, 0.5 mg to 1 mg, 1 mg to 6.5 mg, 1 mg to 6 mg, 1 mg to 5.5 mg, 1 mg to 5 mg, 1 mg to 4.5 mg, 1 mg to 4 mg, 1 mg to 3.5 mg, 1 mg to 3 mg, 1 mg to 2.5 mg, 1 mg to 2 mg, 2 mg to 6 mg, 2 mg to 5.5 mg, 2 mg to 5 mg, 2 mg to 4.5 mg, 2 mg to 4 mg, 2 mg to 3.5 mg, 2 mg to 3 mg, 2 mg to 2.5 mg, 3 mg to 6 mg, 3 mg to 5.5 mg, 3 mg to 5 mg, 3 mg to 4.5 mg, 3 mg to 4 mg, 3 mg to 3.5 mg, 4 mg to 5.5 mg, 4 mg to 5 mg, 4 mg to 4.5 mg, or any range having endpoints falling within any of the preceding ranges. In certain aspects, the total amount of CoQ10 present in the nutritional composition ranges from 50 mg to 200 mg based on the total weight of the nutritional composition.
In certain aspects, CoQ10 is not included in the microparticles of the nutritional composition. In other aspects, a portion of CoQ10 is included in any of the coated layers of the microparticles and another portion of CoQ10 is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of CoQ10 is not in the microparticles, and in this aspect, the remainder of CoQ10 can be included in a portion of the encapsulating body that is not the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin C in the range of from 10 mg to 1000 mg.
In certain aspects, the total amount of Vitamin C present in the nutritional composition is about 70 mg.
In certain aspects, Vitamin C is not included in the microparticles of the nutritional composition. In other aspects, a portion of Vitamin C is included in any of the coated layers of the microparticles and another portion of Vitamin C is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Vitamin C is not in the microparticles, and in this aspect, the remainder of Vitamin C can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin D in the range of from 50 IU to 2000 IU.
In certain aspects, the total amount of Vitamin D present in the nutritional composition is about 1000 IU.
In certain aspects, Vitamin D is not included in the microparticles of the nutritional composition. In other aspects, a portion of Vitamin D is included in any of the coated layers of the microparticles and another portion of Vitamin D is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Vitamin D is not in the microparticles, and in this aspect, the remainder of Vitamin D can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin E in the range of from 10 IU to 1000 IU.
In certain aspects, the total amount of Vitamin E present in the nutritional composition is about 10 IU.
In certain aspects, Vitamin E is not included in the microparticles of the nutritional composition. In other aspects, a portion of Vitamin E is included in any of the coated layers of the microparticles and another portion of Vitamin E is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Vitamin E is not in the microparticles, and in this aspect, the remainder of Vitamin E can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Vitamin C in the range of from 10 mg to 1000 mg.
In certain aspects, the total amount of Vitamin C present in the nutritional composition is about 70 mg.
In certain aspects, Vitamin C is not included in the microparticles of the nutritional composition. In other aspects, a portion of Vitamin C is included in any of the coated layers of the microparticles and another portion of Vitamin C is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Vitamin C is not in the microparticles, and in this aspect, the remainder of Vitamin C can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Calcium in the range of from 5 mg to 200 mg. Calcium may be provided through many different pharmaceutically acceptable salts and one skilled in the art would know of these salts.
In certain aspects, the total amount of Calcium present in the nutritional composition is about 15 mg.
In certain aspects, Calcium is not included in the microparticles of the nutritional composition. In other aspects, a portion of Calcium is included in any of the coated layers of the microparticles and another portion of Calcium is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Calcium is not in the microparticles, and in this aspect, the remainder of Calcium can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally include pharmaceutically acceptable Iodine in the range of from 50 mcg to 300 mcg. Iodine may be provided through many different pharmaceutically acceptable salts and one skilled in the art would know of these salts. In one aspect, iodine is provided as potassium iodide.
In certain aspects, the total amount of Iodine present in the nutritional composition is about 150 mcg.
In certain aspects, Iodine is not included in the microparticles of the nutritional composition. In other aspects, a portion of Iodine is included in any of the coated layers of the microparticles and another portion of Iodine is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Iodine is not in the microparticles, and in this aspect, the remainder of Iodine can be included in the microparticle.
In certain embodiments, the disclosed nutritional composition can optionally included pharmaceutically acceptable Magnesium in the range of from 5 mg to 100 mg. Magnesium may be provided through many different pharmaceutically acceptable salts and one skilled in the art would know of these salts. In one aspect, magnesium is provided as magnesium oxide.
In certain aspects, the total amount of Magnesium present in the nutritional composition is about 20 mg.
In certain aspects, Magnesium is not included in the microparticles of the nutritional composition. In other aspects, a portion of Magnesium is included in any of the coated layers of the microparticles and another portion of Magnesium is included in a portion of the encapsulating body (e.g., tablets and capsules) that is not the microparticle. For example, in certain aspects, at least 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, or 50% of the overall amount of Magnesium is not in the microparticles, and in this aspect, the remainder of Magnesium can be included in the microparticle.
In addition, any standard pharmaceutically acceptable excipient can be used in the nutritional composition. For example, these excipients can include diluents (e.g., mannitol, sorbitol, lactose, sucrose, and compressible sugars such as DiPacTM (dextrinized sucrose), available from Austin Products Inc., Holmdel, N.J.), splitting or swelling agents (e.g., polyvinyl polypyrrolidone, croscarmellose sodium (e.g., Ac-Di-SolTM available from FMC BioPolymer, Philadelphia, Pa.), starches and derivatives, cellulose and derivatives, microcrystalline celluloses, such as AvicelTM PH 101 or AvicelTM CE-15 (a microcrystalline modified with guar gum), both available from FMC BioPolymer, Philadelphia, Pa.), lubricating agents (e.g., magnesium stearate), and flow agents (e.g., colloidal silicon dioxide, such as Cab-O-Sil M5 available from Cabot Corporation, Kokomo, Ind.).
Also, sweeteners can be included in the nutritional compositions described herein. For example, sweeteners can be used to impart a pleasant flavor to the composition. Suitable sweeteners for use in the present disclosure include natural sweeteners such as sucrose, dextrose, fructose, invert sugar, mannitol, sorbitol, and the like, as well as synthetic sweeteners such as saccharin, aspartame, acesulfame potassium, cyclamates, and other commercial artificial sweeteners well-known to those of skill in the art. A preferred sweetener is acesulfame K (SunettTM available from Nutrinova, Frankfort, Germany). The sweetener is added in an amount to achieve a desired sweetness. Typically, the sweetener is present in an amount from about 1.0 wt % to about 5.0 wt % of the overall weight of the nutritional composition. Since the nutritional supplement may capitalize on the DHA being sourced from eggs, egg-friendly flavors are also preferred, which include vanilla and dulce de leche or caramel. Other flavors as chocolate or strawberry are also workable. Those skilled in the part will appreciate that the amount of sweetener may vary depending on the strength of the particular sweetener used and the levels approved by the regulatory authorities for use in pharmaceutical products.
Time Release Coatings
In certain aspects, the outermost surface of the encapsulating body and the outermost surface of the microparticle can independently include a time release coating. For example, in certain aspects the outermost surface of the encapsulating body can include a time release coating while such a coating is omitted from the microparticle. In other aspects, the outermost surface of the microparticle can include a time release coating while such a coating is omitted from the outermost surface of the encapsulating body.
Examples of these time release agents can include but are not limited to hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, pullulan, gelatin, collagen, casein, agar, gum arabic, dextrin, ethyl cellulose, methyl cellulose, chitin, chitosan, mannan, carboxymethylethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol, sodium alginate, poly(vinyl alcohol), cellulose acetate, poly(vinylpyrrolidone), silicone, poly(vinyl acetal) diethylamino acetate, albumin, adenine, cystine, D-tyrosine, or any combination thereof.
In certain aspects, these time release coatings may range from 1-15% of the overall weight of the nutritional composition.
EXAMPLES
Example 1 (Microparticles Coated with Phospholipid Extract)
Microparticle cores can be prepared by extrusion spheronizer technology, and the microparticle cores can be subsequently made of phospholipid extract, cellulose, starch, lactose, mannitol. DHA may comprise 25% to 50% of the microparticle core.
A pharmaceutically acceptable source of phospholipid extract may be mixed with a pharmaceutically acceptable neutral material such as tartaric acid, sugar sphere, calcium carbonate, mannitol, microcrystalline cellulose, silica, or starch which is then subjected to an extruding step to obtain microparticle cores in which 95% of the microparticle cores have an average particle diameter ranging from 90 μm to 500 um. These materials are mixed for 15-25 minutes and then extruded out an extruder.
Next, the microparticle cores are placed into a spheroidizer at 500 rpm for 5 to 10 second to ensure that sufficient microparticle core roundness is obtained.
After ensuring proper microparticle core roundness has been obtained, the microparticle cores are organized into a bed of microparticle cores that are subjected to a coating step. Next, the microparticle cores may also be (i) directly coated with an enteric coating to provide a dissolution rate profile and/or (ii) directly coated with a protective coating: solution, suspension, or dispersion or. The enteric coating may be L30D on different polymers. The enteric coating may comprise 1-5% of the weight of the total microparticle composition. The protective coating maybe hpmc. The protective coating may comprise 1-10% of the weight of the total microparticle composition.
Example 2 (Exemplary Nutritional Composition Formulations)
Table 1 lists exemplary formulations of the nutritional composition of the present disclosure.











TABLE 1






Exemplary
Exemplary
Exemplary
Exemplary



Formulation 1
Formulation 2
Formulation 3
Formulation 4


Ingredient
(wt %)
(wt %)
(wt %)
(wt %)























Total Egg Phospholipid
200
mg
90-95
mg
90-95
mg
90-95
mg


(“Phospholipid extract”)


PC-DHA
20
mg
9
mg
9
mg
9
mg


PE-DHA
5
mg
4.5
mg
4.5
mg
4.5
mg


Folic Acid or other folate
700
mcg
3
mg
6
mg
15
mg


(total folate)


Iron
27.5
mg
0
mg
0
mg
0
mg


Vitamin B6 (any form)
26
mg
35
mg
0
mg
0
mg


Vitamin E
20
IU
0
mg
0
mg
0
mg


Vitamin B12 (any form)
12
mcg
2
mg
2
mg
0
mg


Calcium
15
mg
0
mg
0
mg
0
mg


NAC (any form)
2.5
mg
0
mg
600
mg
0
mg





The formulations above do not include excipients, binders, stabilizers, etc.






The foregoing description provides embodiments of the disclosure by way of example only. It is envisioned that other embodiments may perform similar functions and/or achieve similar results. Any and all such equivalent embodiments and examples are within the scope of the present disclosure and are intended to be covered by the appended claims
It should be emphasized that the embodiments described herein are merely possible examples of implementations, merely set forth for a clear understanding of the principles of the present disclosure. Many variations and modifications may be made to the described embodiment(s) without departing substantially from the spirit and principles of the present disclosure. Further, the scope of the present disclosure is intended to cover any and all combinations and sub-combinations of all elements, features, and aspects discussed above. All such modifications and variations are intended to be included herein within the scope of the present disclosure, and all possible claims to individual aspects or combinations of elements or steps are intended to be supported by the present disclosure.
One should note that conditional language, such as, among others, “can,” “could,” “might,” or “may,” unless specifically stated otherwise, or otherwise understood within the context as used, is generally intended to convey that certain embodiments include, while alternative embodiments do not include, certain features, elements and/or steps. Thus, such conditional language is not generally intended to imply that features, elements and/or steps are in any way required for one or more particular embodiments or that one or more particular embodiments necessarily include logic for deciding, with or without user input or prompting, whether these features, elements and/or steps are included or are to be performed in any particular embodiment. Unless stated otherwise, it should not be assumed that multiple features, embodiments, solutions, or elements address the same or related problems or needs.
Various implementations described in the present disclosure may include additional systems, methods, features, and advantages, which may not necessarily be expressly disclosed herein but will be apparent to one of ordinary skill in the art upon examination of the following detailed description and accompanying drawings. It is intended that all such systems, methods, features, and advantages be included within the present disclosure and protected by the accompanying claims.

## Claims

1. A composition, comprising:
a phospholipid extract at a concentration ranging from 50 mg to 600 mg, the phospholipid extract having phosphatidylcholine-docosahexaenoic acid and phosphatidylethanolamine-docosahexaenoic acid at a ratio ranging from about 1:1 to about 3:1, and
an effective amount of stabilizer that improves shelf life.

2. The composition of claim 1, additionally comprising:
an amount of folic acid,
an amount of Vitamin D,
an amount of Vitamin B6,
an amount of Vitamin B12,
an amount of Vitamin E,
an amount of Vitamin C,
an amount of Iodine between,
an amount of Iron between, and
an amount of Magnesium.

3. The composition of claim 2, wherein the amount of phospholipid extract is 200 mg.

4. The composition of claim 2, wherein the amount of phospholipid-DHA is 99 mg.

5. The composition of claim 2, wherein the amount of folic acid is between 400 mcg and 800 mcg,
the amount of Vitamin D is between 100 IU and 2000 IU,
the amount of Vitamin B6 is between 0.5 mg and 50 mg,
the amount of Vitamin B12 is between 10 mcg and 1 mg,
the amount of Vitamin E is between 10 IU and 100 IU,
the amount of Vitamin C is between 50 mg and 150 mg,
the amount of Iodine is between 50 mcg and 300 mcg,
the amount of Iron is between 10 mg and 30 mg, and
the amount of Magnesium is between 5 mg and 100 mg.

6. The composition of claim 5, wherein
the amount of folic acid is 400 mcg,
the amount of Vitamin D is 1000 IU,
the amount of Vitamin B6 is 26 mg,
the amount of Vitamin B12 is 13 mcg,
the amount of Vitamin E is 10 IU,
the amount of Vitamin C is 60 mg,
the amount of Iodine is 150 mcg,
the amount of Iron is 18 mg, and
the amount of Magnesium is 25 mg.

7. The composition of claim 5, wherein
the amount of folic acid is 800 mcg,
the amount of Vitamin D is 1000 IU,
the amount of Vitamin B6 is 5 mg,
the amount of Vitamin B12 is 1.9 mg,
the amount of Vitamin E is 20 IU,
the amount of Vitamin C is 70 mg,
the amount of Iodine is 150 mcg,
the amount of Iron is 27 mg, and
the amount of Magnesium is 7.5 mg.

8. The composition of claim 7, wherein the phospholipid extract contains less than 3%, by weight, triglycerides.

9. The composition of claim 1, wherein the amount of phospholipid extract is about 150 mg.

10. The composition of claim 1, wherein the amount of phospholipid-DHA is 74 mg.

11. The composition of claim 1, wherein the composition is a capsule or softgel.

12. The composition of claim 1, wherein the phospholipid extract contains less than 3%, by weight, triglycerides.

13. The composition of claim 1, wherein the amount of phosphatidylcholine-docosahexaenoic acid makes up at least 7.5% of the phospholipid extract and phosphatidylethanolamine-docosahexaenoic acid makes up at least 8% of the phospholipid extract.

14. A method of providing a human a source of omega-3 fatty acids, the method comprising:
administering to the human a composition comprising:
a phospholipid extract at a concentration ranging from 50 mg to 600 mg, the phospholipid extract having phosphatidylcholine-docosahexaenoic acid and phosphatidylethanolamine-docosahexaenoic acid at a ratio ranging from about 1:1 to about 3:1, and
an effective amount of stabilizer that improves shelf life.

15. The method of claim 14, wherein the amount of phospholipid extract is 150 mg.

16. The method of claim 14, wherein the amount of phospholipid-DHA is 15 mg.

17. The method of claim 14, wherein the human is administered the composition more than once a day.

18. A method of providing a pregnant or nursing mother a source of omega-3 fatty acids, the method comprising:
administering to the human a composition comprising:
a phospholipid extract at a concentration ranging from 50 mg to 600 mg, the phospholipid extract having phosphatidylcholine-docosahexaenoic acid and phosphatidylethanolamine-docosahexaenoic acid at a ratio ranging from about 1:1 to about 3:1, and
an effective amount of stabilizer that improves shelf life.

19. The method of claim 18, wherein the composition additionally comprises:
an amount of folic acid that is between 400 mcg and 800 mcg,
an amount of Vitamin D is between 100 IU and 2000 IU,
an amount of Vitamin B6 is between 0.5 mg and 50 mg,
an amount of Vitamin B12 is between 10 mcg and 1 mg,
an amount of Vitamin E between 10 IU and 100 IU,
an amount of Vitamin C between 50 mg and 150 mg,
an amount of Iodine between 50 mcg and 300 mcg,
an amount of Iron is between 10 mg and 30 mg, and
an amount of Magnesium between 5 mg and 30 mg.

20. The method of claim 19, wherein
the amount of folic acid is 400 mcg,
the amount of Vitamin D is 1000 IU,
the amount of Vitamin B6 is 26 mg,
the amount of Vitamin B12 is 13 mcg,
the amount of Vitamin E is 10 IU,
the amount of Vitamin C is 60 mg,
the amount of Iodine is 150 mcg,
the amount of Iron is 18 mg, and
the amount of Magnesium is 25 mg.