WO2020132296A1 - Composition de produit de nutrition médical pour diarrhées aiguës - Google Patents

Composition de produit de nutrition médical pour diarrhées aiguës Download PDF

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Publication number
WO2020132296A1
WO2020132296A1 PCT/US2019/067574 US2019067574W WO2020132296A1 WO 2020132296 A1 WO2020132296 A1 WO 2020132296A1 US 2019067574 W US2019067574 W US 2019067574W WO 2020132296 A1 WO2020132296 A1 WO 2020132296A1
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WIPO (PCT)
Prior art keywords
composition
diarrhea
milk
total weight
compared
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PCT/US2019/067574
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English (en)
Inventor
Robert Driver
George STAGNITTI
Julianne Lindemann
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Pantheryx, Inc.
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Publication of WO2020132296A1 publication Critical patent/WO2020132296A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/125—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives containing carbohydrate syrups; containing sugars; containing sugar alcohols; containing starch hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/16—Inorganic salts, minerals or trace elements
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/38—Albumins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals

Definitions

  • a medical nutrition product composition is provided for administration to a patient to reduce the duration of acute infectious diarrhea.
  • 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 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.
  • 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 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.
  • the composition further comprises hydrated silicon dioxide.
  • the medical nutrition product composition comprises from about 20-99 wt%, milk protein concentrate, compared to the total weight of the composition.
  • the medical nutrition product composition comprises from about 1-60 wt%, non-fat dry milk, compared to the total weight of the
  • 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.
  • the medical nutrition product composition comprises from about 0.1- 20 wt% hydrated silicon dioxide, compared to the total weight of the composition.
  • a method for reducing the duration of acute diarrhea in a non-neonate human patient comprising administering an effective amount of a medical nutrition product composition comprising milk protein concentrate, non-fat dry milk, and silicone.
  • the composition further comprises maltodextrin, methylated silica, and hydrated silicon dioxide.
  • a method 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.
  • MPC milk protein concentrate
  • silicone optionally maltodextrin and methylated silica
  • the medical nutrition composition is coadministered with oral rehydration salts and/or zinc to the non-neonate human patient.
  • the medical nutrition composition is coadministered with an active agent to the non-neonate human patient.
  • the medical nutrition composition is coadministered with an active agent selected from one or more of antibiotics, antifungals, and
  • antimicrobials 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.
  • FIG. 1 shows average duration of diarrhea episodes in children participating in 14 studies at International Center for Diarrhoeal Disease Research (icddr,b).
  • 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.
  • FIG. 2 shows average duration of diarrhea in patients following
  • composition-Pantheryx placebo surprisingly significantly reduced duration of diarrhea episodes compared to other standard of care/placebo values found in non-icddr,b studies.
  • percent refers to percent by weight of dry matter.
  • prevention refers 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.
  • preventing and suppressing need not be absolute to be useful.
  • treatment 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.
  • 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.
  • 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.
  • 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.
  • the patient is an adult human.
  • the patient is a non-neonate human infant.
  • the patient is a human toddler, child, or adolescent.
  • nonate or newborn, refers to an infant in the first 28 days after birth.
  • non-neonate refers to an animal older than 28 days.
  • an effective amount 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.
  • 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
  • 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.
  • 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.
  • 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)).
  • SCR standard casein ratio
  • 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.
  • 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.
  • the MPC is from 40-90% complete milk protein on a dry basis.
  • 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.
  • the MPC is manufactured from skim milk, partially separated milk, or whole milk.
  • the MPC is derived from whole milk.
  • 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).
  • Diarrhea is caused mainly by the ingestion of pathogens.
  • WHO World Health Organization
  • 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.
  • Standard treatment protocol in much of the world for pediatric diarrhea includes a concomitant administration of antibiotics and oral rehydrative therapy.
  • antibiotics are a prescription drug.
  • Antibiotics are not effective in the treatment of viral infection.
  • 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.
  • the infection may be caused by a resistant strain of bacteria.
  • use of an appropriate antibiotic may take several days to reduce the severity of the symptoms of diarrhea.
  • 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
  • Zinc syrup or zinc-fortified oral rehydration solution 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.
  • 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).
  • 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).
  • the pathogen is selected from one or a combination of human or veterinary, enteric or gastrointestinal, pathogens causing gastroenteritis.
  • 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
  • the pathogen related toxin includes an endotoxin or exotoxin.
  • the pathogen related adhesion element includes adhesins, cadherins, cilia, fimbrillae, a viral adhesion structure, or a combination thereof.
  • 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.
  • pathogens 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.
  • adhesion to gastrointestinal tract tissue can be prevented or minimized, ultimately resulting in substantially decreased pathology from pathogens that utilize this mode of action.
  • dairy -based compositions are provided for use in combating the symptoms of acute diarrhea in a non-neonate human patient.
  • the compositions comprise non-fat dry milk and milk protein
  • antimicrobial activity of milk is mainly attributed to immunoglobulins, and non-immune proteins, such as lactoferrin, lactoperoxidase and lysozyme.
  • lactoferricin a fragment of lactoferrin
  • other whey proteins such as a - lactalbumin and b - lactoglobulin have also been considered as potential precursors of bactericidal fragments.
  • antibacterial fragments have also been derived from asi-, OLS2 -, b - and k - casein. Fadaei, Ann. Biol. Res., 2012, 3(5):2520-2526.
  • 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.
  • Bangladesh was selected because is known as being one of the most challenging environments in which to combat diarrhea.
  • 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.
  • Test Article performed as expected. Test Article is disclosed in
  • 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.
  • 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.
  • the placebo reduced average duration of diarrhea to 32 hours.
  • the placebo is disclosed herein as a medical nutrition product for acute infectious diarrhea.
  • 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.
  • a medical nutrition product composition comprising Milk Protein Concentrate (MPC) and non-fat dry milk.
  • MPC Milk Protein Concentrate
  • 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.
  • the composition comprises an MPC that is from about 40-95 wt% milk protein.
  • the MPC contains one or more of whey protein concentrate, whey protein isolate, milk protein hydrosylate, or fractions thereof.
  • MPC comprises any complete milk protein (casein plus lactalbumin) concentrate that is 40 percent or more protein by weight.
  • the MPC classification includes concentrates made through other processes, such as blending nonfat dry milk with highly concentrated proteins, such as casein.
  • 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).
  • the MPC is selected from MPC 70 (69.5% min. protein), MPC 80 (79.5% min. protein), or MPC 85 (85% min. protein).
  • the MPC comprises 0.1-5 % fat, 0.5-3% fat or 1- 2% fat content.
  • the MPC may be obtained from a commercial vendor or may be produced by any method known in the art.
  • 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.
  • the MPC is produced by the method of US Published Application US 20060040025, Souppe, which is incorporated herein by reference.
  • 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.
  • skim milk may comprise about 52 % lactose.
  • 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.
  • the medical nutrition product comprises an MPC product processed with low heat which will maintain higher nutritional value.
  • the Milk Protein Concentrate can also contain various immunoglobulins.
  • the most prevalent immunoglobulin in bovine milk or colostrum is IgGl.
  • 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.
  • 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.
  • 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.
  • MPC is employed in the formulation in a dry powder form.
  • 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.
  • 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.
  • MPC Milk Protein Concentrate
  • 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.
  • the medical nutrition product comprises Milk Protein Concentrate (MPC) and non-fat dry milk and further comprises one or more
  • diluents such as carriers, binders, excipients, lubricants, sweetening agents, flavoring agents, wetting agents, or absorbents.
  • 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.
  • the medical nutrition product comprises Milk Protein Concentrate (MPC) and non-fat dry milk and further comprises one or more
  • the antifoam agent includes a powdered food grade antifoam agent.
  • the food grade antifoam agent comprises silicone, maltodextrin, and methylated silica (e.g., Dow Corning XIAMETER® ACP-1920 powdered antifoam).
  • 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.
  • 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.
  • the food grade antifoam agent comprises about 5-30 wt% silicone, 70-90 wt% maltodextrin, and 1-5 wt% methylated silica.
  • the composition comprises from about 0.1-6 wt% silicone, about 1-20 wt% maltodextrin, and/or about 0.01-1 wt% methylated silica.
  • 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).
  • MPC Milk Protein Concentrate
  • 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.
  • 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
  • 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.
  • the medical nutrition product comprises a flavoring selected from spearmint oil, cinnamon oil, oil of wintergreen
  • 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.
  • 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.
  • the flavoring is vanilla used in an amount of about 0.6 wt%.
  • the composition comprises a coloring such as FD&C powdered food coloring employed to enhance the appearance of the composition.
  • the coloring is present in from about 0.001-1 wt%, 0.01-0.5 wt%, or 0.02-0. lwt% of the composition.
  • 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.
  • saccharin as used herein includes saccharin itself, saccharin acids, and saccharin salts such as sodium saccharin.
  • 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.
  • the medical nutrition product composition comprises
  • 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.
  • the medical nutrition product is packaged in a solid form.
  • solid form refers to a dried form of the composition as a powder, compressed tablet, troche, or capsule.
  • the solid dosage form is intended for oral administration.
  • the powder is a formulation for suspension.
  • 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.
  • 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.
  • an inert solid diluent e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate or kaolin
  • 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.
  • composition may also be provided in a liquid form for administration.
  • 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,
  • one dose of the dried dosage form is provided as a loose powder in a sealed packet.
  • the contents of a single dose packet are dissolved in water and administered orally.
  • the contents of a 7 g single dose packet are dissolved in 1-2 ounces of water and administered orally.
  • compositions of the disclosure are used to treat patients suffering from various pathogenic enteric infections.
  • the composition is administered orally, by ingestion.
  • 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.
  • a liquid such as water, milk, juice, or electrolyte solution
  • 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.
  • the composition is administered once per day for 3 consecutive days.
  • 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.
  • 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.
  • the composition is administered twice per day for five days for the treatment of a pathogenic enteric infection.
  • 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.
  • the composition may be regularly administered for the prophylaxis of a pathogenic enteric infection.
  • the disclosure provides a composition effective for treating undifferentiated diarrhea in non-neonate humans.
  • 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.
  • the disclosure provides an economical composition for the effective treatment of undifferentiated pediatric diarrhea.
  • 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.
  • 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.
  • the composition of the disclosure is administered as an adjunct therapy to treatment with an active agent.
  • 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.
  • the active agent is an antibiotic selected from the group consisting of Prulifloxacin, Ulifloxacin, Fidaxomicin, Minocyclin,
  • Metronidazole 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the active agent is an anticholinergic selected from the group consisting of a belladonna alkaloid, atropine and hyoscyamine, or a combination thereof.
  • 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.
  • the active agent is an antimotility drug selected from the group consisting of loperamide and diphenoxylate, or a combination thereof.
  • the active agent is a composition comprising bovine colostrum and whole dry egg (DIARESQ®, Pantheryx).
  • the medical nutrition composition may be administered once per day for the first three days of treatment.
  • the composition of the disclosure is administered with oral rehydration solution (ORS).
  • the composition of the disclosure is co-administered with an oral zinc formulation.
  • 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.
  • 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.
  • compositions of the disclosure are used to treat traveler's diarrhea (TD).
  • TD traveler's diarrhea
  • 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.
  • 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.
  • 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.
  • TEC and other bacterial pathogens a variety of viral and parasitic enteric pathogens also are potential causative agents.
  • 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.
  • 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.
  • 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.
  • the medical nutrition product composition-placebo formulation was prepared from the materials as shown in Table 1.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne une composition de produit de nutrition médicale destinée à être administrée à un patient afin de réduire la durée de la diarrhée aiguë.
PCT/US2019/067574 2018-12-20 2019-12-19 Composition de produit de nutrition médical pour diarrhées aiguës WO2020132296A1 (fr)

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CN115869306A (zh) * 2022-12-23 2023-03-31 华中科技大学协和深圳医院 Iowh-032用于制备抗革兰氏阳性细菌感染药物中的应用

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US20030203042A1 (en) * 2002-04-24 2003-10-30 Cook Lisa Ann Compositions comprising milk protein concentrate and fatty acid and processes of their preparation
US20120141458A1 (en) * 2010-11-23 2012-06-07 Pantheryx, Inc. Compositions and methods for treatment in broad-spectrum, undifferentiated or mixed clinical applications
US20140037603A1 (en) * 2011-04-12 2014-02-06 Doug Bolster Nutritional compositions including branched chain fatty acids for improving gut barrier function
WO2017021795A1 (fr) * 2015-08-01 2017-02-09 Upl Limited Composition herbicide et procédé correspondant
US20170143022A1 (en) * 2015-11-20 2017-05-25 Senomyx, Inc. Compositions Incorporating an Umami Flavor Agent

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030203042A1 (en) * 2002-04-24 2003-10-30 Cook Lisa Ann Compositions comprising milk protein concentrate and fatty acid and processes of their preparation
US20120141458A1 (en) * 2010-11-23 2012-06-07 Pantheryx, Inc. Compositions and methods for treatment in broad-spectrum, undifferentiated or mixed clinical applications
US20140037603A1 (en) * 2011-04-12 2014-02-06 Doug Bolster Nutritional compositions including branched chain fatty acids for improving gut barrier function
WO2017021795A1 (fr) * 2015-08-01 2017-02-09 Upl Limited Composition herbicide et procédé correspondant
US20170143022A1 (en) * 2015-11-20 2017-05-25 Senomyx, Inc. Compositions Incorporating an Umami Flavor Agent

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115869306A (zh) * 2022-12-23 2023-03-31 华中科技大学协和深圳医院 Iowh-032用于制备抗革兰氏阳性细菌感染药物中的应用
CN115869306B (zh) * 2022-12-23 2024-03-19 华中科技大学协和深圳医院 Iowh-032用于制备抗革兰氏阳性细菌感染药物中的应用

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