WO2020132296A1 - Medical nutrition product composition for acute diarrhea - Google Patents

Abstract

A medical nutrition product composition is provided for administration to a patient to reduce the duration of acute diarrhea.

Description

MEDICAL NUTRITION PRODUCT COMPOSITION FOR

ACUTE DIARRHEA

[0001] This application is being filed on December 19, 2019, as a PCT

International Patent application and claims priority to U.S. Provisional patent application Serial No. 62/782,575, filed December 20, 2018, the entire disclosure of which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

[0002] A medical nutrition product composition is provided for administration to a patient to reduce the duration of acute infectious diarrhea.

DESCRIPTION OF THE RELATED ART

[0003] Infectious diarrhea is a major killer of children under the age of five in developing countries. The WHO defines diarrhea as three or more watery stools per day. The current WHO standard of care calls for the administration of oral rehydration salts (ORS) and zinc. ORS is used to rehydrate and prevent dehydration while zinc can modestly reduce the duration of a diarrhea episode and boosts the child’s immune system. Neither ORS nor zinc (nor any other product of which we are currently aware) is known to reduce the duration of acute nondysentery, non-cholera diarrhea episodes in a pediatric population to less than 48 hours. A broad-spectrum, efficacious, safe and palatable product is needed to address infectious diarrhea.

SUMMARY OF THE INVENTION

[0004] In some embodiments, a medical nutrition product composition is provided comprising milk protein concentrate (MPC), non-fat dry milk, silicone, maltodextrin, and methylated silica; wherein the composition is effective to reduce the duration of acute infectious diarrhea following administration of an effective amount to a non neonate human patient suffering from an infection of the gastrointestinal tract due to undifferentiated pathogenic sources which may include one or more of E. coli, Salmonella spp., rotavirus, and/or a gram negative bacteria. In some embodiments, the composition further comprises hydrated silicon dioxide.

[0005] In some embodiments, the medical nutrition product composition comprises from about 20-99 wt%, milk protein concentrate, compared to the total weight of the composition.

[0006] In some embodiments, the medical nutrition product composition comprises from about 1-60 wt%, non-fat dry milk, compared to the total weight of the

composition.

[0007] In some embodiments, the medical nutrition product composition comprises from about 0.1-6 wt% silicone, about 1-20 wt% maltodextrin, and/or about 0.01-1 wt% methylated silica, compared to the total weight of the composition.

[0008] In some embodiments, the medical nutrition product composition comprises from about 0.1- 20 wt% hydrated silicon dioxide, compared to the total weight of the composition.

[0009] In some embodiments, a method is provided for reducing the duration of acute diarrhea in a non-neonate human patient, the method comprising administering an effective amount of a medical nutrition product composition comprising milk protein concentrate, non-fat dry milk, and silicone. In some embodiments, the composition further comprises maltodextrin, methylated silica, and hydrated silicon dioxide.

[0010] In some embodiments, a method is provided for reducing the duration of acute diarrhea in a non-neonate human patient suffering from an infection of the gastrointestinal tract due to undifferentiated pathogenic sources which may include one or more of E. coli, Salmonella spp., rotavirus, and/or a gram negative bacteria comprising administering a medical nutrition product composition comprising milk protein concentrate (MPC), non-fat dry milk, and silicone, and optionally maltodextrin and methylated silica.

[0011] In some embodiments, the medical nutrition composition is coadministered with oral rehydration salts and/or zinc to the non-neonate human patient. [0012] In some embodiments, the medical nutrition composition is coadministered with an active agent to the non-neonate human patient.

[0013] In some embodiments, the medical nutrition composition is coadministered with an active agent selected from one or more of antibiotics, antifungals,

antimicrobials, antiparasitics, antiprotozoal drugs, antivirals, probiotics, bacteriocins, micronutrients, oral rehydration salts, antidiarrheal adsorbants, anticholinergics, antisecretory agents, antimotility drugs, additional non-immunoglobulin colostrum components, antisecretory agents, or a composition comprising bovine colostrum and whole dry egg.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014] FIG. 1 shows average duration of diarrhea episodes in children participating in 14 studies at International Center for Diarrhoeal Disease Research (icddr,b).

Patients receiving Study Article DiaResQ and the medical nutrition product composition-Pantheryx placebo, both co-administered with ORS-zinc, exhibited average duration of 29 and 32 hours, respectively. Other icddr,b studies with standard of care, ORS or ORS+zinc, with or without placebo, exhibited average duration of 72- 139 hours, with an average duration across all studies of 95 hours. The medical nutrition product composition-Pantheryx placebo surprisingly significantly reduced duration of diarrhea episodes compared to other standard of care/placebo values found in other icddr,b studies.

[0015] FIG. 2 shows average duration of diarrhea in patients following

administration of Study Article DiaResQ (29 hours) and Pantheryx placebo (32 hours) compared to average duration in 37 studies conducted outside of icddr,b. The average duration of diarrhea episodes in those studies ranges from 51 to 174 hours, with an average duration across studies of 91 hours. The medical nutrition product

composition-Pantheryx placebo surprisingly significantly reduced duration of diarrhea episodes compared to other standard of care/placebo values found in non-icddr,b studies. DETAILED DESCRIPTION OF THE INVENTION

[0016] Definitions.

[0017] The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the embodiments of the invention and the appended claims, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise. Also, as used herein, "and/or" refers to and encompasses any and all possible combinations of one or more of the associated listed items. Furthermore, the term "about," as used herein when referring to a measurable value such as an amount of a compound, amount, dose, time, temperature, and the like, is meant to encompass variations of 20%, 10%, 5%, 1%, 0.5%, or even 0.1% of the specified amount. It will be further understood that the terms "comprises" and/or "comprising," when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and/or groups thereof. Unless otherwise defined, all terms, including technical and scientific terms used in the description, have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0018] Unless otherwise specified, the term“percent” or“%” refers to percent by weight of dry matter.

[0019] The terms "prevention", "prevent", "preventing", "prophylaxis" and as used herein refer to a course of action (such as administering a compound or pharmaceutical composition of the present disclosure) initiated prior to the onset of a clinical manifestation of a disease state or condition so as to prevent or reduce such clinical manifestation of the disease state or condition. Such preventing and suppressing need not be absolute to be useful.

[0020] The terms "treatment", "treat" and "treating" as used herein refers a course of action (such as administering a compound or pharmaceutical composition) initiated after the onset of a clinical manifestation of a disease state or condition so as to eliminate or reduce such clinical manifestation of the disease state or condition. Such treating need not be absolute to be useful.

[0021] The term "in need of treatment" as used herein refers to a judgment made by a caregiver that a patient requires or will benefit from treatment. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the patient is ill, or will be ill, as the result of a condition that is treatable by a method, compound or pharmaceutical composition of the disclosure.

[0022] The term "in need of prevention" as used herein refers to a judgment made by a caregiver that a patient requires or will benefit from prevention. This judgment is made based on a variety of factors that are in the realm of a caregiver's expertise, but that includes the knowledge that the patient will be ill or may become ill, as the result of a condition that is preventable by a method, compound or pharmaceutical composition of the disclosure.

[0023] The term "individual", "subject" or "patient" as used herein refers to any animal, including birds or mammals, such as mice, Norway rats, cotton rats, gerbils, cavies, hamsters, other rodents, rabbits, dogs, cats, swine, cattle, sheep, goat, horses, or primates, and humans. The term may specify male or female or both, or exclude male or female. In one aspect, the patient is an adult human. In another aspect, the patient is a non-neonate human infant. In another aspect, the patient is a human toddler, child, or adolescent.

[0024] The term "neonate", or newborn, refers to an infant in the first 28 days after birth. The term "non-neonate" refers to an animal older than 28 days.

[0025] The term "effective amount" as used herein refers to an amount of an agent, either alone or as a part of a pharmaceutical composition, that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease state or condition. Such effect need not be absolute to be beneficial.

[0026] The term "including" as used herein is non-limiting in scope, such that additional elements are contemplated as being possible in addition to those listed; this term may be read in any instance as "including, but not limited to." [0027] The term "undifferentiated diarrhea" means that the causative agent of the diarrhea is undiagnosed.

[0028] The term“milk protein concentrate” refers to any complete milk protein (casein plus whey) concentrate that is greater than 40% milk protein that has been processed to remove lower molecular weight components. The milk protein concentrate is derived from whole milk, partially separated milk, or skim milk from cows using physical separation techniques to remove sufficient non-protein

components. In some embodiments, the manufacturing techniques employed to concentrate protein and remove non-protein constituents from milk are based on the use of membrane technologies, such as ultrafiltration or microfiltration. For example, the raw material (milk) is circulated along a semi-permeable membrane in a pressure driven process. The membrane is permeable to low molecular weight components such as sugars (e.g. lactose), minerals and other low molecular weight components. The ratio of casein and whey proteins is in a similar ratio as milk. For example, in some embodiments, the casein to whey ratio may be from about 75:25 to about 98:3, from about 82:18 to about 95:5, or about 80:20 (e.g., standard casein ratio (SCR)). The casein to whey ratio may be determined by any method known in the art, for example by capillary gel electrophoresis or CD-SDS analysis. Preferably, the proteins are in a form that resembles their native state. The caseins are in a form that resembles the initial casein micelles in milk and the whey proteins are largely undenatured. In some embodiments, the MPC is from 40-90% complete milk protein on a dry basis. In some embodiments, the MPC has less than 45 % fat, less than 20%, less than 10%, less than 5%, less than 2%, less than 1.5% or less than 1% by weight. In some embodiments, the MPC is manufactured from skim milk, partially separated milk, or whole milk. In some embodiments, the MPC is derived from whole milk. In some embodiments, the protein content is determined by SM 15.132 (Kjeldahl), the lactose content is determined by SM 15.092 (Enzymatic), the milkfat content is determined by AO AC 989.05 (Mojonnier).

[0029] All patents, patent applications and publications referred to herein are incorporated by reference in their entirety. In the event of conflicting terminology, the present specification is controlling. [0030] The embodiments described in one aspect of the present invention are not limited to the aspect described. The embodiments may also be applied to a different aspect of the invention as long as the embodiments do not prevent these aspects of the invention from operating for its intended purpose.

[0031] Diarrhea is caused mainly by the ingestion of pathogens. According to the World Health Organization (WHO), eighty- eighty percent of cases diarrhea worldwide are attributed to unsafe water, inadequate sanitation or insufficient hygiene. These cases result in about 760,000 deaths a year are in children under five.

(http://www.who.int/mediacentre/factsheets/fs330/en/).

[0032] Of particular global concern are instances of infectious diarrhea in the developing world, which are a cause of tremendous ongoing morbidity and mortality, particularly in the pediatric population. For example, India has one of the highest infant mortality rates in the world according to a 2009 United Nations Human Development report. Of India's more than 2.3 million annual deaths among children, 334,000 are attributed to diarrheal disease (http://www.who.int/bulletin/volumes/90/10/12- 101873/en/). Rotavirus vaccines, hand washing with soap, safe drinking water, improved sanitation, exclusive breastfeed for the first six months of life, good personal and food hygiene, and health education are recommended by WHO for prevention of diarrhea; however, these measures are not effective to treat the

disease (http://www.who.int/bulletin/volumes/90/10/12-101873/en/).

[0033] Standard treatment protocol in much of the world for pediatric diarrhea includes a concomitant administration of antibiotics and oral rehydrative therapy. For many reasons, antibiotics are a prescription drug. Antibiotics are not effective in the treatment of viral infection. For example, rotavirus is estimated to cause about 40 percent of all hospital admissions due to diarrhea among children under five years of age worldwide. (Weekly Epidemiological Record, vol. 83, no. 47, 21 Nov. 2008). The inappropriate use of antibiotics can promote resistant strains of bacteria. Conversely, the infection may be caused by a resistant strain of bacteria. Even under the best of circumstances, use of an appropriate antibiotic may take several days to reduce the severity of the symptoms of diarrhea. [0034] Another disadvantage of antibiotics is that administration can induce the destruction of both pathogenic and benign bacteria found in the GI tract which can further result in release of endotoxic lipopolysaccharides. (Holzheimer, The

significance of endotoxin release in experimental and clinical sepsis in surgical patients— evidence for antibiotic-induced endotoxin release? Infection. 1998 March- April; 26(2):77-84). These endotoxins have a host of adverse systemic effects including fever, changes in white blood cell counts, disseminated intravascular coagulation, hypotension, shock and death, malabsorption; in fact, the direct injection of fairly small doses of endotoxin results in death in most mammals. Todar K. Bacterial Endotoxin. Textbook of Bacteriology. 2008. textbookofbacteriology.net.

[0035] According to WHO, oral rehydration therapy and zinc with continued feeding, including breastfeeding, is recommended for treatment of childhood diarrhea. Zinc syrup or zinc-fortified oral rehydration solution (ORS, 40 mg/L) is typically employed at a dose of about 15 to 30 mg per day. Zinc is inexpensive, but has modest efficacy. Zinc syrup results in only about a 25 percent reduction in duration of acute diarrhea, and a 40 percent reduction in treatment failure or death. (Bhutta et al.

Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. The American Journal of Clinical Nutrition. 2000; 72(6): 1516-22). One study evaluated the efficacy and safety of a zinc-fortified (40 mg/L) ORS among 1,219 children with acute diarrhea. Clinical outcomes among the zinc-fortified ORS group were modestly improved, compared with those for the control group, who received standard ORS only. In that study, the total number of stools was lower among the zinc-ORS group compared with the total number for the control group. No substantial effect on duration of diarrhea or risk for prolonged diarrhea was noted. (Bahl R, Bhandari N, Saksena M, et al. Efficacy of zinc-fortified oral rehydration solution in 6- to 35-month-old children with acute diarrhea. J Pediatr 2002; 141 :677-82).

[0036] It is known that antibiotics are ineffective to treat a viral infection, such as a rotavirus infection. Other interventions have limited effectiveness. Additionally, appropriate diagnostic tools to distinguish the cause of diarrhea are not always readily available or affordable. [0037] Clearly a rapid, effective and economical alternative for the treatment of undifferentiated diarrhea is desirable. There remains a need for effective, economical compositions and methods for treatment of diarrhea and enteric infections in broad- spectrum, undifferentiated, or mixed clinical applications.

[0038] In some embodiments, methods and compositions are provided for use in combating the symptoms of acute diarrhea in a non-neonate human patient. Acute diarrhea can result from enteric or gastrointestinal infection in a patient with a variety of pathogens or agents including, without limitation, cholera toxin (Vibrio cholera), E. coli (including enterotoxigenic (ETEC)), Shigella, Salmonella, Campylobacter, Clostridium difficile, parasites (e.g., Giardia, Entamoeba histolytica, Cryptosporidiosis, Cyclospora), and diarrheal viruses (e.g., rotavirus).

[0039] In various embodiments, the pathogen is selected from one or a combination of human or veterinary, enteric or gastrointestinal, pathogens causing gastroenteritis. In various aspect, the pathogen is selected from the group consisting of: Campylobacter jejuni, Salmonella, Salmonella typhimurium, Salmonella enterica serovar Typhi, Shigella dystenteriae, Plesiomonas shigelloides, Escherichia coli [including (EPEC) enteropathogenic E. coli, (ETEC) enterotoxigenic E. coli, (EaggEC) enteroaggregative E. coli, (EIEC) enteroinvasive E. coli, and (EHEC) haemorrhagic E. coli], Yersinia enterocolitica, Vibrio cholerae 01, Vibrio 0139, Non-Ol Vibrios, Vibrio

parahaemolyticus, Aeromonas hydrophile, Clostridium perfringens, Clostridium difficile, enterohepatic Helicobacter (including Helicobacter pylori), Staphylococcus aureus, Klebsiella, rotavirus, coronavirus, norovirus, calicivirus, enteric adenovirus, cytomegalovirus, and astrovirus. In another aspect, the pathogen related toxin includes an endotoxin or exotoxin. In another aspect, the pathogen related adhesion element includes adhesins, cadherins, cilia, fimbrillae, a viral adhesion structure, or a combination thereof.

[0040] After entering the gastrointestinal tract many pathogens, including but not limited to bacteria such as E. coli, bind (adhere) to epithelial, mucosal, or other tissue and become embedded in gastrointestinal tract tissue, such as the wall of the intestine.

After binding to tissue in the gastrointestinal tract the pathogens replicate, causing an increase in toxin concentrations, either directly from production or indirectly from increased lysing of pathogen cells by immune system action. Inhibiting the ability of pathogens to bind to the gastrointestinal tract tissue promotes a more effective mobilization of the pathogens, digestion and excretion before colonies of sufficient size to cause lesions and other symptoms are formed. Without being bound by theory, by blocking the class of receptors and ligands on the pathogen that would be used to adhere to the gastrointestinal tract, including but not limited to adhesins, cadherins, cilia, fimbrillae, and/or viral adhesion structures, adhesion to gastrointestinal tract tissue can be prevented or minimized, ultimately resulting in substantially decreased pathology from pathogens that utilize this mode of action.

[0041] In some embodiments, dairy -based compositions are provided for use in combating the symptoms of acute diarrhea in a non-neonate human patient. In some embodiments, the compositions comprise non-fat dry milk and milk protein

concentrate.

[0042] In the literature, antimicrobial activity of milk is mainly attributed to immunoglobulins, and non-immune proteins, such as lactoferrin, lactoperoxidase and lysozyme. One of the most potent antimicrobial peptides corresponds to a fragment of lactoferrin, named lactoferricin. More recently, other whey proteins such as a - lactalbumin and b - lactoglobulin have also been considered as potential precursors of bactericidal fragments. Similarly, antibacterial fragments have also been derived from asi-, OLS2 -, b - and k - casein. Fadaei, Ann. Biol. Res., 2012, 3(5):2520-2526.

[0043] For example, Adoui et al. hydrolyzed bovine casein with porcine pepsin and reported the total casein hydrosylate contains some antibacterial peptides mixed with a large number of peptides without antimicrobial activity. Therefore, Adoui et al.

isolated and purified certain as2-caseinate peptides by reverse phase high pressure liquid chromatography on a C-18 RP column. Antibacterial activities of fractions were studied by plate diffusion assay and minimum inhibitory concentrations (MICs) in a microtiter plate system after 18h at 37 °C of certain extracts and isolated peptide a_S2- CN(164-207) was determined for a few gram positive (L. innocua, B. subtilis, L.

monocytogenes, S. aureus) and gram negative bacterial E.coli strains. Modest MIC values for some isolated extracts and peptides were reported in Table IV. However, Adoui reports when added to skimmed milk and to carrot juice, the peptides resulting from a_S2-casein hydrolysis exhibited substantial loss of activity. Adoui et al., March 2013, Int Rev Chem Engineer 5(2): 179-187. Therefore, the rapid anti -diarrheal activity exhibited by herein disclosed medical nutrition product comprising non-fat dry milk and MPC80 is an extremely surprising result.

[0044] A randomized, double-blind, placebo-controlled clinical trial was performed at the distinguished International Centre for Diarrhoeal Disease Research (icddr,b) for the purpose of evaluating the efficacy of a Test Article in reducing the duration of diarrhea episodes in children between 6 months and 5 years old. Located in Dhaka, Bangladesh, icddr,b is an international health research organization, and is a leading hospital for research on diarrhea among populations impacted by poverty and malnutrition.

[0045] Bangladesh was selected because is known as being one of the most challenging environments in which to combat diarrhea. In past published studies conducted at icddr,b, the average duration range of diarrhea episodes of patients that received ORS and/or zinc (with and without a placebo) has been reported to be 72 to 139 hours. Dysentery and some cholera patients respond to antibiotic treatment.

Children who tested positive for dysentery and cholera were excluded from the study.

[0046] The Test Article performed as expected. Test Article is disclosed in

WO2012/071346, and US 2012/0141458, Starzl, each of which is incorporated herein by reference. Test article included whole dry egg and bovine colostrum. The activity of test article in the double-blind, placebo-controlled clinical trial was in line with results for several previous open-label studies, for example as disclosed in WO2012/071346, and US 2012/0141458, Starzl.

[0047] When compared to diarrhea durations from comparable studies reported in published scientific literature, the Test Article performed very well, with an average diarrhea duration of 29 hours. An evaluation of 14 icddr,b studies published since 1995, whose study populations were similar to those in the present study is shown in Figure 1 and Annexure A.

[0048] The average diarrhea durations in those 14 studies ranged from 72 to 139 hours with an average duration across all studies of 95 hours. Another 37 studies were identified that were conducted outside of icddr,b, but that had entry criteria similar to the present study. See Figure 2 and Annexure B. The average duration of diarrhea episodes in those studies ranged from 51 to 174 hours with an average duration across all studies of 91 hours.

[0049] Quite unexpectedly, the placebo reduced average duration of diarrhea to 32 hours. The placebo is disclosed herein as a medical nutrition product for acute infectious diarrhea.

[0050] However, here both the Test Article and surprisingly, the Placebo, performed significantly better on average than what has ever been seen in prior studies conducted at icddr,b with zinc and/or ORS as the standard of care (with or without a placebo). Although the 29-hour average duration of diarrhea following administration of the Test Article was consistent with pre-study expectations, the 32-hour average duration of diarrhea following administration of the placebo was a wholly unanticipated and surprising result.

[0051] Unexpectedly, the placebo demonstrated a significant improvement over the historically reported average duration of diarrhea following administration of ORS and zinc (with or without placebo). The study confirmed that both Test Article and Placebo were safe and that both Test Article and Placebo significantly reduced the duration of acute non-dysentery, noncholera diarrhea episodes in a pediatric population in comparison to the duration of diarrhea reported in prior icddr,b studies that evaluated ORS and/or zinc (with or without a placebo). Placebo unexpectedly and inexplicably demonstrated efficacy. There was not a statistically significant difference between the Test Article group and the Placebo group.

[0052] Medical Nutrition Product Compositions

[0053] In some embodiments, a medical nutrition product composition is provided comprising Milk Protein Concentrate (MPC) and non-fat dry milk. The composition is effective in reducing the duration, stool output and/or stool frequency in a non-neonate human patient suffering from acute diarrhea. MPC is a concentrated milk product or milk protein isolate that contains 40 percent or more milk protein by weight. In some embodiments, the composition comprises an MPC that is from about 40-95 wt% milk protein. In some embodiments, the MPC contains one or more of whey protein concentrate, whey protein isolate, milk protein hydrosylate, or fractions thereof. In some embodiments, MPC comprises any complete milk protein (casein plus lactalbumin) concentrate that is 40 percent or more protein by weight. In addition to ultrafiltered milk products, the MPC classification includes concentrates made through other processes, such as blending nonfat dry milk with highly concentrated proteins, such as casein. In some embodiments, the MPC is selected from MPC 40 (39.5% min. protein), MPC 42 (41.5% min. protein), MPC 56 (55.5% min. protein), MPC 70 (69.5% min. protein), MPC 80 (79.5% min. protein), MPC 85 (85% min. protein), or Milk Protein Isolate (MPI) (89.5% min. protein). In some embodiments, the MPC is selected from MPC 70 (69.5% min. protein), MPC 80 (79.5% min. protein), or MPC 85 (85% min. protein). In some embodiments, the MPC comprises 0.1-5 % fat, 0.5-3% fat or 1- 2% fat content. In some embodiments, the MPC may be obtained from a commercial vendor or may be produced by any method known in the art. In some embodiments, the MPC is produced, for example, by the method of Vikram Mistry. Manufacture and application of high milk protein powder. Le Lait, INRA Editions, 2002, 82 (4), pp.515- 522. In another embodiment, the MPC is produced by the method of US Published Application US 20060040025, Souppe, which is incorporated herein by reference.

[0054] Milk protein concentrate may be prepared by a process comprising pasteurization, separation of skim milk from cream, and ultrafiltration of the skim milk to remove low molecular weight components. The skim milk may be fractionated using ultrafiltration to make a skim concentrate that is lactose-reduced. For example, skim milk may comprise about 52 % lactose. Thus MPC may be lactose-reduced, and in some embodiments the MPC comprises 0-52% lactose, or less than 52%, less than 50%, less than 45%, less than 35%, less than 30%, less than 25%, less than 20%, less than 15%, less than 10%, less than 5%, less than 3%, or less than 1% lactose. This process separates milk components according to their molecular size. Milk then passes through a membrane that allows some of the lactose, minerals, and water to cross through. The casein and whey proteins, however, will not pass through the membrane due to their larger molecular size. The proteins, lactose, and minerals that do not go through the membrane are then spray dried. Spray drying and evaporation further concentrate the remaining materials to form a powder. Depending on the purpose of the final product, different heat treatments can be used to process ultrafiltered or blended varieties of MPC. In some embodiments, the medical nutrition product comprises an MPC product processed with low heat which will maintain higher nutritional value.

[0055] The Milk Protein Concentrate can also contain various immunoglobulins. The most prevalent immunoglobulin in bovine milk or colostrum is IgGl. However, according to Stelwagen et al., Bovine colostrum contains about 47.6 mg/mL IgGl; whereas milk contains only 0.59 mg/mL IgGl. Therefore, the unexpected efficacy of the Medical Nutrition Product comprising non-fat dry milk and MPC may be unlikely to be due exclusively to the presence of any serendipitous specific immunoglobulins. Stelwagen et al., J. Anim. Sci., 2009, 87(Suppl. l):3-9. In addition, the medical nutrition product comprises MPC obtained from non-hyperimmune milk obtained from non-hyperimmune cows; in other words, cows that have not been intentionally immunized with an antigen for the sole purpose of harvesting antigen-specific antibodies.

[0056] In some embodiments, the MPC may be MPC 80 that is at least about 80 wt% milk protein minimum on a dry basis. The MPC 80 may be prepared by a process comprising removing small molecule components for example having a molecular weight less than 1,000 g/mol, or less than 500 g/mol, for example, such as lactose (342.3 g/mol). The MPC may be selected to have not more than 12%, not more than 10%, not more than 5%, or preferably not more than 4% lactose. The MPC may be prepared from skim milk. In some embodiments, the MPC 80 may have no more than about 3 wt% fat. The MPC 80 may be processed such that it is undenatured giving it a high level of protein subfractions. In some embodiments, MPC is employed in the formulation in a dry powder form. In some embodiments, the MPC is instantized, in which case an emulsifier such as soy lecithin may be present to enable rapid dissolution in a liquid such as water prior to administration.

[0057] In some embodiments, the medical nutrition product comprises Milk Protein Concentrate (MPC) in an amount from about 20-99 wt%, 40-90 wt%, or 50-70 wt%, compared to the total weight of the medical nutrition product.

[0058] In some embodiments, the medical nutrition product comprises non-fat dry milk in an amount from about 1-80 wt%, 1-60 wt %, 10-60 wt%, or 30-50 wt%, compared to the total weight of the medical nutrition product. [0059] In some embodiments, the medical nutrition product comprises Milk Protein Concentrate (MPC) and non-fat dry milk and further comprises one or more

pharmaceutically acceptable diluents such as carriers, binders, excipients, lubricants, sweetening agents, flavoring agents, wetting agents, or absorbents.

[0060] In the medical nutrition product, the one or more pharmaceutically acceptable diluents, including carriers, binders, excipients, lubricants, sweetening agents, flavoring agents, wetting agents, or absorbents are present in a combined amount of from 0.1- 90 wt%, 0.5-50 wt%, or 1-10 wt% compared to the total weight of the formulation.

[0061] In some embodiments, the medical nutrition product comprises Milk Protein Concentrate (MPC) and non-fat dry milk and further comprises one or more

pharmaceutically acceptable carriers and/or excipients including an antifoam agent. In some embodiments, the antifoam agent includes a powdered food grade antifoam agent. In a specific embodiment, the food grade antifoam agent comprises silicone, maltodextrin, and methylated silica (e.g., Dow Corning XIAMETER® ACP-1920 powdered antifoam). Other powdered silicone antifoams may be employed, as provided by, for example, Trans-Chemco, Inc., or Basildon Chemicals. In some embodiments, the one or more powdered food-grade antifoams are present in a combined amount selected of from 0.1- 20 wt%, 0.5-10 wt%, or 1-5 wt% compared to the total weight of the formulation. In a specific embodiment, the food grade antifoam agent comprises about 5-30 wt% silicone, 70-90 wt% maltodextrin, and 1-5 wt% methylated silica.

[0062] In some embodiments, the composition comprises from about 0.1-6 wt% silicone, about 1-20 wt% maltodextrin, and/or about 0.01-1 wt% methylated silica.

[0063] In some embodiments, the medical nutrition product composition comprises Milk Protein Concentrate (MPC) and non-fat dry milk and further comprises one or more pharmaceutically acceptable excipients including synthetic amorphous silica (hydrated silicon dioxide, silica gel, SYLOID® 244, Grace). In some embodiments, the one or more hydrated silicon dioxides are present in a combined amount selected of from 0.1- 20 wt%, 0.5-10 wt%, or 1-5 wt% compared to the total weight of the formulation. [0064] In some embodiments, the medical nutrition product composition comprises pharmaceutical acceptable diluents for formulating the composition, wherein said pharmaceutical acceptable diluents are selected from the group consisting of a lactose, mannitol, sorbitol, microcrystalline cellulose, sucrose, sodium citrate, dicalcium phosphate, or any other ingredient of the similar nature alone or in a suitable combination thereof; binder selected from the group consisting of gum tragacanth, gum acacia, methyl cellulose, gelatin, polyvinyl pyrrolidone, starch or any other ingredient of the similar nature alone or in a suitable combination thereof; excipients selected from the group consisting of agar-agar, calcium carbonate, sodium carbonate, silicates, alginic acid, corn starch, potato tapioca starch, primogel or any other ingredient of the similar nature alone or in a suitable combination thereof; lubricants selected from the group consisting of a magnesium stearate, calcium stearate or steorotes, talc, solid polyethylene glycols, sodium lauryl sulfate or any other ingredient of the similar nature alone; glidants selected from the group consisting of colloidal silicon dioxide or any other ingredient of the similar nature alone or in a suitable combination thereof; a sweetening agent selected from the group consisting of such as sucrose, saccharin or any other ingredient of the similar nature alone or in a suitable combination thereof; a flavoring agent selected from the group consisting of vanilla, butterscotch, peppermint, orange flavor, or any other pharmaceutically acceptable flavor alone or in a suitable combination thereof; wetting agents selected from the group consisting of acetyl alcohol, glyceryl monostearate or any other pharmaceutically acceptable wetting agent alone or in a suitable combination thereof; absorbents selected from the group consisting of kaolin, bentonite clay or any other pharmaceutically acceptable absorbents alone or in a suitable combination thereof; retarding agents selected from the group consisting of wax, paraffin, or any other pharmaceutically acceptable retarding agent alone or in a suitable combination thereof.

[0065] In some embodiments, the medical nutrition product composition comprises Milk Protein Concentrate (MPC), non-fat dry milk, pharmaceutically acceptable carriers and/or excipients and further comprises flavorings and/or colorings. Palatability in the medical nutrition product composition is very important as the children suffering from diarrhea are very ill. In some embodiments, the medical nutrition product comprises a flavoring selected from spearmint oil, cinnamon oil, oil of wintergreen

(methyl salicylate), peppermint oil, clove oil, bay oil, anise oil, eucalyptus oil, thyme oil, cedar leaf oil, oil of nutmeg, allspice, oil of sage, mace, oil of bitter almonds, and cassia oil. Also useful are natural, natural and artificial, or artificial flavors such as vanilla, citrus oils including, without limitation, lemon, orange, lime, grapefruit, and fruit essences including apple, pear, peach, grape, strawberry, raspberry, cherry, plum, pineapple, apricot and so forth. These flavoring agents may be used in liquid or solid form and may be used individually or in admixture. Commonly used flavors include mints such as peppermint, menthol, artificial vanilla, cinnamon derivatives, and various fruit flavors, whether employed individually or in admixture. Other useful flavorings include aldehydes and esters such as cinnamyl acetate, cinnamaldehyde, citral diethyl acetal, dihydrocarvyl acetate, eugenyl formate, p-methylamisol, and so forth may be used. In some embodiments, the medical nutrition product composition comprises flavoring present in an amount of from about 0-5 wt%, 0.1-3 wt%, or 0.3-2 wt%, compared to the total weight of the composition. In some embodiments, the flavoring is vanilla used in an amount of about 0.6 wt%.

[0066] In some embodiments, the composition comprises a coloring such as FD&C powdered food coloring employed to enhance the appearance of the composition. In some embodiments, the coloring is present in from about 0.001-1 wt%, 0.01-0.5 wt%, or 0.02-0. lwt% of the composition.

[0067] In some embodiments, the composition optionally further comprises one or more sweeteners. The sweetener may be selected from a solid natural or synthetic sweetener. The natural sugar may be selected from sucrose, dextrose, fructose, lactose, maltose, glucose syrup, invert sugar, and hydrolyzed lactose. The synthetic sweetener may be selected from aspartame, a cyclamate, saccharin, acesulfame salts, neo- hesperidin dihydrochalcone, sucralose, alitame, stevia, talin, glcyrrhizin, thaumatin, xylitol, and mixtures thereof. The term saccharin as used herein includes saccharin itself, saccharin acids, and saccharin salts such as sodium saccharin. In one aspect, the sweetener is acesulfame K. The sweetener is present from about 0 to about 5 wt % by weight compared to the weight of the composition.

[0068] In some embodiments, the medical nutrition product composition comprises

50-70 wt% MPC; 30-50 wt% non-fat dry milk; 1-5 wt% hydrated silicon dioxide; and

1-5 wt% of a powdered food-grade antifoam. In some embodiments, the composition further comprises one or more flavorings at 0.01 wt%-2 wt%. In some embodiments, the composition further comprises one or more colorings at 0.001-2 wt%. In some embodiments, the composition comprises 50-70 wt% MPC; 30-50 wt% non-fat dry milk; 1-5 wt% hydrated silicon dioxide; 0.1-1 wt% silicone; 1-2 wt% maltodextrin; and about 0.01-1 wt% methylated silica. In some embodiments, the composition further comprises 0.05-0.1 wt% of a flavoring, and 0.05-0.5 wt% of one or more FD&C food colorings.

[0069] In some embodiments, the medical nutrition product is packaged in a solid form. The term "solid form" refers to a dried form of the composition as a powder, compressed tablet, troche, or capsule. In one aspect, the solid dosage form is intended for oral administration. In one aspect, the powder is a formulation for suspension. In one aspect, the powdered composition is packaged in an airtight packet. Immediately prior to oral administration, the contents of the packet are suspended, or dissolved, in about a liquid and administered orally. In some embodiments, the composition is administered by gavage.

[0070] Formulations for oral use may also be prepared as troches, chewable tablets, or as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil. Powders and granulates may be prepared using the ingredients mentioned above under tablets and capsules in a conventional manner using, e.g., a mixer, a fluid bed apparatus or a spray drying equipment.

[0071] In one aspect, the composition may also be provided in a liquid form for administration.

[0072] In one aspect, one dose contains 0.5 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5 g, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, 10 g, 10.5 g, 11 g, 11.5 g,

12 g, 12.5 g, 13 g, 13.5 g, 14 g, 14.5 g, or 15 g of dried composition. In one aspect, one dose of the dried dosage form is provided as a loose powder in a sealed packet. In some embodiments, the contents of a single dose packet are dissolved in water and administered orally. In a specific aspect, the contents of a 7 g single dose packet are dissolved in 1-2 ounces of water and administered orally. [0073] Administration

[0074] In some embodiments, the compositions of the disclosure are used to treat patients suffering from various pathogenic enteric infections.

[0075] In a preferred method of administration, the composition is administered orally, by ingestion. To consume, the powdered substance is mixed with a small quantity of a liquid, such as water, milk, juice, or electrolyte solution, immediately prior to consumption, and is taken as directed by a physician. Other methods of delivery are also contemplated.

[0076] Prior to use, the contents of the packet, or sachet, containing a single dose of the composition, are mixed into approximately 1-2 ounces of water, or some other liquid. The entire reconstituted formulation is administered orally to the subject. The composition can be administered one to four times per day for one to ten days, or as needed. In a specific embodiment, the composition is administered once per day for 3 consecutive days. In some embodiments, the disclosure provides a method of treating undifferentiated pediatric diarrhea, by administration of the composition of the disclosure once per day for two, three or four days.

[0077] The compositions and formulations for oral administration can be administered once, twice, three times, or four times a day for one, two, three, four, five, six, seven, eight, nine, 10, 11, or 12 consecutive days for the treatment of a pathogenic enteric infection. In one aspect, the composition is administered twice per day for five days for the treatment of a pathogenic enteric infection. In another specific aspect, the composition is administered once per day for three consecutive days for the effective treatment of undifferentiated diarrhea in non-neonatal children, or in the treatment of traveler's diarrhea in non-neonatal children or adults. In another aspect, the composition may be regularly administered for the prophylaxis of a pathogenic enteric infection.

[0078] In a preferred embodiment, the disclosure provides a composition effective for treating undifferentiated diarrhea in non-neonate humans. In some embodiments, methods are provided for reducing duration of diarrhea, decreasing vomiting, decreasing stool frequency, improving stool consistency and/or improving food intake in a non-neonatal patient in need thereof, comprising administering to the patient an effective amount of the medical nutrition product composition.

[0079] In a preferred embodiment, the disclosure provides an economical composition for the effective treatment of undifferentiated pediatric diarrhea. In some embodiments, the composition is used to treat acute diarrhea in a patient suffering from an infection of the gastrointestinal tract due to undifferentiated pathogenic sources which may include one or more of E. coli, Salmonella spp., rotavirus, and/or a gram negative bacteria. In some embodiments, a method is provided for reducing the duration of acute diarrhea, the method comprising administering an effective amount of a medical nutrition product composition comprising milk protein concentrate, non-fat dry milk, silicone, maltodextrin, methylated silica and hydrated silicon dioxide.

[0080] In some embodiments, the composition of the disclosure is administered as an adjunct therapy to treatment with an active agent. In various embodiments, the additional active agent is selected from one or more of antibiotics, antifungals, antimicrobials, antiparasitics, antiprotozoal drugs, antivirals, probiotics, bacteriocins, micronutrients, oral rehydration salts, antidiarrheal adsorbants, anticholinergics, antisecretory agents, antimotility drugs, additional non-immunoglobulin colostrum components, or antisecretory agents.

[0081] In some embodiments the active agent is an antibiotic selected from the group consisting of Prulifloxacin, Ulifloxacin, Fidaxomicin, Minocyclin,

Metronidazole, Metronidazole, Sulfamethoxazole, Trimethoprim, Ofloxacin,

Norfloxacin, Tinidazole, Norfloxacin, Ofloxacin, Ornidazole, Levofloxacin, Nalidixic acid, Ceftriaxone, Azithromycin, Cefixime, Ceftriaxone, Cefalexin, Ceftriaxone, Rifaximin, Ciprofloxacin, Norfloxacin, Ofloxacin, Levofloxacin, Gatifloxacin, Gemifloxacin, Prufloxacin, Ulifloxacin, and Moxifloxacin, or a combination thereof.

[0082] In some embodiments the active agent is an antifungal selected from nystatin, amphotericin B, flucytosine, ketoconazole, posaconazole, clotrimazole, voriconazole, griseofulvin, miconazole nitrate, and fluconazole, or a combination thereof.

[0083] In some embodiments the active agent is an antimicrobial selected from the group consisting of Metronidazole, Tinidazole, Nitazoxanide, Satranidazole,

Ornidazole, Ofloxocin, Diloxanide furoate, Trimethoprim, Sulfamethoxazole, Albendazole, Paromomycin, Ciprofloxacin, Diloxanide furoate, and Fumagillin, or a combination thereof.

[0084] In some embodiments the active agent is a probiotic selected from the group consisting of Pediococcus spp., Saccharomyces spp., Bacillus spp., Lactobacillus spp., Enterococcus spp., and Bifidobacterium spp, or a combination thereof.

[0085] In some embodiments the active agent is a micronutrient selected from the group consisting of vitamin A, vitamin D, vitamin E, vitamin B12, riboflavin, niacin, pantothenic acid, thiamine, choline, folic acid, biotin, vitamin K, vitamin C, cobalt, copper, iron, manganese, zinc, and selenium, or a combination thereof.

[0086] In some embodiments the active agent is an oral rehydration salt solution comprising one or more of sodium chloride, potassium citrate, potassium chloride, and sodium citrate, or a combination thereof.

[0087] In some embodiments the additional active agent in the composition is an anti diarrheal adsorbant selected from the group consisting of bismuth subsalicylate, kaolin, attapulgite and pectin, or a combination thereof.

[0088] In some embodiments the active agent is an anticholinergic selected from the group consisting of a belladonna alkaloid, atropine and hyoscyamine, or a combination thereof.

[0089] In some embodiments the active agent is an antisecretory agent selected from the group consisting of Racecadotril, Crofelemer, iOWH032, albumin tannate, Sulfasalazine, Mesalazine, Olsalazine, and Octreotide, or a combination thereof.

[0090] In some embodiments the active agent is an antimotility drug selected from the group consisting of loperamide and diphenoxylate, or a combination thereof.

[0091] In some embodiments, the active agent is a composition comprising bovine colostrum and whole dry egg (DIARESQ®, Pantheryx).

[0092] In some embodiments, the medical nutrition composition may be administered once per day for the first three days of treatment. In another aspect, the composition of the disclosure is administered with oral rehydration solution (ORS). In another aspect, the composition of the disclosure is co-administered with an oral zinc formulation. In another aspect, the composition of the disclosure is administered as an adjunct to antibiotic treatment to prevent overgrowth of a particular pathogenic organism that is resistant to the antibiotic. As described in detail in the examples, the composition and method is effective to rapidly resolve the symptoms of undifferentiated pediatric diarrhea, resulting in significantly decreased stool volume, stool frequency and duration of diarrhea, as well as significantly improved physician reported well-being.

[0093] In one alternative embodiment, the compositions of the disclosure are used to treat traveler's diarrhea (TD). The onset of TD usually occurs within the first week of travel but may occur at any time while traveling, and even after returning home. The most important determinant of risk is the traveler's destination. High-risk destinations are the developing countries of Latin America, Africa, the Middle East, and Asia. Persons at particular high-risk include young adults, immunosuppressed persons, persons with inflammatory-bowel disease or diabetes, and persons taking H-2 blockers or antacids. Most TD cases begin abruptly. The illness usually results in increased frequency, volume, and weight of stool. Altered stool consistency also is common. Typically, a traveler experiences four to five loose or watery bowel movements each day. Other commonly associated symptoms are nausea, vomiting, diarrhea, abdominal cramping, bloating, fever, urgency, and malaise.

[0094] Infectious agents are the primary cause of TD. Bacterial enteropathogens cause approximately 80% of TD cases. The most common causative agent isolated in countries surveyed has been enterotoxigenic Escherichia coli (ETEC). ETEC produce watery diarrhea with associated cramps and low-grade or no fever. Besides ETEC and other bacterial pathogens, a variety of viral and parasitic enteric pathogens also are potential causative agents.

[0095] In one aspect, the composition of the disclosure is administered to the subject once per day for three consecutive days as an alternative or adjunct to antibiotic treatment of traveler's diarrhea. Alternatively, two doses per day of the composition of the disclosure are administered on day 1, followed by a single dose on days 2 and 3. In one aspect, the composition of the disclosure is administered on an alternate daily or weekly schedule, or on a reduced dosage schedule to for prophylaxis of traveler's diarrhea. EXAMPLES

Example 1. Medical Nutrition Product-Placebo Formulation.

[0096] The medical nutrition product composition-placebo formulation was prepared from the materials as shown in Table 1.

[0097] Table 1. Medical Nutrition Product Composition-Placebo Formulation

[0098] The composition was prepared in a dry powder form and sealed in single dose packets. Immediately prior to oral administration, the contents of the packet are suspended, or dissolved, in about a liquid and administered orally. Specifically, the contents of a single dose packet were dissolved in about 1 ounce of water and administered orally. One dose of the formulation (7 grams) was administered once per day for three days.

Example 2. Clinical Study.

[0099] A randomized, double-blind, placebo-controlled clinical trial was performed at the distinguished International Centre for Diarrhoeal Disease Research (icddr,b) for the purpose of evaluating the efficacy of Test Article in reducing the duration of diarrhea episodes in children between 6 months and 5 years old. [00100] Participants were admitted to the Short Stay Ward of the Dhaka hospital of icddr,b and once a day for three days were administered either a Test Article or a Placebo comprised primarily of non-fat dried milk and milk protein concentrate according to Table 1. All participants also received the WHO standard of care of ORS and zinc. Sixty-eight children were enrolled into the study and 56 were evaluated for efficacy. Children who tested positive for dysentery and cholera were excluded from the study.

[00101] Only children with a preadmission duration of diarrhea (i.e., the length of time the child had been sick prior to admission) of less than 48 hours were permitted to participate in the study. The mean preadmission diarrhea duration of the children who participated in the study was 25 hours. Because in all but the most severe cases acute pediatric diarrhea is a self-limiting condition, most children will eventually get better on their own after a period of time. Therefore, preadmission diarrhea duration is a critical variable when evaluating the potential effectiveness of a diarrhea product. The key objectives of the study were to determine whether Test Article, when used along with the WHO standard of care (ORS and zinc) would reduce the duration of diarrhea episodes, and to evaluate the safety of the product. Secondary objectives were to measure the consistency and frequency of stool.

Results

[00102] In the test Article group, 27 children received Test Article and completed the study. Of the 27 Test Article group, 9 were rotavirus positive, while 18 were rotavirus negative. In the Placebo Group, 29 children received placebo and completed the study. Of the 29 children in the Placebo group, 15 were rotavirus positive, while 14 were negative for rotavirus.

[00103] No adverse events were attributed to Test Article or Placebo; both were confirmed to be safe.

[00104] The average duration of diarrhea in the Test Article group was 29 hours, as compared to 32 hours in the Placebo group. This difference is not statistically significant. The average duration of the diarrhea in both the Test Article group and the Placebo group was significantly shorter than the average duration of diarrhea reported in prior icddr,b studies that evaluated ORS and/or zinc (with or without a placebo).

[00105] Stool frequencies declined from a daily average of 11.7 at baseline to 3.9 by Day 2, and to 1.3 on Day 4 in the Test Article group. Stool frequencies were numerically greater in the Placebo group on Days 1 and 2, but the differences were not statistically significant from the Test Article Group.

Example 3. Comparison of duration of diarrhea episodes to Literature Studies.

[00106] The average duration of diarrhea in the Test Article group was 29 hours, as compared to 32 hours in the Placebo group. This difference is not statistically significant. The average duration of the diarrhea in both the Test Article group and the Placebo group was significantly shorter than the average duration of diarrhea reported in prior icddr,b studies that evaluated ORS and/or zinc (with or without a placebo) as shown in Table 2.

[00107] Table 2. Published Studies in Children receiving standard of care at iccdr,b.

[00108] The average duration of diarrhea in the Test Article group was 29 hours, as compared to 32 hours in the Placebo group. This difference is not statistically significant. The average duration of the diarrhea in both the Test Article group and the Placebo group was significantly shorter than the average duration of diarrhea reported in prior non-icddr,b studies that evaluated ORS and/or zinc (with or without a placebo) as shown in Table 3.

[00109] Table 3. Non-iccdr,b Studies in Children receiving Standard of Care.

[00110] As shown in Tables 2 and 3 and graphically in FIG. 1 and FIG. 2, surprisingly, the average duration in the Placebo group was significantly shorter than the average duration of diarrhea reported in prior icddr,b and non-icddr,b studies that evaluated ORS and/or zinc (with or without a placebo).

REFERENCES CITED

U.S. Pat. No. 5,017,372, 05/21/1991, Hastings

U.S. Pat. No. 5,198,213 A, 03/30/1993, Stott et al.

US 2012/0141458 Al, 06/07/2012, Starzl

WO2012/071346 Al, 05/31/2012, Pantheryx, Inc.

ADOUI ET AL.,“A Simple Method to Separate the Antimicrobial Peptides from Complex Peptic Casein Hydrolysate and Identification of a Novel Antibacterial Domains within the Sequence of Bovine a_s-Casein,” International Review of Chemical Engineering , Vol. 5, No. 2, pp. 179-187, March 2013.

ALAM ET AL.,“Partially Hydrolyzed Guar Gum- Supplemented Oral Rehydration Solution in the Treatment of Acute Diarrhea in Children,” Journal of Pediatric

Gastroenterology and Nutrition, Vol. 31, pp. 503-507, November 2000.

ALAM ET AL.,“L-Isoleucine-supplemented Oral Rehydration Solution in the

Treatment of Acute Diarrhoea in Children: A Randomized Controlled Trial,” J Health Popul Nutr, Vol. 29, No. 3, pp. 183-190, June 2011.

ALAM,“Oral Rehydration Solution: Future Prospect,” Presented at Global Healthshare Initiative on October 18, 2010.

ASHRAF ET AL.,“Folic acid in the treatment of acute watery diarrhoea in children: a double-bind, randomized, controlled trial f Acta Pcediatr, Vol. 87, pp. 1113-1115,

1998.

BAQUI ET AL.,“Effect of zinc supplementation started during diarrhoea on morbidity and mortality in Bangladeshi children: community randomised trial,” Papers, BMJ , Vol. 325, November 9, 2002.

BASU ET AL.,“Efficacy of Lactobacillus rhamnosus GG in acute watery diarrhoea of Indian children: a randomised controlled trial,” Journal of Paediatrics and Child Health , Vol. 43, pp. 837-842, 2007.

BASU ET AL., Efficacy of High-dose Lactobacillus rhamnosus GG in Controlling Acute Watery Diarrhea in Indian Children, A Randomized Controlled Trial,” J Clin Gastroenterol , Vol. 43, No. 3, pp. 208-213, March 2009. BHATNAGAR ET AL.,“Zinc With Oral Rehydration Therapy Reduces Stool Output and Duration of Diarrhea in Hospitalized Children: A Randomized Controlled Trial,” Journal of Pediatric Gastroenterology and Nutrition, Vol. 38, pp. 34-40, January 2004. BROOKS ET AL.,“Efficacy of zinc in young infants with acute watery diarrhea,” The American Journal of Clinical Nutrition, Vol. 82, pp. 605-610, 205.

CANANI ET AL.,“Probiotics for treatment of acute diarrhoea in children: randomised clinical trial of five different preparations,” BMJ , Online First, undated.

CASSWALL ET AL.,“Treatment of Enterotoxigenic and Enteropathogenic

Escherichia coli- induced Diarrhoea in Children with Bovine Immunoglobulin Milk Concentrate from Hyperimmunized Cows: A Double-blind, Placebo-controlled,

Clinical Trial,” ScandJGostroenterol, 2000.

CHEN ET AL.,“Probiotics Have Clinical, Microbiologic, and Immunologic Efficacy in Acute Infectious Diarrhea,” The Pediatric Infectious Disease Journal, Vol. 29, No.

2, pp. 135-138, February 2010.

DUTTA ET AL.,“Impact of Zinc Supplementation in Malnourished Children with Acute Watery Diarrhoea,” Journal of Tropical Pediatrics, Vol. 46, pp. 259-263, October 2000.

FADAEI,“Milk Proteins-derived antibacterial peptides as novel functional food ingredients,” Scholars Research Library, Annals of Biological Research, Vol. 3, No. 5, pp. 2520-2526, 2012.

FARUQUE ET AL.,“Randomized, controlled, clinical trial of rice versus glucose oral rehydration solutions in infants and young children with acute watery diarrhoea,” Acta Pcediatr, Vol. 86, pp. 1308-1311, 1997.

FARUQUE ET AL.,“Double-blind, randomized, controlled trial of zinc or vitamin A supplementation in young children with acute diarhhoea,” Acta Pcediatr, Vol. 88, pp. 154-160, 1999.

FISCHER WALKER ET AL.,“Zinc Supplementation for the Treatment of Diarrhea in Infants in Pakistan, India and Ethiopia,” Journal of Pediatric Gastroenterology and Nutrition, Vol. 43, pp. 357-363, September 2006.

FISCHER WALKER ET AL.,“Does Age Affect the Response to Zinc Therapy for Diarrhoea in Bangladeshi Infants?” J Health Popul Nutr, Vol, 26 (I), pp. 105-109, March 2008. GUANDALINI ET AL.,“Lactobacillus GG Administered in Oral Rehydration Solution to Children with Acute Diarrhea: a Multicenter European Trial,” Journal of Pediatric Gastroenterology and Nutrition, Vol. 30, No. 1, pp. 54-60, January 2000. GUARINO ET AL.,“Oral Bacterial Therapy Reduces the Duration of Symptoms and of Viral Excretion in Children with Mild Diarrhea,“ Journal of Pediatric

Gastroenterology and Nutrition, Vol. 25, No. 5, pp. 516-519, November 1997.

HURLEY ET AL.,“Perspectives on Immunoglobulins in Colostrum and Milk,” Nutrients, Vol. 3, pp. 442-474, 2011.

ISOLAURI ET AL.,“Oral Bacteriotherapy for Viral Gastroenteritis,” Digestive Diseases and Sciences, Vol. 39, No. 12, pp. 2595-2600, December 1994.

KHANNA ET AL.,“Efficacy of Tyndalized Lactobacillus acidophilus in Acute Diarrhea,” Indian Journal of Pediatrics,“Vol. 72, pp. 935-938, November 2005.

MAO ET AL.,“Effect of a lactose-free milk formula supplemented with bifidobacteria and streptococci on the recovery from acute diarrhoea,” Asia Pac J Clin Nutr, Vol. 17, No. 1, pp. 30-34, 2008.

MISTRY, Vikram. Manufacture and application of high milk protein powder. Le Lait, INRA

Editions, 2002, 82 (4), pp.515-522.

MITRA ET AL.,“Hyperimmune cow colostrum reduces diarrhoea due to rotavirus: a double-blind, controlled clinical trial, Acta Pcediatr, Vol. 84, pp. 996-1001, 1995. NARAYANAPPA,“Randomized Doubled Blinded Controlled Trial to Evaluate the Efficacy and Safety of Bifilac in patients with Acute Viral Diarrhea,” Indian Journal of Pediatrics, Vol. 75, pp. 709-713, July 2008.

PLAYFORD ET AL.,“Colostrum and milk-derived peptide growth factors for the treatment of gastrointestinal disorders,” The American Journal of Clinical Nutrition, Vol. 72, pp. 5-14, 2000.

RITCHIE ET AL.,“Efficacy of Lactobacillus GG in Aboriginal Children With Acute Diarrhoeal Disease: A Randomised Clinical Trial,” Journal of Pediatric

Gastroenterology and Nutrition, Vol. 50, No. 6, pp. 619-624, June 2010.

ROSENFELDT ET AL.“Effect of probiotic Lactobacillus strains in young children hospitalized with acute diarrhea,” The Pediatric Infectious Disease Journal, Vol. 21, No. 5, pp. 411-416, 2002. ROSENFELDT ET AL.“Effect of probiotic Lactobacillus strains on acute diarrhea in a cohort of nonhospitalized children attending day-care centers,” The Pediatric Infectious Disease Journal , Vol. 21, No. 5, pp. 417-419, 2002.

ROY ET AL.“Randomised controlled trial of zinc supplementation in malnourished Bangladeshi children with acute diarrhoea,” Archives of Disease in Childhood , Vol. 77, pp. 196-200, 1997.

SARKER ET AL.,“Successful treatment of rotavirus diarrhea in children with immunoglobulin from immunized bovine colostrum,” The Pediatric Infectious Disease Journal , Vol. 17, No. 12, pp. 1149-1154, 1998.

SARKER ET AL.,“ Lactobacillus paracasei Strain ST11 Has No Effect on Rotavirus but Ameliorates the Outcome of Nonrotavirus Diarrhea in Children From Bangladesh,” Pediatrics , Vol. 116, pp. e221-e228, July 1, 2005.

SARKER ET AL.,“Randomized, Placebo-Controlled, Clinical Trial of

Hyperimmunized Chicken Egg Yolk Immunoglobulin in Children With Rotavirus Diarrhea f Journal of Pediatric Gastroenterology and Nutrition, Vol. 32, pp. 1-25, January 2001.

SARKER ET AL.,“Anti-Rotavirus Protein Reduces stool Output in Infants With Diarrhea: A Randomized Placebo-Controlled Trial,” Gastroenterology , Vol. 145, pp. 740-748, 2013.

SHORNIKOVA ETA L.,“A trial in the Karelian Republic of oral rehydration and Lactobacillus GG for treatment of acute diarrhoea,” Acta Pcediatr , Vol. 86, pp. 460- 465, 1997.

STELWAGEN ET AL.,“Immune components of bovine colostrum milk, Journal of Animal Science , Vol. 87, pp. 3-9, 2009.

Claims

WE CLAIM:

1. A medical nutrition product composition comprising milk protein concentrate (MPC), non-fat dry milk, silicone, maltodextrin, and methylated silica; wherein the composition is effective to reduce the duration of acute diarrhea following administration of an effective amount to a non-neonate human patient suffering from an infection of the gastrointestinal tract due to undifferentiated pathogenic sources which may include one or more of E. coli, Salmonella spp., rotavirus, and/or a gram negative bacteria.

2. The composition of claim 1 further comprising hydrated silicon dioxide.

3. The composition of claim 1, wherein the composition comprises from about 20-99 wt%, milk protein concentrate, compared to the total weight of the composition.

4. The composition of claim 1, wherein the composition comprises from about 1-60 wt%, non-fat dry milk, compared to the total weight of the composition.

5. The composition of claim 1, wherein the composition comprises from about 0.1-6 wt% silicone, about 1-20 wt% maltodextrin, and/or about 0.01-1 wt% methylated silica, compared to the total weight of the composition.

6. The composition of claim 2, wherein the composition comprises from about 0.1- 20 wt% hydrated silicon dioxide, compared to the total weight of the composition.

7. A method for reducing the duration of acute diarrhea in a non-neonate human patient, the method comprising administering an effective amount of a medical nutrition product composition comprising milk protein concentrate, non-fat dry milk, and silicone.

8. The method of claim 7, wherein the composition further comprises maltodextrin, methylated silica, and hydrated silicon dioxide.

9. The method of claim 7, wherein the non-neonate human patient is suffering from an infection of the gastrointestinal tract due to undifferentiated pathogenic sources which may include one or more of E. coli, Salmonella spp., rotavirus, and/or a gram negative bacteria.

10. The method of claim 7, further comprising co-administering oral rehydration salts and/or zinc to the non-neonate human patient.

11. The method of claim 7, further comprising administering an active agent to the non-neonate human patient.

12. The method of claim 11, wherein the active agent is selected from one or more of antibiotics, antifungals, antimicrobials, antiparasitics, antiprotozoal drugs, antivirals, probiotics, bacteriocins, micronutrients, oral rehydration salts, antidiarrheal adsorbants, anticholinergics, antisecretory agents, antimotility drugs, additional non immunoglobulin colostrum components, antisecretory agents, or a composition comprising bovine colostrum and whole dry egg.

13. A composition for use in the manufacture of a product for reducing the duration of acute infectious diarrhea in a non-neonate human patient, wherein the composition comprises a milk protein concentrate, a non-fat dry milk, and a silicone.

14. The composition for use according to claim 13 further comprising hydrated silicon dioxide.

15. The composition for use according to claim 13 or 14, wherein the composition comprises from about 20-99 wt%, milk protein concentrate, compared to the total weight of the composition.

16. The composition for use according to any one of claims 13 to 15, wherein the composition comprises from about 1-60 wt%, non-fat dry milk, compared to the total weight of the composition.

17. The composition for use according to any one of claims 13 to 16, wherein the composition comprises from about 0.1-6 wt% silicone, about 1-20 wt% maltodextrin, and/or about 0.01-1 wt% methylated silica, compared to the total weight of the composition.

18. The composition for use according to any one of claims 14 to 17, wherein the composition comprises from about 0.1- 20 wt% hydrated silicon dioxide, compared to the total weight of the composition.

19. A medical nutrition product composition for use as a medicament, wherein the composition comprises milk protein concentrate (MPC), non-fat dry milk, silicone, maltodextrin, and methylated silica.

20. The medical nutrition product composition of claim 19, for use in the treatment of infectious diarrhea.