Bile binding blenderized tube feeding formulations for treating gastrointestnal and respiratory diseases / conditions

Abstract

Provided herein are formulations for use in enteral tube feeding, that contain one or more whole food-based ingredients, mineral nutrients, small molecules, and / or large molecules, the combination of which is effective to bind bile acids when administered to a subject in need thereof. The combination of crafted ingredients for tube feeding reduce symptoms of gastroesophageal reflux, vomiting, abdominal pain, irregular stooling (diarrhea or constipation) and to reduce organ damage including pneumonia, pharyngitis, aspiration, esophagitis, gastritis and enteritis.

Description

[0001] PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0002] Attorney Docket #: CMCC 4458 PCT

[0003] BILE BINDING BLENDERIZED TUBE FEEDING FORMULATIONS FOR TREATING GASTROINTESTNAL AND RESPIRATORY DISEASES / CONDITIONS CROSS REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 691,145, filed September 5, 2024, which is hereby incorporated herein by reference in its entirety.

[0005] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0006] This invention was made with government support under Grant nos. DK097112 and DK133679, awarded by The National Institutes of Health. The government has certain rights in the invention.

[0007] FIELD OF THE INVENTION

[0008] The disclosed invention is generally in the field of blenderized tube feeding and specifically in the area of compositions and methods for prevention / treatment of gastrointestinal diseases / conditions with blenderized tube feedings.

[0009] BACKGROUND OF THE INVENTION

[0010] Over the past decade, hospitalization rates and health care costs for children with medical complexity (defined by the AAP as children who have multiple chronic health problems, functional limitations, and high health care and resource needs and / or utilization) soared with 75% of all costs in pediatric hospitals resulting from the care of these children. Respiratory and gastrointestinal causes make up almost half of such hospitalizations, despite therapeutic advances such as the use of proton pump inhibitors and postpyloric feedings.

[0011] For example, current therapies fail to treat a critical proinflammatory component of gastric fluid including bile acids. In vitro, bile acids may trigger inflammation by altering microbial populations, disrupting the lung surfactant, and triggering inflammatory cascades. In humans, gastric bile acids have been implicated as a cause for disorders such as gastritis, esophagitis, lung transplant allograft rejection, aspiration pneumonitis and Barrett’s esophagus. It has been shown that bile can be problematic in children, in addition to in adults, including CMC, specifically (1) retrograde bile acid reflux is common, as evidenced by bile acids’ presence in 100% of gastric fluid and 98% of bronchoscopy fluid samples; and (2) bile aspiration is harmful, as higher pulmonary bile concentrations correlate with worse clinical outcomes such as pulmonary hospitalizations and lung allograft rejection. Despite the potential harm of upper gastrointestinal and extraesophageal bile acids, no medications targeting the gastric binding of bile acids are commercially available. i

[0012] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0013] Attorney Docket #: CMCC 4458 PCT

[0014] One possible therapeutic option might be cholestyramine, a medication known to sequester intestinal bile acids. Cholestyramine binds intestinal BA at neutral or alkaline pHs, but its efficacy in binding BA in the human gastric milieu that has pH 1-2 is not known. However, mouse studies found that administration of cholestyramine particularly at low pHs actually can worsen gastric mucosal damage and limited studies in adults have shown no healing benefit. Even if cholestyramine were to bind gastric BA, its administration to via gastrostomy or other enteral tube is extremely difficult because it binds to other medications, thus reducing their efficacy and must be diluted in large fluid volume to avoid clogging enteral tubes, but this excess free water increases aspiration risk. Given the limitations of cholestyramine and the lack of another commercially available pharmacologic therapy, a therapeutic nutritional intervention offers appeal because of its availability, cost, and accessibility.

[0015] Therefore, there remains a need for an effective and economical treatment of respiratory and gastrointestinal conditions triggered by bile acids.

[0016] SUMMARY OF THE INVENTION

[0017] Provided herein are formulations for use in oral feeding or enteral tube feeding, that contain one or more whole food-based ingredients, mineral nutrients, small molecules, and / or large molecules, the combination of which is effective to bind bile acids when administered to a subject in need thereof. The oral tube feeding or enteral tube feeding composition in some forms, includes bile sequestering foods as well as complete sources of protein, carbohydrates, and fats.

[0018] In some forms, the whole food-based ingredients include vegetables, fruits, grains, protein foods, dairy, oils and solid fats. In some embodiments, the small molecules and large molecules include carbohydrates, lipids, proteins, nucleic acids, sugars, lipids, amino acids, fatty acids, phenolic compounds, and / or alkaloids.

[0019] In some forms, the formulations includes high bile sequestrants at least 20% by weight of the formulation, for example about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 etc, by weight of the formulation. Bile sequestrants include food sources such as but are not limited to, banana, prunes, kale, chickpeas and phyllium husk.

[0020] The formulations are used to treat one or more gastrointestinal conditions or symptoms associated therewith, such as gastroesophageal reflux, vomiting, recurrent pneumonia, gastric or esophageal inflammation, gastric, esophageal or duodenal dysmotility, diarrhea, aspiration pneumonia, constipation, abdominal pain, nausea, and / or flatulence.

[0021] In preferred embodiments, the disclosed feed formulations are used to treat symptoms of gastroesophageal reflux. In some embodiments, the whole food-based ingredients exhibit an

[0022] 2

[0023] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0024] Attorney Docket #: CMCC 4458 PCT improved bile binding capacity compared to cholestyramine of between 10% and 100% more, between 10% and 100% more, between 20% and 100% more, between 30% and 100% more, between 40% and 100% more, between 50% and 100% more, between 60% and 100% more, between 70% and 100% more, between 80% and 100% more, between 90% and 100% more, between 95% and 100% more in comparison to cholestyramine.

[0025] The tube feeding composition has a desirable viscosity profile for tube feeding applications and may be manufactured using at least two homogenization steps. A suitable viscosity for the food composition is a viscosity that prevents gastroesophageal reflux and promotes satiety. The viscosity is preferably between 1,000 cP and 15,000 cP, between 1,000 cP and 10,000 cP, between 1,000 cP and 8,000 cP, between 1,000 cP and 6,000, between 1,000 cP and 4,000, between 1,000 cP and 3,000, between 1,000 cP and 2,500, or between 1,500 cP and 2,500. Viscosity is determined by the International Dysphagia Diet Standardization Initiative (IDDSI) framework syringe flow test (Cichero JA, Lam P, Steele CM, et al. Development of International Terminology and Definitions for Texture-Modified Foods and Thickened Fluids Used in Dysphagia Management: The IDDSI Framework. Dysphagia. 2017;32(2) :293-314. doi:10.1007 / s00455-016-9758-y).

[0026] Also disclosed are methods of treating a subject in need thereof, by administering an effective amount of the food formulation.

[0027] Additional advantages of the disclosed method and compositions will be set forth in part in the description which follows, and in part will be understood from the description, or can be learned by practice of the disclosed method and compositions. The advantages of the disclosed method and compositions will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.

[0028] BRIEF DESCRIPTION OF THE DRAWINGS

[0029] FIG. 1 is a schematic of the bile reflux progressing from the duodenum into the stomach then into the esophagus and oropharynx (black dotted arrows) with possible aspiration into the lung (black solid arrows).

[0030] FIG. 2A and 2B are graphs showing the relationship between oral and enteral tube type. FIG. 2A shows the relationship with gastric bile concentrations; and FIG. 2B shows the relationship with pulmonary hospitalizations within six months after bile collection.

[0031] 3

[0032] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0033] Attorney Docket #: CMCC 4458 PCT

[0034] FIG. 3 is a graph showing that gastric bile acid subtypes were universally lower in patients receiving blenderized formula compared to patients receiving standard formula. Only UDCA was statistically different between groups (p=0.02).

[0035] FIG. 4 is a schematic showing the first methodological step to assess for bile acid binding capacity of the high bile binding blenderized diet (H-BBB). Human bile is incubated with the H-BBB for 1 hour.

[0036] FIG. 5 is a schematic showing the subsequent methodologic steps to measure bile acid binding capacity. Following incubation, solid phase extraction (SPE) is performed under vacuum manifold. The amount of unbound bile acids is measured using solid phase extraction and liquid chromatography-mass spectrometry.

[0037] FIG. 6 is a graph showing the amount and percentage of unbound bile acids over time when high bile acid blend (H-BBB) was incubated with human bile acids.

[0038] FIG. 7 is a bar graph showing Differences in serum C4 levels by tube and diet type, demonstrating significantly lower levels in patients with blenderized tube feeds compared to formula.

[0039] DETAILED DESCRIPTION OF THE INVENTION

[0040] I. Definitions

[0041] As used herein, a “blenderized tube feed” is a composition containing food and liquid, prepared to be administered to the human gastrointestinal system, including orally, or by enteral access devices, including but not limited to a nasogastric tube, orogastric tube, gastric tube, jejunostomy tube (“J-tube”), percutaneous endoscopic gastrostomy (“PEG”), such as a chest wall port that provides access to the stomach, jejunum and other suitable access ports. The “blenderized tube feed”, as used herein, is understood to include any number of optional additional ingredients, including conventional food additives, for example one or more, acidulants, thickeners, buffers or agents for pH adjustment, chelating agents, colorants, emulsifies, excipients, flavor agents, minerals, osmotic agents, a pharmaceutically acceptable carrier, preservatives, stabilizers, sugars, sweeteners, texturizers, and / or vitamins. The optional ingredients can be added in any suitable amount.

[0042] As used herein, "whole food", "whole food ingredient", "real food", or "real food ingredient" is understood to mean food typically consumed by an individual in their normal daily diet when in their natural or prepared state. For example, whole foods can include any known fruit, vegetable, grain, meat, or protein, carbohydrate, or fat source. A "whole food," "whole food ingredient," "real food," or "real food ingredient" may have been processed such that they

[0043] 4

[0044] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0045] Attorney Docket #: CMCC 4458 PCT can be used in blenderized tube feeding. In some embodiments, this processing is minimal so as to keep it as close to "raw" food as possible and still useable in blenderized tube feeding. In some embodiments, the food is cooked before being prepared into a blenderized tube feeding. Those skilled in the art will appreciate that the use of "whole food," "whole food ingredient," "real food," or "real food ingredient" does not limit the use of other nutritional sources. For example, powdered fruits and vegetables may also be included in the composition.

[0046] As used herein, a “processed whole food” is a whole food that has been modified from its natural or prepared state and is in a state so that it can be placed into a blenderized tube feed formulation.

[0047] As used herein, the term “mineral” is understood to include boron, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, nickel, phosphorus, potassium, selenium, silicon, tin, vanadium, zinc, or combinations thereof.

[0048] As used herein the term “vitamin” is understood to include any of various fat-soluble or water-soluble organic substances, non-limiting examples of which include choline, vitamin A, vitamin Bl (thiamine), vitamin B2 (riboflavin), vitamin B3 (niacin or niacinamide), vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine, pyridoxal, or pyridoxamine, or pyridoxine hydrochloride), vitamin B7 (biotin), vitamin B9 (folic acid), and vitamin B 12 (various cobalamins; commonly cyanocobalamin in vitamin supplements), vitamin C, vitamin D, vitamin E, vitamin K, folic acid and biotin) essential in minute amounts for normal growth and activity of the body and obtained naturally from plant and animal foods or synthetically made, provitamins, derivatives, analogs.

[0049] As used herein the term “patient” is understood to include an animal, especially a mammal, and more especially a human that is receiving or intended to receive treatment, as it is herein defined.

[0050] IL Blenderized Tube Feeding

[0051] Blenderized tube feedings that have high bile binding capabilities for treating oropharyngeal, lung, esophageal, intestinal and stomach diseases / conditions are disclosed herein.

[0052] Bile, or gall, is a yellow-green fluid produced by the liver of most vertebrates, that aids the digestion of lipids in the small intestine. In humans, bile is primarily composed of water and is produced continuously by the liver, and stored and concentrated in the gallbladder. In the human liver, bile is composed of 97-98% water, 0.7% bile salts, 0.2% bilirubin, 0.51% fats (cholesterol, fatty acids, and lecithin), and 200 meq / L inorganic salts. The two main pigments of bile are bilirubin, which is orange-yellow, and its oxidized form biliverdin, which is green.

[0053] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0054] Attorney Docket #: CMCC 4458 PCT

[0055] While bile acids are normally secreted into the small intestine, if the bile is refluxed back into the stomach or is present in high quantities in the intestine, symptoms ensue. An ideal bile sequestrant will bind all bile acids.

[0056] Generally, the disclosed blenderized tube feedings contain whole foods, nutrient minerals, small molecules, large molecules, and / or additives. For example, the blenderized tube feeding contains whole food ingredients. Suitable whole food ingredients for forming the blenderized tube feeding include vegetables, fruits, grains, oils, solid fats, beans, nuts, meat, poultry, fish, seafood, and / or diary. In some embodiments, the blenderized tube feeding contains nutrient minerals, small molecules and large molecules. Suitable small and large molecules for the blenderized tube feedings include carbohydrates, lipids, proteins, nucleic acids, sugars, lipids, amino acids, fatty acids, phenolic compounds, and alkaloids.

[0057] Specific embodiments of the tube feeding composition disclosed herein also include a source of protein, a source of carbohydrate, and a source of fat. Generally, beyond the bile sequestering ingredients, a variety of sources of protein, carbohydrate, and fat that is suitable for use in a nutritional product can also be suitable for use herein, provided that they are also compatible with the other elements of the tube feeding composition as described herein. As mentioned above, the source of protein, the source of carbohydrate, and the source of fat are distinct from the fruit, the vegetable, and the whole grain, although the fruit, vegetable and whole grain can contribute to total amounts of protein, carbohydrate, and fat present in the tube feeding composition disclosed herein.

[0058] The amount of bile binding components, protein, carbohydrate, and fat in the tube feeding composition can be expressed in terms of weight percentage based on the total weight of the tube feeding composition. For example, the formulations include high bile sequestrants at least 20% by weight of the formulation, for example about 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 etc., by weight of the formulation.

[0059] Alternatively, the amount of bile binding components, protein, carbohydrate, and fat in the tube feeding composition can be expressed as a mass concentration.

[0060] The amount of bile binding components, protein, carbohydrate, and fat in the tube feeding composition in specific embodiments is expressed in terms of the percentage of the total calories of the tube feeding composition contributed by each component.

[0061] The present disclosure also provides compositions and methods of feeding that provide an emotional appeal for tube fed patients and / or their caretakers, as well as possible physiological benefits to the patient. In order to provide such an emotional appeal, the

[0062] 6

[0063] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0064] Attorney Docket #: CMCC 4458 PCT formulas / compositions of the present disclosure may, for example, 1) incorporate organic, natural and sustainable ingredients, 2) provide formulations that are specific to a certain ethnicity, religion (Jewish, Islam, Budhist, etc), use natural ingredients to provide coloring, 3) provide pediatric -friendly food blends that a parent would consider “normal” for children consuming an oral diet, and / or 4) provide methods of tube feeding that mimic typical meal times or a cycling menus.

[0065] In some forms, the sourced food sources used to make the disclosure formulations and methods of making, are Kosher. Kosher foods are foods that conform to the Jewish dietary regulations of kashrut. The main components of kashrut are 1) certain animals (and their eggs and milk) cannot be consumed including pigs, shellfish, and hooved animals or bottom feeding fish; 2) dairy and meat products are not eaten together; 3) animals must be slaughtered in specific manners; 4) Kosher preparation must be approved and certified. In some forms, the sourced food sources used to make the disclosure formulations and methods of making are Kosher. Kosher foods are foods that conform to the Jewish dietary regulations of kashrut. The laws of kashrut apply to food derived from living creatures and Kosher foods are restricted to certain types of mammals, birds and fish meeting specific criteria; the flesh of any animals that do not meet these criteria is forbidden by the dietary laws. Furthermore, Kosher mammals and birds must be slaughtered according to a process known as shechita and their blood may never be consumed and must be removed from the meat by a process of salting and soaking in water for the meat to be permissible for use. All plant-based products, including fruits, vegetables, grains, herbs and spices, are intrinsically Kosher, although certain produce grown in the Land of Israel is subjected to other requirements, such as tithing, before it may be consumed. Kosher food also distinguishes between meat and dairy products. Meat products are those that comprise or contain kosher meat, such as beef, lamb or venison, kosher poultry such as chicken, goose, duck or turkey, or derivatives of meat, such as animal gelatin; non-animal products that are processed on equipment used for meat or meat-derived products are also considered to belong to this category. Dairy products are those which contain milk or any derivatives such as butter or cheese; non-dairy products that are processed on equipment used for milk or milk-derived products are also considered as belonging to this category. Because of this categorization, meat and milk or their respective derivatives are not combined in kosher foods, and separate equipment for the storage and preparation of meat-based and dairy-based foods is used in order for food to be considered kosher.

[0066] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0067] Attorney Docket #: CMCC 4458 PCT

[0068] Another category of Kosher food, called pareve contains neither meat, milk nor their derivatives; they include foods such as fish, eggs from permitted birds, produce, grains, fruit and other edible plants. They remain pareve if they are not mixed with or processed using equipment that is used for any meat or dairy products. Because of the complexities of modern food manufacturing, kashrut agencies supervise or inspect the production of kosher foods and provide a certification called a hechsher to verify for kosher food consumers that it has been produced in accordance with Jewish law.

[0069] According to Muslim dietary law, there are two types of food and drink: permissible (halal) and not permissible (haram). One of the main principles of halal is that all foods and drinks must be free from any substances considered haram (forbidden) including pork and its products, animals not slaughtered in accordance with Islamic guidelines (Zabiha), alcohol, and other things. Meat from animals that have been slaughtered in a specific way, known as “Zabiha”, is considered halal.

[0070] One manner in which a nutritional composition (e.g., a tube feed formulation) may evoke an emotional appeal (and / or potential physiological benefit) is to provide organic, natural and sustainable ingredients. For example, compositions of the present disclosure may include 100% organic fruits and / or vegetables and organic meat products such as chicken or beef. To be certified organic, ingredients must be grown and manufactured according to country-specific standards. The United States Department of Agriculture (“USDA”) Organic Certified Fruits and vegetables or Meat provides that fruits and vegetables must be grown without synthetic or non- organic pesticides, insecticides or herbicides.

[0071] For organic meat, the USDA provides that meat must be grown without the use of antibiotics and growth hormones. Organic products are typically free of artificial food additives, and are processed with fewer artificial methods such as chemical ripening, food irradiation, genetically modified organisms, etc. In an embodiment, the compositions of the present disclosure may include meat that is obtained from free range chicken and / or grass-fed beef and milk. Standards such as these, although not necessary, are more aligned with the current marketing message of “the way nature intended.” Indeed, it is known that a cow's rumen is not intended to process grains, and these standards assure that the meat is raised without the use of antibiotics and growth hormones. See, Steve Windley, Grass-fed Beef, purehealthMD.com (2008).

[0072] Similarly, all natural ingredients may be used in the coloring of present compositions to avoid the chemicals in artificial coloring. For example, to achieve a composition with red color,

[0073] 8

[0074] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0075] Attorney Docket #: CMCC 4458 PCT amaranth, beets, or hibiscus may be added to the compositions. Alternatively, to achieve a composition with yellow / orange color, turmeric may be added to the compositions. The skilled artisan will appreciate that these are merely examples of color-providing fruits / vegetables and that any known fruits or vegetables capable of providing color to the compositions may be used.

[0076] Another manner in which a nutritional composition may evoke an emotional appeal (and / or potential physiological benefit) is to create ethnicity specific tube feed formulas. In an embodiment, the present compositions are formulated with fruits, vegetables, macronutrient sources and spices typically consumed in specific regions of the world. For example, a tube feed formulation may include curcumin or turmeric and be marketed as an Indian cuisine formulation that also have anti-inflammatory properties. Curcumin is a component of the spice turmeric (curcuma longa) and is responsible for the yellow color of curry. Curcumin has specifically been shown to possess anti-inflammatory, antioxidant and anti-proteolytic properties. With regards to long-term, tube fed pediatric patients who experience profound decrements in lean body mass, for example, curcumin may provide some attenuation of skeletal muscle proteolysis. Importantly, curcumin has been shown to antagonize the upregulation of nuclear factor-K|3 (NF- Kp) and this gene is inextricably tied to initiating an intracellular signaling cascade responsible for inducing skeletal muscle atrophy during unloading conditions. See, Farid, et al., Effects of dietary curcumin or N-acetylcysteine on NF-KB activity and contractile performance in ambulatory and unloaded murine soleus, J. Clin. Invest., 114(10): 1504-11 (2005).

[0077] Similarly, cumin, oregano and chili powder may be included in compositions that are marketed as a Mexican cuisine formulation. Other cuisine options include, but are not limited to, That, Italian, Mediterranean, or American.

[0078] Yet another manner in which a nutritional composition may evoke an emotional appeal (and / or potential physiological benefit) is to provide an extra, add-on component that has at least one characteristic selected from the group consisting of visually appealing / appetizing, an appealing aroma, an appealing flavor or smell to stimulate the natural response to eating, or combinations thereof. These components (smell, taste, thought, etc.) may also have physiological benefits such that they elicit the cephalic phase or the first part of digestion, which would allow the patient begin the digestive processes in a more similar way to an oral diet. Therefore, digestive processes begin with the sight, smell or thought of food and physiological processes occur to prime the body for digestion (e.g., salivation, gastric acid secretion, pancreatic endocrine and exocrine).

[0079] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0080] Attorney Docket #: CMCC 4458 PCT

[0081] The aroma may be any aroma known in the art. For example, the aroma may be a dessert aroma such as, but not limited to vanilla, chocolate, strawberry, lemon, custard, etc. The aroma may also be related to an ethnic food such as, for example, curry, chili powder, roasted red pepper, basil, etc. In another embodiment, the aroma may be an aroma that is associated with common American foods such as, but not limited to, meatloaf, chicken, roast, mashed potatoes, etc. By providing a wide range of aromas, the patients may be able to select an aroma that sounds satisfying to the patient at the time of tube feeding.

[0082] In some embodiments, the whole food ingredients, additives small molecules, and / or large molecules exhibit bile binding capability. For example, the whole food ingredients exhibit bile binding capability.

[0083] In some embodiments, the stomach disease / condition treated by the blenderized tube feeding is gastroparesis, gastroesophageal reflux, diarrhea, aspiration pneumonia, diarrhea, constipation, abdominal pain, nausea, flatulence, or signs / symptoms of oropharyngeal, esophageal gastric and intestinal dysmotility, which may include pneumonitis, pharyngitis, esophagitis, gastritis or enteritis.

[0084] The blenderized tube feedings can be in any form suitable for delivery through an enteral access device or even , for patients who enjoy the taste, orally. In some embodiments, the blenderized tube feeding is bite-sized, minced, pureed or liquidized. For example, the blenderized tube feeding has been pureed, resulting in a smooth, thick paste.

[0085] A. Composition

[0086] In some forms, the composition is exemplified as bile blend Recipe 1 (the components (and heir proportions) of which are shown in Table 1) or Recipe 2 (the components (and their proportions of which are shown in Table 2).

[0087] 1. Whole Foods

[0088] In some embodiments, the blenderized tube feedings are composed of whole food ingredients. The whole food ingredients may be vegetables, fruits, grains, oils, solid fats, beans, nuts, meat, poultry, fish, seafood, and / or diary.

[0089] A variety of fruits and vegetables can be used in the tube feeding compositions disclosed herein. Exemplary fruits suitable for use in the tube feeding composition include, but are not limited to one or more of apple, banana, blueberry, mango, pear, strawberry, pineapple, avocado, peach, and lemon. Exemplary vegetables suitable for use in the tube feeding composition include, but are not limited to, one or more of squash, sweet potato, carrot, pumpkin, spinach, kale, broccoli, and zucchini. The fruits and vegetables that are used in the tube feeding io

[0090] 45756690.1 PCT / US25 / 43841 28 August 2025 (28.08.2025)

[0091] Attorney Docket #: CMCC 4458 PCT composition are generally modified from their natural state to be in a state suitable for administration via tube feeding. For example, in specific embodiments, the fruits and vegetables are provided in the form of a puree, a concentrate, or a combination thereof. In certain embodiments, the fruits and / or vegetables used in the tube feeding composition can either be certified organic (e.g., USDA organic) or not certified organic, and also can be non-genetically modified (non-GMO) or genetically modified.

[0092] A variety of whole grains, in specific embodiments, are used in the tube feeding compositions disclosed herein. Exemplary whole grains suitable for use in the tube feeding composition include, but are not limited to, rice, oats, amaranth, barley, buckwheat, millet, quinoa, sorghum, corn, wheat, and / or soy. The whole grains used in the tube feeding composition are generally modified from their natural state to be in a state suitable for administration via tube feeding. For example, in specific embodiments, the whole grains are milled and incorporated into the tube feeding composition in powder form. In certain embodiments, the whole grain used in the tube feeding composition is certified organic (e.g., USDA organic), or is not certified organic, and in specific embodiments is non-genetically modified (non-GMO), or is genetically modified.

[0093] The fruit and vegetable and the whole grain in specific embodiments of the tube feeding composition contribute to the total amount of carbohydrate present in the tube feeding composition. The source of carbohydrate for use in the tube feeding composition of the present disclosure in specific embodiments is simple, complex, or variations or combinations thereof. Sources of carbohydrate suitable for use in the tube feeding composition of the present disclosure include, but are not limited to, maltodextrin (e.g., rice maltodextrin, corn maltodextrin), hydrolyzed or modified starch or cornstarch, glucose polymers, com syrup, com syrup solids, sucrose, glucose, fructose, lactose, high fructose corn symp, sugar alcohols (e.g., maltitol, erythritol, sorbitol), isomaltulose, sucromalt, pullulan, potato starch, fructooligosaccharides (FOS), and galactooligosaccharides (GOS). The source of carbohydrate in specific embodiments is certified organic (e.g., USDA organic) or is not certified organic, and in specific embodiments is non-genetically modified (non-GMO) or is genetically modified. The tube feeding composition of the present disclosure in specific embodiments includes any individual source of carbohydrate or a combination of the various sources of carbohydrate listed above. In specific embodiments, the carbohydrate sources are fmit and vegetable purees including organic banana puree, organic mango puree, organic spinach puree, organic pumpkin n

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[0095] Attorney Docket #: CMCC 4458 PCT puree, and / or organic carrot juice concentrate, and rice sources such as organic rice maltodextrin and / or organic whole grain brown rice milk powder.

[0096] The fruit and vegetable and the whole grain in the tube feeding composition in specific embodiments contributes to the total amount of fat present in the tube feeding composition. In specific embodiments of the present disclosure, the tube feeding composition includes a source of fat that is not provided by the fruit, vegetable, or whole grain. The source of fat for use in specific embodiments of the tube feeding composition of the present disclosure is derived from various sources including, but not limited to, plants, animals, and / or a combination thereof. Sources of fat that are suitable for use in the tube feeding composition of the present disclosure include, but are not limited to, coconut oil, fractionated coconut oil, soy oil (e.g., high oleic soy oil), com oil, olive oil, safflower oil (e.g., high oleic safflower oil), medium chain triglyceride oil (MCT oil), high gamma linolenic (GLA) safflower oil, sunflower oil (e.g., high oleic sunflower oil), palm oil, palm kernel oil, palm olein, canola oil (e.g., high oleic canola oil), marine oils, fish oils (e.g., tuna oil), algal oils, borage oil, cottonseed oil, fungal oils, eicosapentaenoic acid (EP A), docosahexaenoic acid (DHA), arachidonic acid (ARA), conjugated linoleic acid (CLA), alpha- linolenic acid, interesterified oils, transesterified oils, structured lipids, and combinations thereof. Generally, the source of fat used in the tube feeding composition provides fatty acids needed both as an energy source and for the healthy development of the toddler, child, or adult. The source of fat typically comprises triglycerides, although the source of fat can also comprise diglycerides, monoglycerides, phospholipids (e.g., lecithin) and / or free fatty acids. Fatty acids provided by the source of fat in the tube feeding composition of the present disclosure include, but are not limited to, capric acid, lauric acid, myristic acid, palmitic acid, palm itoleic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, ARA, EPA, and DHA. Specific embodiments of the tube feeding composition of the present disclosure include any individual source of fat or combination of the various sources of fat listed above. Specific embodiments of the compositions are kosher, halal, and / or suitable for vegetarians and / or vegans. For example, specific embodiments do not contain chicken broth or tuna oil.

[0097] Specific exemplary whole food ingredients include, but are not limited to, banana, prune, kale, chickpeas, psyllium husk, grapeseed oil, chicken, sunflower seed butter, olive oil, rice milk, coconut milk, and / or oat milk.

[0098] In an embodiment, the nutritional composition includes at least six or seven different whole food components.

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[0100] Attorney Docket #: CMCC 4458 PCT

[0101] In some embodiments, the whole food ingredient is selected from the group consisting of processed fruits, processed vegetables, processed meats, processed grains, or combinations thereof. In some embodiments, whole food ingredients need not be processed.

[0102] In some embodiments, the whole food ingredients are fermented foods. Some of the most widely available include kombucha, yogurt, aged / raw cheeses, sauerkraut, pickles, miso, tempeh, natto and kimchi. Other healthy foods that are fermented include apple cider vinegar, wine, sourdough bread, cottage cheese and coconut kefir.

[0103] In some embodiments, the whole food ingredients are cooked. For example, the whole food ingredients are steamed, poached, grilled, roasted, broiled, sauteed, baked, fried, or boiled.

[0104] 2. Nutrient Minerals, Small and Large Molecules

[0105] In some embodiments, the blenderized tube feedings contain nutrient minerals, small and / or large molecules. In some embodiments, the small and / or large molecules are carbohydrates, lipids, proteins, nucleic acids, sugars, lipids, amino acids, fatty acids, phenolic compounds, and / or alkaloids.

[0106] In an embodiment, the protein is selected from the group consisting of dairy based proteins, plant based proteins, animal based proteins, artificial proteins, or combinations thereof.

[0107] Plant-based proteins suitable for use in the tube feeding composition of the present disclosure include, but are not limited to, soy protein (e.g., soy protein isolate), pea protein, rice protein (e.g., rice protein concentrate), and potato protein.

[0108] In an embodiment, the dairy based proteins are selected from the group consisting of casein, caseinates, casein hydrolysates, whey, whey hydrolysates, milk protein concentrate, milk protein isolate, or combinations thereof.

[0109] Animal-based proteins suitable for use in the tube feeding composition of the present disclosure include, but are not limited to, poultry protein (e.g., chicken protein), fish protein, ovine protein, porcine protein, and bovine protein. Milk-based proteins suitable for use in the tube feeding composition of the present disclosure include, but are not limited to, whole cow's milk, partially or completely defatted milk, milk protein concentrates, milk protein isolates, nonfat dry milk, condensed skim milk, whey protein concentrates, whey protein isolates, acid caseins, sodium caseinates, calcium caseinates, and potassium caseinates. The source of protein in specific embodiments is certified organic (e.g., USDA organic) or is not certified organic, and also in specific embodiments is non-genetically modified (non-GMO) or genetically modified. The tube feeding composition of the present disclosure in specific embodiments includes any individual source of protein or combination of the various sources of protein listed above.

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[0113] In specific embodiments of the present disclosure, the tube feeding composition comprises a plant-based protein and an animal-based protein. In specific embodiments of the present disclosure, the tube feeding composition includes a plant-based protein comprising at least one of soy protein, pea protein, rice protein, and potato protein and an animal-based protein comprising at least one of poultry protein, fish protein, ovine protein, porcine protein, and bovine protein. In specific embodiments of the present disclosure, the tube feeding composition comprises soy protein, rice protein, and poultry protein. In specific embodiments of the present disclosure, the tube feeding composition comprises pea protein, rice protein, and poultry protein.

[0114] In addition, the source of protein in the tube feeding composition in specific embodiments includes one or more free amino acids. Free amino acids in specific embodiments used in the tube feeding composition disclosed herein include, but are not limited to, L-lysine, L- tryptophan, L-glutamine, L-tyrosine, L-methionine, L-cysteine, taurine, L-arginine, and L- carnitine.

[0115] 3. Additives

[0116] In some embodiments, one or more antioxidants may also be present in the blenderized tube feeding. Non-limiting examples of ingredients with antioxidant activities selected from the group consisting of herbs, spices, and flavorings, carotenoids, flavonoids, polyphenols, lignan, lutein, lycopene, quercetin, limonin, coenzyme Q10 (“CoQlO”), glutathione, Goji (wolfberry), lactowolfberry, hesperidine, selenium, vitamin A, vitamin C, vitamin E, elderberry, or combinations thereof. In some embodiments, the blenderized tube feeding includes herbs, spices, and / or flavorings.

[0117] In some embodiments, herbs may be selected from the group consisting of angelica, bay laurel, chives, dill, fennel, lavender, lemon balm, majoram, mint, oregano, parsley, rosemary, rue, sage, tarragon, thyme, verbena, or combinations thereof.

[0118] In some embodiments, spices may be selected from the group consisting of black pepper, cumin, cardamom, cayenne, celery seeds, chili pepper, cinnamon, clove, cumin, garlic, ginger, mustard, nutmeg, onion, paprika, peppercorns, tabasco, capsaicin derivative, turmeric or combinations thereof.

[0119] In some embodiments, flavorings may be any natural or artificial flavors or flavor enhancers such as, for example, MSG, vanilla extract, etc.

[0120] The skilled artisan will appreciate that many herbs, spices and flavorings may overlap in uses such that, for example, a typical herb may be used as a spice.

[0121] In some embodiments, probiotics are included in the disclosed feed formulation. Probiotics are live microorganisms that are generally considered safe to consume and may

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[0124] Attorney Docket #: CMCC 4458 PCT provide health benefits. Exemplary probiotics include but are not limited to the core genera of lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus,

[0125] Escherichia, and / or Bacillus. In some embodiments, one or more prebiotics are included in the disclosed feed formulations. Prebiotics are compounds in food that foster growth or activity of beneficial microorganisms such as bacteria and fungi. Dietary prebiotics are typically nondigestible fiber compounds that pass undigested through the upper part of the gastrointestinal tract and help growth or activity of advantageous bacteria in the colon by acting as substrates for them. Fermentable carbohydrates derived from fructans and xylans are one well documented example of prebiotics. Resistant starch from starchy foods are also well documented prebiotics and have historically been the highest source of prebiotics in the diet, as 4-10% of starch in mixed diets has been shown to reach the large intestine. Exemplary prebiotics include, but are not limited to fructo-oligosaccharides (FOS), galacto-oligosaccharides (GOS), and / or transgalacto-oligosaccharides (TOS), chicory root, Jerusalem artichoke, dandelion greens, garlic, leek, onion, asparagus, wheat bran, whole wheat flour, and banana.

[0126] In some embodiments, the disclosed feed formulations include fiber or a blend of different types of fiber. The fiber blend may contain a mixture of soluble and insoluble fibers. Soluble fibers may include, for example, fructooligosaccharides, acacia gum, inulin, etc. Insoluble fibers may include, for example, pea outer fiber.

[0127] In specific embodiments of the present disclosure, the feeding composition comprises vitamins and minerals. In specific embodiments of the present disclosure, the tube feeding composition comprises at least one of vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pyridoxine, vitamin Bl 2, niacin, folic acid, pantothenic acid, biotin, vitamin C, choline, and inositol. In specific embodiments of the present disclosure, the tube feeding composition comprises at least one of calcium, phosphorus, magnesium, iron, zinc, manganese, copper, sodium, potassium, molybdenum, chromium, selenium, chloride, and iodine.

[0128] In some embodiments, the blenderized food composition can further include cinnamon, capsaicin, congee, apple cider vinegar, peppermint, Greek yogurt, kefir, black strap molasses, fruit juice such as pomegranate juice, vegetable juice, cocoa powder, and / or green tea.

[0129] B. Properties

[0130] The disclosed fees have an effective property selected from the group consisting of viscosity or bile-binding capacity and optionally one or more micronutrients.

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[0132] Attorney Docket #: CMCC 4458 PCT

[0133] 1. Viscosity

[0134] Typically, a suitable viscosity for the disclosed food compositions is a viscosity that prevents gastroesophageal reflux and promotes satiety.

[0135] Optionally, the viscosity is preferably between 1,000 cP and 15,000 cP, between 1,000 cP and 10,000 cP, between 1,000 cP and 8,000 cP, between 1,000 cP and 6,000, between 1,000 cP and 4,000, between 1,000 cP and 3,000, between 1,000 cP and 2,500, or between 1,500 cP and 2,500.

[0136] Viscosity is determined by IDDSI syringe flow test (Cichero JA, Lam P, Steele CM, et al. Development of International Terminology and Definitions for Texture-Modified Foods and Thickened Fluids Used in Dysphagia Management: International Dysphagia Diet Standardization Initiative (IDDSI) Framework. Dysphagia. 2017;32(2):293-314. doi:10.1007 / s00455-016-9758-y).

[0137] The preferred viscosity for G-tube feeds is IDDSI category 3 or higher. If fed post- pylorically, then preferred viscosity is IDDSI category 1 or 2.

[0138] 2. Bile Binding Capacity

[0139] Typically, a suitable bile binding capacity for the whole food, additives, small molecules and / or large molecules is a bile binding capacity that reduces gastric and salivary bile concentrations. The bile sequestrant binds all bile acids.

[0140] Foods can be characterized based on their bile binding potential relative to cholestyramine. For example, kale (90% binding capacity), prunes (53% binding capacity), bananas (85% binding capacity), and chickpeas (65% binding capacity) are effective sequestrants of bile acid in addition to fibers such as pectin and psyllium.

[0141] In some embodiments, the whole food, additives, small molecules, and large molecules show bile binding capacity. Optionally, the bile binding capacity is more than between 10% and 100%, between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, between 90% and 100%, between 95% and 100% in comparison to cholestyramine.

[0142] 3. Macronutrients

[0143] Typically, the blenderized tube feedings contains at least one macronutrient source, vitamin source and / or mineral source. Macronutrient sources can be selected from calories, fiber, fats, carbohydrates, and proteins.

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[0147] The protein source is provided in an amount to provide between 5% to 50%, between 5% to 40%, between 5% to 35%, between 10% to 35%, or between 10 to 20% of the total energy, the carbohydrate source is provided in an amount sufficient to provide between 10% to 90%, between 10% to 80%, between 10% to 70%, between 20% to 70%, between 20% to 60%,

[0148] 5 between 20% to 50%, or between 30% to 45% of the total energy, and the total energy provided from fat is provided in an amount sufficient to provide between 10% to 90%, between 10% to 80%, between 10% to 70%, between 20% to 70%, between 30% to 70%, between 30% to 60%, or between 40% to 60%.

[0149] For example, the blenderized tube feedings include a range of macronutrients: 30% to 45% carbohydrates, 10% to 20% protein, and 40% to 55% fat.

[0150] These ranges are comparable to other commercialized blend formulas on the market. The necessity of these ranges would be most applicable if making changes in non-bile binding ingredient, swapping bile -binding ingredients, or changing volumes that may benefit an individual patient.

[0151] 15 In some forms, the disclosed tube feed compositions include, kale, prunes, bananas (85% binding capacity), and chickpeas (65% binding capacity) are among the most effective sequestrants in addition to fibers such as pectin and psyllium. Using these ingredients, a high bile-binding blenderized feed (H-BBB, can be made (Table 1).

[0152] An exemplary recipe for blenderized tube feedings includes 2oz chicken 1 / 3 cup chickpeas (canned, drained), 4 prunes, * / 2 cup baby kale, 2 tablespoons sunbutter, 2 tablespoons psyllium husk, 2 tablespoons olive oil, and 1 cup oat whole fat oat milk with a macronutrient profile of 1040 calories, 51% fat, 36% carb, and 13% protein. Additional exemplary recipes for blenderized tube feedings are disclosed in the tables below.

[0153] The ingredients are selected to include a combination of ingredients (i) with bile binding

[0154] 25 profiles, (ii) that were commonly available, (iii) accessible, (iv) shelf stable and (v) of low allergenic profile. The exact quantities are then determined based on desired macronutrient composition and quality, balance of vegetable / fruit composition and desired viscosity in an iterative process.

[0155] Table 1. Bile Blend Recipe 1

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[0159] Table 2. Bile Blend Recipe 2

[0160] Table 3. Nutritional comparison of the commercial low bile binding blend (Real Food 5 Blends Orange Chicken) and the high bile binding blend.

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[0164] In specific embodiments of the present disclosure, the tube feeding composition is dairy free, lactose free, galactose free, gluten free, and does not contain any artificial preservatives, colors, or flavors.

[0165] By using the improved compositions and methods of administering same, the present disclosure improved nutritional compositions to adult and pediatric patients that have an increased number and variety of fruits and vegetables, an increased variety of macronutrient sources, and the addition of other components found in whole foods, and high bile binding capabilities. The formulations help to mimic a “whole food” tube feeding that best meets the nutritional needs of the target population and also provides physiological / therapeutic benefits and emotional appeal.

[0166] III. Methods of Making Blenderized Tube Feedings

[0167] Methods for the formulation of oral feeding or tube feedings containing at least one whole food ingredient has been developed.

[0168] In general, the disclosed blenderized foods are made from collecting the desired ingredients and blending them together in a suitable blender to generate a smooth, thick paste.

[0169] The method comprises mixing together water, a source of protein, a source of carbohydrate, whole grain, a source of fat, fruit, and vegetable to form an initial blend. The method further comprises homogenizing the initial blend in a first homogenization step to form an intermediate blend, and homogenizing the intermediate blend in a second homogenization step to form a feeding composition. The method further comprises packaging the blenderized feeding composition.

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[0172] The oral feeding or tube feeding composition of specific embodiments of the present disclosure are formulated with sufficient kinds and amounts of nutrients to provide a sole, primary, or supplemental source of nutrition to the end user. In specific embodiments of the present disclosure, the oral feeding tube feeding composition is nutritionally complete to allow the oral feeding tube feeding composition to be the sole source of nutrition for a human. The phrase “nutritionally complete” as used herein refers to a composition that contains sufficient types and levels of macronutrients (protein, carbohydrate, and fat) and micronutrients to be sufficient to be a sole source of nutrition for the subject to whom the composition is administered. Subjects, including toddlers, children, or adults, can receive 100% of their nutritional requirements from such nutritionally complete compositions. In specific embodiments the nutritional requirements are determined according to the Food and Drug Administration's (FDA) publication “Food Labeling: Revision of the Nutrition and Supplement Facts” published on May 27, 2016.

[0173] In specific embodiments of the present disclosure, the initial blend is homogenized in a first homogenization step to form an intermediate blend. In specific embodiments, the first homogenization step is performed using a two-stage homogenizer that applies a first-stage pressure from about 1,500 psi to about 3,500 psi, or from about 2000 psi to about 3000 psi, which in specific embodiments is about 2,500 psi, and applies a second-stage pressure from about 250 psi to about 750 psi, or from about 400 psi to about 600 psi, that in specific embodiments is about 500 psi. In specific embodiments, the intermediate blend is cooled to a temperature from about 34° F. to about 45° F. and transferred to a holding tank, where the intermediate blend is stored prior to further processing for up to about 72 hours at a temperature from about 34° F. to about 45° F.

[0174] In specific embodiments, the intermediate blend, which can be a sterilized intermediate blend, is homogenized in a second homogenization step to form the final feeding composition. In specific embodiments, the second homogenization step is performed using a two-stage homogenizer that applies a first-stage pressure from about 1,500 psi to about 3,500 psi, or from about 2000 psi to about 3000 psi, such as about 2,500 psi, and applies a second-stage pressure from about 250 psi to about 750 psi, or from about 400 psi to about 600 psi, such as about 500 psi. In specific embodiments, the intermediate blend is cooled to a temperature from about 160° F. to about 180° F. prior to undergoing the second homogenization step. In specific embodiments, the final feeding composition is cooled to a temperature from about 65° F. to

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[0177] Attorney Docket #: CMCC 4458 PCT about 75° F. and transferred to an aseptic holding tank, where the final feeding composition is stored prior to packaging at a temperature from about 60° F. to about 80° F.

[0178] In specific embodiments, the final feeding composition is packaged. In specific embodiments, the container in which the final feeding composition is packaged is sterilized prior to filling the container with the final feeding composition. For example, the container is sterilized by the application of hydrogen peroxide or other suitable disinfectant to the inside surface of the container. The hydrogen peroxide or other disinfectant is applied via an atomized mist. To complete the packaging step, in specific embodiments, the sterilized container is filled with the sterilized final feeding composition under aseptic processing conditions and is then sealed with a sterilized closure.

[0179] In specific embodiments, the feeding composition is packaged using a retort processing method. In specific embodiments, the retort processing method includes filling a container with the final feeding composition, sealing the container, and then subjecting the sealed, filled container to a heat sterilization step to form a retort packaged feeding composition.

[0180] A packaged oral or tube feeding composition of the present disclosure can be shelf-stable. In other words, the packaged oral or tube feeding composition of the present disclosure can be stored at room temperature (e.g., from about 20° C. to about 25° C.) without spoiling for an extended period of time. In embodiments of the present disclosure, the packaged oral or tube feeding composition is shelf-stable for at least about 3 months, including at least about 6 months, at least about 12 months, from about 3 months to about 18 months, from about 6 months to about 15 months, and also including from about 12 months to about 15 months. Such shelf stability renders the packaged oral or tube feeding composition portable and convenient to use because refrigeration is not required.

[0181] IV. Methods of Using Blenderized Tube Feeding

[0182] The blenderized feeding formulation may be administered through an enteral device or orally. In general, the methods include administering a first blenderized feed formulation containing at least one whole food based ingredient to a patient at a first time of a day corresponding to a typical breakfast time, administering a second blenderized feed formulation having at least one whole food to the patient at a second time of the day corresponding to a typical lunch time, and administering a third blenderized feed formulation having at least one whole food to the patient at a third time of the day corresponding to a typical dinner time. The blenderized feeding formulation may also be administered at several additional times, mimicking

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[0185] Attorney Docket #: CMCC 4458 PCT snack times. In this manner, the methods may include administering fourth, fifth, sixth, etc. formulations correlating with typical daily snack times.

[0186] The disclosed blenderized feed formulations may be administered at a temperature that is either warm or cold with no change in the nutritional benefits of the composition. Prior research has shown that temperature (hot, warm, cold) of a simple food beverage, sweetened instant coffee, administered via nasogastric tube did not impact gastric acid secretion, serum gastrin concentrations, or gastric emptying. McArthur, et al., , Am. J. Clin. Nu.tr., 49:51-54 (1989).

[0187] Blenderized feeds can be given in a variety of different volumes and with different scheduled depending on the patient’s tolerance. Each feed can be administered by a syringe attached to a feeding tube or by a feeding pump depending on patient preference and tolerance. Each feed will be available in 240 ml aliquots which can be administered at one time or administered in smaller aliquots over the course of 24 hours. 240 ml is the standard volume sold in the industry. The volume given per patients at a given time is determined by the patient’s care team as is the case with all commercial nutritional products.

[0188] Along these lines, another manner in which to evoke an emotional appeal is to provide methods of administering nutritional compositions (e.g., tube feedings) that mimic regular meal times, or create a cycling menu with unique foods, as mentioned above. For example, in an embodiment, a tube feed formulations may be administered three times daily at normal meal times of breakfast, lunch and dinner, and / or with several snacks. Similarly, the present compositions may be packaged with an appealing or appetizing label or product name.

[0189] In another embodiment, the tube feedings may be administered such that the administration creates a cycling menu with unique foods having, for example, different protein sources, and different fruits and vegetables. The skilled artisan will appreciate that many different combinations of whole foods may be used in the present compositions. Different examples of such combinations include, as with Clinutren Mix products, but are not limited to, turkey with mixed vegetables, veal with broccoli, spring vegetables stew, cod with leek, Hungarian beef, salmon and spinach, chicken and vegetables, and beef and carrots.

[0190] In another example, tube or oral feedings may be administered at normal meal times. For example, a first feeding may be administered at a typical breakfast time in the morning. A second feeding may be administered at a typical lunch time around noon, and a third feeding may be administered at a typical dinner time in the evening. The oral or tube feeding formula may also be administered at several additional times, mimicking snack times.

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[0194] In another embodiment, feedings may vary from week to week or month to month. In this regard, a patient may be administered a specific oral tube feed formulation for a week or a month before the formulation changes to a second formulation. Similarly, the patient may be administered a daily feeding menu of first, second and third feedings, wherein each first feeding is the same for a week or a month, each second feeding is the same for a week or a month, and each third feeding is the same for a week or a month before the feedings are changed to a second formulation.

[0195] The changing of a first formulation to a second formulation, regardless of how frequently the formulations are changed, may include changing of a specific component of the formulation. For example, a tube feed formulation may be administered to a patient on day one that has a certain amounts of protein, carbohydrates and fats. On day two, a similar tube feed formulation may be administered to the patient that has the same amount of protein and carbohydrates, but an increased or decreased amount of fats. In this manner, the amounts of macro and micronutrients in the nutritional compositions of the present claims may vary from formula to formula. In an embodiment, at least one source of protein of a nutritional composition is different than a new, or second, nutritional composition. In an embodiment, at least one source of carbohydrates of a nutritional composition is different than a new, or second, nutritional composition. In an embodiment, at least one source of fats of a nutritional composition is different than a new, or second, nutritional composition.

[0196] Methods of administering oral or tube feeding formulations are also provided. The methods include administering a first feed formulation having a whole food to a patient at a first time of a day corresponding to a typical breakfast time, administering a second feed formulation having a whole food to the patient at a second time of the day corresponding to a typical lunch time, and administering a third feed formulation having a whole food to the patient at a third time of the day corresponding to a typical dinner time. The first, second and third feed formulations include at least one protein, and at least one of a fruit and a vegetable. The protein of each of the first, second and third feed formulations may be different. The at least one of a fruit and a vegetable of each of the first, second and third feed formulations may also be different. The disclosed formulations may also be administered at several additional times with different fruits and vegetables and macronutrient sources, mimicking snack times. In this manner, the methods may include administering fourth, fifth, sixth, etc. formulations correlating with typical daily snack times.

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[0198] Attorney Docket #: CMCC 4458 PCT

[0199] In humans, gastric bile acids have been implicated as a cause for disorders such as gastritis, esophagitis, lung transplant allograft rejection, aspiration pneumonitis and Barrett’s esophagus. It has been shown that bile can be problematic in children, in addition to in adults, including CMC, specifically (1) retrograde bile acid reflux is common, as evidenced by bile acids’ presence in 100% of gastric fluid and 98% of bronchoscopy fluid samples; and (2) bile aspiration is harmful, as higher pulmonary bile concentrations correlate with worse clinical outcomes such as pulmonary hospitalizations and lung allograft rejection. Thus, the disclosed compositions can be administered to a subject in need of bile acid reduction. In some forms, the subject is a pediatric patient.

[0200] Treating or Reducing Gastroesophageal Reflux

[0201] Methods of administering blenderized oral or tube feeding formulations, reducing gastric bile acid concentration, and treating gastroesophageal reflux in a subject are provided.

[0202] The methods include administering an effective amount of the disclosed blenderized feed to a subject in need thereof. lin some forms, the subject has been diagnosed as having gastroesophageal reflux. The methods can include administering a first, second third, fourth blenderized feed, The first, second and third blenderized feed formulations may include at least one whole-food based ingredient with bile binding capacity. The blenderized feeding formulation administered, mimicking snack times, may contain at least one whole food, additives, small molecules and / or large molecule with bile binding capacity.

[0203] The methods and compositions herein described are further illustrated in the following examples, which are provided by way of illustration and are not intended to be limiting. It will be appreciated that variations in proportions and alternatives in elements of the components shown will be apparent to those skilled in the art and are within the scope of disclosed forms. All parts or amounts, unless otherwise specified, are by weight.

[0204] EXAMPLES

[0205] Example 1: Relationship Between Bile Acid Concentration and Pulmonary Outcome

[0206] Reflux of bile acids from the intestines into the stomach, esophagus, oropharynx and / or lungs can result in clinically significant gastrointestinal and pulmonary disease (Figure 1). It has been shown that high bile acid concentrations in the lung correlate with worse pulmonary outcomes including increased emergency room visits, increased pulmonary hospitalizations and, in transplant patients, lung allograft dysfunction. However, reduction of bile acid concentrations

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[0208] Attorney Docket #: CMCC 4458 PCT in the stomach or oropharynx (Figure 1), may reduce the pulmonary consequences of bile acid aspiration.

[0209] Materials and methods

[0210] A pilot study of 83 patients with and without enteral tubes was conducted. Rates of pulmonary hospitalization within 6 months were obtained from chart review. Gastric aspirates were obtained by collecting gastric fluid by endoscopy and then performing bile acid analyses on the extracted fluid. Bile acid profiling by ultra-performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS / MS) was performed as follows: the bile acid profiling was determined by stable-isotope dilution tandem mass spectrometry after extraction of bile acids from biological samples by protein precipitation. Specifically, the internal standards, a cocktail of 15 deuterium labeled standards were added to samples (20 L of gastric fluid). Calibrators and QC samples were processed following the same procedure. The samples were vortexed before adding acetonitrile. After vortexing and centrifuging at 13,400 g at 4°C, the supernatant was removed and dried under nitrogen gas. The extract was then dissolved in methanol / water (50 / 50 v / v) for UPLC-MS / MS analysis. Quantitative analysis of the individual major BA in the samples, i.e. TCA, TUDCA, TCDCA, TDCA, TLCA, GCA, GUDCA, GCDCA, GDCA, GLCA, CA, UDCA, CDCA, DCA, and LCA was conducted. UPLC-MS / MS with electrospray ionization (ESI) analysis was conducted on a Waters Xevo TQ-S triple quadruple mass spectrometer interfaced with an Equity UPLC system (Waters Corporation, Milford, MA). Individual bile acid species were separated on a Kinetex C18 (2.6 pm, 100 x 3.0 mm) column (Phenomenex, Torrance, CA) with gradient elution consisting of mobile phase A (20% acetonitrile / water with lOmM ammonium acetate) and mobile phase B (80% acetonitrile / water with lOmM ammonium acetate) programmed from 5% B to 100%B with a total run time of 20 min. Quality control (QC) samples were prepared at concentrations of 0.1, 0.5, 1.0, and 2.5 pg / mL for both conjugated and unconjugated BA and an additional QC sample of 20.0 pg / mL for the conjugated BA only. Intra- and inter-assay imprecision of the method for the 15 individual bile acids measured was within 20% coefficient of variance for these QC samples. The lower limit of quantification (LLOQ) of the assay was set at 0.1 pg / mL and bile acid concentration was measured, who receive blenderized feeds have lower gastric bile acid concentrations than patients who receive standard formulas. While this study of did not include patients specifically receiving an H-BBB, these data suggest that administering pureed foods has the potential to modify gastric BA concentrations more effectively than standard commercial formulas.

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[0214] Results

[0215] In this study of 83 patients with and without enteral tubes, it was found that pediatric patients with gastrojejunal tubes (GJ) tubes and gastrostomy tubes had more gastric bile than orally fed children did (Figure 2A) and that the pulmonary hospitalizations correlate with higher gastric bile concentrations (Figure 2B). This data suggests that a reduction of gastric bile acids improves clinical outcomes.

[0216] Example 2: Impact of Enteral Tubes on Bile Concentrations

[0217] The impact of enteral tubes on bile concentrations was studied. It was discovered that patients receiving blenderized tube feeds had lower gastric bile acid concentrations than patients on standard formulas (Figure 3). This observation suggests that bile acids can be bound by food administration.

[0218] After researching ingredients that have high bile acid binding capacities, ingredients that had both high binding capacity as well as affordability and accessibility were identified. For example, banana, prunes, kale, chickpeas, psyllium husk. These ingredients have high bile sequestering properties and are relatively easy to find in a typical grocery store. These five ingredients were used in the bile acid binding blend. Other ingredients with a high bile acid sequestering ability that are readily available include spinach, beets, blueberries, grapes, pineapple. These alternate ingredients are examples of some ingredients that could be considered approved swaps for the original blend.

[0219] Example 3: Impact of Blenderized Tube Feeding With Bile Binding Capability on Bile Concentration

[0220] Materials and methods

[0221] A high viscosity formula commonly used in patients at high risk for aspiration was identified and was then analyzed with a diet analysis program to develop a recipe with similar macronutrients and similar caloric density, but ingredients identified as high bile acid binding. Many variables were comparable, and the only change is the addition of high bile acid sequestering ingredients so as to limit other variables in later research.

[0222] Oat milk was used given it has a common non-dairy base used in home blending that has a higher carbohydrate to protein ratio than dairy milk and is easily accessible and often balances other high protein foods in the blend. Olive oil was also used given this is commonly used in the home and has an excellent fat profile rich in monounsaturated fats. Using oil in blends is a good source of unsaturated fats and calories but in high aspiration risk population, oil comes with drawbacks as it is particularly dangerous for the lungs if aspirated. The amount of oil used was

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[0225] Attorney Docket #: CMCC 4458 PCT reduced and the plant oil was changed to grapeseed in the interest of keeping ingredients as similar as possible to the intended control blend. Canned coconut milk can be used for caloric density as well. The liquid base can be changed to water if the calories from the non-dairy milk base are not necessary. In some embodiments, the blend can be fortified with additional calcium, vitamin D, and potentially other micronutrient fortification.

[0226] The first iterations of this blend were of higher volume in order to allow more room for experimenting with different volumes of ingredients. Once a blend that worked with a higher volume was found, the volume of each ingredient was reduced proportionally to make the final volume of the blend equal to one pouch of the intended commercialized control blend. During this step, the recipe was fine tuned to match calories and macronutrient profile as much as possible as the intended control blend.

[0227] Gastrointestinal tolerance to the ingredients was kept in mind as many patients have gastrointestinal distress. For example, chickpeas are a potentially problematic ingredient in large amounts as it tests high fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) at 4 tablespoons (1 / 4 cup) per sitting, so chickpeas were limited to 1 tablespoon per batch to avoid any intolerances. Psyllium husk, while a helpful fiber for those with sensitive GI tracts and considered low FODMAP, may be bothersome to the gut if used in larger quantities than typically recommended on label. These fibers assist bile binding functionality; therefore, suitable quantities were found.

[0228] Several variations of the recipe were made in the blender to find a recipe variation that was high enough viscosity to pass the “fork test” in IDDSI testing to denote an “extremely thick” or puree viscosity. Developing a recipe with high viscosity ensures that the blend is effective in minimizing the risk of aspiration. The recipe variations were cross-checked in the diet analysis program to ensure that the recipe variations met the calorie and macronutrient balance goals.

[0229] Figure 4 oudines the first methodological step to assess for bile acid binding capacity of the high bile binding blenderized diet (H-BBB). Human bile is incubated with the H-BBB for 1 hour. Figure 5 depicts the subsequent methodologic steps to measure bile acid binding capacity. Following incubation, solid phase extraction (SPE) is performed under vacuum manifold. The amount of unbound bile acids is measured using solid phase extraction and liquid chromatography-mass spectrometry.

[0230] Results

[0231] An in vitro experiment was performed in which the formula was exposed to human bile in concentrations comparable to that seen in vivo in children (up to 1,000 pmol / L, the upper

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[0234] Attorney Docket #: CMCC 4458 PCT concentration range for children with enteral tubes) to assess the efficacy of binding over time. The study showed that the high binding blend bound 70%-80% of bile acids, that binding occurred nearly instantaneously, and that binding persisted throughout the 60-minute study (Figure 6). Additionally, the present data shows that C4 (7a-hydroxy-4-cholesten-3-one) levels

[0235] 5 with blenderized tube feeds are not higher than formula, which suggests that, even with upper gastrointestinal binding of bile acids, they are effectively reabsorbed in the lower GI tract thus not altering the total bile acid pool. These data are reassuring from a safety perspective.

[0236] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

[0237] References:

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[0254] Attorney Docket #: CMCC 4458 PCT

[0255] 14. Aldhahrani A, Verdon B, Ward C, et al. Effects of bile acids on human airway epithelial cells: implications for aerodigestive diseases. ERJ Open Res 2017;3.

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[0263] 20. Griffin SM, Robertson AG, Bredenoord AJ, et al. Aspiration and allograft injury secondary to gastroesophageal reflux occur in the immediate post- lung transplantation period (prospective clinical trial). Ann Surg 2013;258:705-11; discussion 711-2.

[0264] 20 21. Grabowski M, Kasran A, Seys S, et al. Pepsin and bile acids in induced sputum of chronic cough patients. Respir Med 2011;105: 1257-61.

[0265] 22. Blondeau K, Mertens V, Vanaudenaerde BA, et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J 2008;31 :707-13.

[0266] 25 23. Farre R, van Malenstein H, De Vos R, et al. Short exposure of oesophageal mucosa to bile acids, both in acidic and weakly acidic conditions, can impair mucosal integrity and provoke dilated intercellular spaces. Gut 2008;57: 1366-74.

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[0268] 30 25. Jenkins GJ, Cronin J, Alhamdani A, et al. The bile acid deoxycholic acid has a non-linear dose response for DNA damage and possibly NF-kappaB activation in oesophageal cells, with a mechanism of action involving ROS. Mutagenesis 2008;23:399-405.

[0269] 26. Wu J, Gong J, Geng J, et al. Deoxycholic acid induces the overexpression of intestinal mucin, MUC2, via NF-kB signaling pathway in human esophageal adenocarcinoma cells.

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[0273] 40 associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-betal production and fibroblast proliferation. Chest 2007;132:1548-56.

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[0299] 45756690.1

Claims

Attorney Docket #: CMCC 4458 PCTWe claim:

1. A food formulation comprising at least one or more whole food-based ingredients, wherein the formulation treats stomach diseases / conditions, and wherein the formulation is a blenderized tube feed.

2. The food formulation of claim 1 , wherein the gastrointestinal tract are gastroparesis, gastroesophageal reflux, esophageal dysmotility, oropharyngeal dysphagia, diarrhea, aspiration pneumonia, constipation, abdominal pain, nausea, and / or flatulence.

3. The food formulations of anyone of claims 1 or 2, wherein gastrointestinal condition is gastroesophageal reflux.

4. The food formulation of anyone of claims 1 to 3, wherein the whole food-based ingredients are vegetables, fruits, grains, oils, solid fats, beans, nuts, meat, poultry, fish, seafood, and / or diary.

5. The food formulation of anyone of claims 1 to 4, wherein the formulation further comprises nutrient minerals, small molecules, and / or large molecules.

6. The food formulation of claim 5, wherein the small molecules and large molecules are carbohydrates, lipids, proteins, nucleic acids, sugars, lipids, amino acids, fatty acids, phenolic compounds, and / or alkaloids.

7. The food formulation of anyone of claims 1 to 6, wherein the formulation further comprises additives.

8. The food formulation of claims 5 to 6, wherein the whole foods, additives, small molecules and / or large molecules show bile binding capacity between 10% and 100%, between 20% and 100%, between 30% and 100%, between 40% and 100%, between 50% and 100%, between 60% and 100%, between 70% and 100%, between 80% and 100%, between 90% and 100%, between 95% and 100% in comparison to cholestyramine.

9. The food formulation of anyone of claims 1 to 8, wherein the viscosity is between 1,000 cP and 15,000 cP, between 1,000 cP and 10,000 cP, between 1,000 cP and 8,000 cP, between 1,000 cP and 6,000, between 1,000 cP and 4,000, between 1,000 cP and 3,000, between 1,000 cP and 2,500, or between 1,500 cP and 2,500, as measured by the International Dysphagia Diet Standardization Initiative (IDDSI) framework.

10. The formulation of claim 8, wherein the whole foods, additives, small molecules and / or large molecules show bile binding capacity between 20% and 100% compared to cholestyramine.3145756690 1Attorney Docket #: CMCC 4458 PCT11. The formulation of claim 8, wherein the whole foods, additives, small molecules and / or large molecules show bile binding capacity between 30% and 50%, compared to cholestyramine12. The formulation of claim 8, wherein the whole foods, additives, small molecules and / or large molecules show bile binding capacity between 60% and 100% compared to cholestyramine13. A method of treating a subject thereof, comprising feeding the subject the formulation according to anyone of claims 1 to 9 through an enteral access device.

14. The method of claim 13, wherein the subject is a pediatric patient.

15. The method of claim 13 or 14, wherein the formulation is effective in reducing bile acids in the subject.45756690 1

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