WO2017106074A1 - Méthodes de traitement de la diarrhée chez des animaux non humains avant le sevrage, nouveau-nés et jeunes - Google Patents

Méthodes de traitement de la diarrhée chez des animaux non humains avant le sevrage, nouveau-nés et jeunes Download PDF

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WO2017106074A1
WO2017106074A1 PCT/US2016/066083 US2016066083W WO2017106074A1 WO 2017106074 A1 WO2017106074 A1 WO 2017106074A1 US 2016066083 W US2016066083 W US 2016066083W WO 2017106074 A1 WO2017106074 A1 WO 2017106074A1
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enteric
proanthocyanidin polymer
composition
animals
diarrhea
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PCT/US2016/066083
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English (en)
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Siobhan MCAULIFFE
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Jaguar Animal Health
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/47—Euphorbiaceae (Spurge family), e.g. Ricinus (castorbean)
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K10/00—Animal feeding-stuffs
    • A23K10/30—Animal feeding-stuffs from material of plant origin, e.g. roots, seeds or hay; from material of fungal origin, e.g. mushrooms
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/10—Feeding-stuffs specially adapted for particular animals for ruminants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/20—Feeding-stuffs specially adapted for particular animals for horses
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/30—Feeding-stuffs specially adapted for particular animals for swines
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/60—Feeding-stuffs specially adapted for particular animals for weanlings
    • 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
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals

Definitions

  • the invention relates to the treatment of diarrhea in pre-weaned, neonatal and young non-human animals with a composition comprising a proanthocyandin polymer isolated from the plant Croton spp. or Calophyllum spp., or with a latex, extract, or food supplement derived therefrom, which is not formulated to protect it from the stomach environment, i.e., is not enterically coated.
  • a non-enterically coated product is effective in treating secretory diarrhea of various etiologies and reducing the severity and duration of diarrhea in neonatal and young non-human animals.
  • the proanthocyanidin polymer compositions can be administered to neonatal non-human animals to treat watery diarrhea and accompanying dehydration symptoms and to improve weight gain and survivability.
  • Infectious diseases are among the most widespread problems of neonatal and young animals, such as calves of different animal species, as well as equine foals.
  • Diarrhea called “scours” in calves, frequently occurs within the first several days of life and is an important cause of calf sickness and death in the United States.
  • Dehydration from diarrhea in neonatal and young farm or larger-sized animals results in measurable morbidity and mortality in many millions of animals worldwide.
  • a wide array of infectious and pathogenic agents including bacteria, viruses, and parasites cause diarrhea in animals, particularly, domesticated livestock animals associated with farming, food, and labor. Many of these enteropathogens cause one or more adverse effects in the animals, such as severe intestinal lesions, dehydration, alterations in enzyme activity, and/or alterations in nutrient transport mechanisms.
  • the clinical presentation of diarrhea caused by these agents may vary; some diarrheas are self-limiting, while others are associated with high morbidity or high mortality (R E. Holland, 1990, Clin. Microbiol. Rev., 3(4):345-375).
  • Infectious diarrhea of pre-weaned animals is an extremely common and economically devastating condition confronted by the animal agriculture and animal husbandry industries.
  • acute infectious diarrhea is often difficult to manage, contain and cure, because of the large numbers of potential enteropathogens involved; the differences in natural immunity among animals within the herd or population; environmental conditions and stresses; nutritional factors; the dynamics of the animal population; management conditions; and a difficulty in determining an etiological diagnosis.
  • a diagnosis is frequently not established for a large percentage of cases of neonatal animal diarrheas.
  • pre-weaned neonatal and young animals such as calves and foals
  • the resistance of the neonatal or young animal to infectious diseases for example, is lowered, and exposure to and invasion by infectious agents play pivotal roles in producing diarrhea.
  • E. coli e.g., E. coli K-99
  • rotavirus and coronavirus rotavirus and coronavirus
  • Cryptosporidia Salmonella spp.
  • Campylobacter jejuni a human pathogen
  • human handlers of the animals and those who treat the animals may also be at risk of infection and disease.
  • Diarrhea in neonatal and young animals can also be due to noninfectious causes, such as changes to a feeding program, energy deficiencies and vitamin shortages related to pregnant adult females that can extend to the newborn offspring, causing weakness and susceptibility to infection.
  • Environmental and sanitation conditions associated with the birth of newborn animals can also be associated with outbreaks of disease and resulting diarrhea.
  • an unclean environment e.g., an accumulation of urine and manure in an area where animals are born and nursed, can lead to disease syndromes that are characterized by diarrhea.
  • problems related to giving birth by adult females such as difficult calving and insufficient colostrum, can lead to weak newborns and a lack of passive immunity provided by the colostrum.
  • Noninfectious diarrhea while oftentimes not severe enough to cause death, can weaken the young animal and make it more susceptible to infectious diarrhea, which contributes to a neonatal and young animal's inability to survive.
  • Diarrhea in young equines is very common and there are many causative agents and conditions (e.g., viral, bacterial, protozoa, parasites, drug or dietary associated, toxins and changes in the intestinal flora) that manifest with clinical signs of watery diarrhea in the foals.
  • cAMP cyclic adenosine monophosphate
  • cGMP cyclic guanosine monophosphate
  • the available and commonly used treatments for diarrhea in neonatal and young non-human animals typically involve vital fluid replacement and electrolyte replenishment to counter or stop fluid and electrolyte loss.
  • Other types of treatments include the administration of gut-lining protectants, e.g., bismuth, oral antibiotics, and agents that affect gut motility.
  • gut-lining protectants e.g., bismuth, oral antibiotics, and agents that affect gut motility.
  • the various known treatments may or may not be effective, and the animals may or may not respond adequately.
  • the economic and humane impacts of diarrhea and its related conditions on the afflicted animals, their handlers and caregivers are so great, there is a compelling need for alternative, safe, and medically effective, as well as cost effective, treatments and remedies for veterinary use.
  • the present invention addresses such a need.
  • the present invention relates to methods of treating diarrhea in neonatal, young, or non-adult animals, particularly pre-weaned non-human animals, in need thereof by administering a polymeric proanthocyanidin, i.e., a proanthocyanidin polymer, from a Croton species or Calophyllum species, in the absence of an enteric coating, or that has not been formulated to protect the proanthocyanidin polymer from the stomach environment.
  • a pharmaceutically or physiologically acceptable non-enteric formulation or composition comprising a proanthocyanidin polymer from a Croton species or Calophyllum species is administered.
  • a proanthocyanidin polymer from Croton lechleri or pharmaceutically acceptable non-enteric formulation or composition comprising a proanthocyanidin polymer from Croton lechleri is administered.
  • a non-enteric composition comprising the proanthocyanidin polymer, e.g., a Croton lechleri latex or botanical extract product, efficiently and effectively resolved diarrhea and dehydration in pre-weaned animals (foals) requiring treatment, as further described herein.
  • the treatment effect was rapid in the animals, e.g., within 24-48 hours and beyond, and resolution of diarrhea was attained in a high percentage of treated animals.
  • non- enteric means “not enterically coated” or “non-enterically formulated,” such that the proanthocyanidin polymer is not formulated in a way to protect it from the stomach environment, and may include formulations that are direct release as opposed to sustained or delayed release formulations.
  • the non-enteric composition comprising the proanthocyanidin polymer is a latex or extract from a Croton species or Calophyllum species, in particular, Croton lechleri.
  • the non-enteric composition is a botanical extract of Croton lechleri containing a proanthocyanidin oligomer, or a non-enteric food supplement formulation of the botanical extract of Croton lechleri.
  • Croton species or Calophyllum species latex or extract compositions can be more highly purified as described herein.
  • the methods involve the administration of a pharmaceutically acceptable, non-enteric composition comprising a proanthocyanidin polymer from Croton lechleri to a non-human animal in need thereof.
  • the methods involve the administration of a proanthocyanidin polymer from Croton lechleri, or a pharmaceutically acceptable, non-enteric composition comprising a proanthocyanidin polymer from Croton lechleri, wherein the proanthocyanidin polymer or oligomer from C lechleri is also known as crofelemer (a purified proanthocyanidin oligomer), SP 303, or SB 300, as further described herein.
  • the C lechleri proanthocyanidin polymer or crofelemer product is administered to a pre-weaned, neonatal or young animal in need thereof without an enteric coating that typically protects the active product from the acidic stomach environment of the non-human animal.
  • the animal receiving treatment is a pre-weaned animal, such as an equine foal.
  • the C lechleri proanthocyanidin polymer, botanical extract, or compositions thereof are preferably in a non- enteric coated form.
  • the invention provides a method of treating and preventing the debilitating effects of diarrhea and its symptoms in neonatal and young non-human animals.
  • the methods treat and prevent dehydration associated with water, fluid and electrolyte losses in animals afflicted with diarrhea.
  • the methods of the invention further prevent or reduce the incidence of intestinal lesions, weakness and death in pre-weaned, neonatal and young non- human animals.
  • the methods treat and prevent diarrhea associated with colitis, including acute colitis, in afflicted animals.
  • the methods of the invention provide antisecretory treatments for diarrhea, particularly, secretory or watery diarrhea, in neonatal and young non-human animals.
  • the animals may also be treated concurrently (or before or after treatment with the proanthocyanidin polymer composition) with an anti-acid product, particularly a proton pump inhibitor, such as omeprazole, e.g., Prilosec, Losec, lansoprazole (Prevacid) and the like.
  • an anti-acid product particularly a proton pump inhibitor, such as omeprazole, e.g., Prilosec, Losec, lansoprazole (Prevacid) and the like.
  • the animal is also administered a probiotic.
  • the invention is more particularly directed to a method of improving gut health and treating and controlling diarrhea in neonatal non-human animals, such as pre-weaned bovine or camel calves and equine foals in need thereof, by administering a non-enteric proanthocyanidin polymer from Croton lechleri in an effective amount to treat or control the diarrhea in these animals.
  • a non-enteric proanthocyanidin polymer from Croton lechleri in an effective amount to treat or control the diarrhea in these animals.
  • the proanthocyanidin polymer is a non-enteric formulation, composition, or extract from Croton lechleri.
  • the proanthocyanidin polymer from Croton lechleri is a more highly purified, non-enteric composition containing proanthocyanidin polymer or oligomer, or latex, or botanical extract, such as crofelemer or SB 300 compositions described herein.
  • the invention is also more particularly directed to a method of improving gut health, controlling diarrhea and normalizing stool formation in pre-weaned neonatal or young horses (foals) in need thereof by administering a proanthocyanidin polymer from Croton lechleri, without an enteric coating, in an effective amount to control or treat the diarrhea in these animals.
  • the proanthocyanidin polymer is a non-enteric formulation, composition, or botanical extract from Croton lechleri.
  • the non-enteric formulation, composition, or botanical extract from Croton lechleri is in the form of a paste or gel.
  • the paste formulation comprises non-enterically coated SB 300 or SP 303 and is orally administered to foals in need.
  • the orally administered paste formulation comprises non-enterically coated SB 300.
  • the paste comprising non-enteric coated SB 300 is orally administered to a foal twice daily for three days (i.e., six treatments). In some embodiments, the paste is orally administered for three consecutive days.
  • the paste comprising a non-enteric proanthocyanidin polymer composition, formulation, or botanical extract from Croton lechleri, such as the SB 300 product is orally administered to a foal in need at a dose of 4 mg/kg to 10 mg/kg twice daily for three days.
  • the paste comprising a non-enteric coated SB 300 product is orally administered to a foal in need at a dose of 4 mg/kg to 8 mg/kg twice daily for three days.
  • the, non-enteric formulation, composition, or botanical extract from Croton lechleri is formulated as beads (nano or microparticles), which can be provided in a paste.
  • the paste comprising a non-enteric coated proanthocyanidin polymer composition, formulation, or botanical extract from Croton lechleri, such as the SB 300 product is orally administered to a pre-weaned foal twice daily for three days.
  • the paste comprising a non-enteric coated SB-300 product is orally administered to a pre-weaned foal three times daily for three days.
  • the paste comprising a non-enteric SB-300 product is orally administered to a pre- weaned foal four times daily for three days.
  • the paste is orally administered to the animal two or more times daily for two or more consecutive days.
  • the paste is orally administered for three or more consecutive days.
  • the paste comprising a non-enteric SB-300 product is orally administered to a pre- weaned foal in need at a dose of 2-15 mg/kg twice daily, or three times daily, or four times daily, or more frequently per day, for three days.
  • the paste comprising a non-enteric SB-300 product is orally administered to a pre-weaned foal in need thereof, at a dose of 4-10 mg/kg twice daily, or three times daily, or four times daily, preferably for three days.
  • the paste comprising a non-enteric SB-300 product is orally administered to a pre-weaned foal in need thereof, at a dose of 4-8 mg/kg twice daily, or three times daily, or four times daily, for two to six days, preferably for three days.
  • the paste comprising a non-enteric SB-300 product is orally administered to a pre-weaned foal in need thereof, at a dose of 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 11 mg/kg, 12 mg/kg, 13 mg/kg, 14 mg/kg, 15 mg/kg, 16 mg/kg, 17 mg/kg, 18 mg/kg, 19 mg/kg, or 20 mg/kg twice daily for three days, or three times daily for three days, or four times daily for three days.
  • the non-enteric proanthocyanidin polymer composition, formulation, or botanical extract from Croton lechleri, such as the SB 300 product is orally administered to a pre-weaned animal, e.g., a foal, with diarrhea in a range of 8 mg/kg to 24 mg/kg per dose.
  • the non-enteric proanthocyanidin polymer composition, formulation, or botanical extract from Croton lechleri, such as the SB 300 product is orally administered to a pre-weaned animal having diarrhea in a daily dose of 17 mg/kg to 48 mg/kg twice a day (BID).
  • non-enteric SB 300 is administered to a pre-weaned young animal such as a foal in an amount of 1600 mg per animal (foal) per dose.
  • non-enteric coated SB 300 is administered to pre-weaned young animals, such as a foal, in an amount of 500 mg, 800 mg, 1000 mg, 1200 mg, 1400 mg, 1500 mg, 1800 mg or 2000 mg per animal per dose.
  • the invention provides a method of treating a neonatal or young non- human animal having diarrhea associated with enteropathogenic infection, the method comprising orally administering to an animal in need thereof a pharmaceutically acceptable, non- enteric composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri, wherein the composition is formulated as a bolus or as a reconstituted powder and administered to the animal in an amount of at least 40 mg to 2000 mg, preferably 800 mg to 1600 mg, for consecutive days greater than one day, thereby treating the diarrhea in the neonatal or young animal.
  • a pharmaceutically acceptable, non- enteric composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri, wherein the composition is formulated as a bolus or as a reconstituted powder and administered to the animal in an amount of at least 40 mg to 2000 mg, preferably 800 mg to 1600 mg, for consecutive days greater than one day, thereby treating the diarrhea in the neonatal or young animal
  • the neonatal or young animal is selected from a bovine calf, a camel calf, a buffalo calf, a bison calf, a lamb, a kid, a foal, or a piglet.
  • the animals are at a pre-weaned stage.
  • the neonatal or young animal is a bovine calf or a camel calf.
  • the neonatal or young animal is an equine foal.
  • the non-enteric proanthocyanidin polymer composition is administered twice daily for three consecutive days.
  • the non-enteric proanthocyanidin polymer composition is administered three times daily or, in other embodiments, for 4 times daily, for three consecutive days.
  • the diarrhea is secretory or watery diarrhea associated with enteropathogen infection of the animal with one or more of E. coli, rotavirus, or coronavirus.
  • the diarrhea is episodic.
  • the animal is additionally infected with Salmonella spp. and/or Cryptosporidia.
  • lechleri is administered as a powder reconstituted with oral electrolytes, milk or a milk substitute, physiological saline, or water; or as a bolus; or as a paste or gel, or in animal feed.
  • the treated animals such as calves or foals, can be less than two weeks of age, or two to four weeks of age, or four to eight weeks of age.
  • the non-enteric composition or botanical extract e.g., non-enteric SB 300, is orally administered to a pre-weaned or young animal in an amount of 500 mg to 2000 mg per dose, or in an amount of 500 mg to 1800 mg per dose, or in an amount of 800 mg to 1600 mg per dose.
  • non-enteric SB 300 is orally administered to an animal in need in an amount of 8 mg/kg to 24 mg/kg, or 1600 mg per dose. In a specific embodiment, non-enteric SB 300 is orally administered to an animal in need in an amount of 17 mg/kg to 48 mg/kg twice daily.
  • the neonatal or young animal is approximately 30 to 50 kg in weight; is a lamb, a kid of approximately 2 to 8 kg in weight, a bovine calf of approximately 30 to 40 kg in weight, or a camel calf of approximately 40 to 50 kg in weight.
  • the lechleri is administered in a paste formulation at a dose of 4 to 10 mg/kg, or 4 to 8 mg/kg, or a daily dose of 17 to 48 mg/kg where the approximate body weight of a foal may range from about 35 kg to about 200 kg or about 70 kg to about 200 kg (birth to 16 weeks).
  • the proanthocyanidin polymer is administered as a non-enteric coated pharmaceutical composition.
  • the proanthocyanidin polymer can be SB 300, SP 303, crofelemer, botanical extract and pharmaceutically acceptable compositions thereof.
  • the invention provides a method of treating a neonatal, pre-weaned or unweaned equine animal for diarrhea associated with enteropathogenic infection, the method comprising orally administering to the animal a pharmaceutically acceptable, non- enteric composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri, wherein the composition is provided in a form selected from a bolus, a reconstituted powder, or a gel, paste, or gel-paste, and is administered to the animal in an amount of at least 100 mg for consecutive days greater than one day, thereby treating the diarrhea in the neonatal or unweaned equine animal.
  • a pharmaceutically acceptable, non- enteric composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri, wherein the composition is provided in a form selected from a bolus, a reconstituted powder, or a gel, paste, or gel-paste, and is administered to the animal
  • the animal is infected with bacteria, viruses and protozoa, in which the infection induced the diarrhea.
  • the non-enteric proanthocyanidin polymer composition is administered to the animal in an amount of at least 250 mg and optionally can be in the form of a gel or paste contained in a delivery device, which can be a syringe.
  • the gel or paste comprises polymeric microparticles or nanoparticles containing the non-enteric composition, and the polymeric microparticles or nanoparticles are optionally pH-sensitive.
  • the animal is less than two weeks of age and/or is approximately 30 to 50 kg in weight.
  • the animals are three months or less in age (birth to 16 weeks) and/or are about 35 to about 200 kg in weight.
  • the proanthocyanidin polymer is administered as a non-enteric coated pharmaceutical composition.
  • the proanthocyanidin polymer can be crofelemer, latex or botanical extract forms, e.g., SB 300 or SP 303, and non-enteric, pharmaceutically acceptable compositions thereof.
  • the methods of the present invention provide prophylactic or preventative treatment of neonatal and young animals against the debilitating effects of diarrheal disease and its associated symptoms, e.g., dehydration and weight loss.
  • a non-enteric C. lechleri proanthocyanidin polymer composition can be administered to neonatal and young animals at a suitable time after birth to protect the animals from diarrhea outbreaks typically caused by infections and environmental conditions.
  • Administering a non- enteric C. lechleri proanthocyanidin polymer composition to pre-weaned neonatal and young animals may also serve to ameliorate or reduce the risk of the animals' suffering from a more serious or severe form of disease relative to animals that are not provided with the C.
  • administration of the non- enteric C. lechleri proanthocyanidin polymer composition to neonatal animals within 1, 2, 3 or 4 days after birth for a period of 1, 2, 3, 4 or more days may increase weight gain and/or improve survivability in a population of animals, including in bovines, camels, buffalo, bisons, lambs, goats, horses and pigs.
  • the non-enteric C. lechleri proanthocyanidin polymer composition can be non-enterically coated or formulated SB 300 or SP 303. The dose and regimen for administering such C.
  • lechleri proanthocyanidin polymer compositions are within the skill of the practitioner and will depend on the environmental conditions of the animals to be treated. In nonlimiting embodiments, it is envisioned that the animals can be prophylactically treated just after birth, e.g., days one to four, for from one to five days, or fewer, as necessary or desired.
  • a non- enterically coated Croton lechleri proanthocyanidin polymer composition such as a C. lechleri botanical extract product without an enteric coating according to the invention provides one or more beneficial effects, for example, lower dehydration and higher fecal dry matter content, in treated animals.
  • Such beneficial effects may also endure beyond the time period of actual administration of the non-enteric product to the animals, for example, after cessation of the administration of the product to the animal.
  • the present invention also embraces the notion that the administration of a non-enteric C. lechleri proanthocyanidin polymer composition or C. lechleri botanical extract product, particularly an early administration to the young animal, followed by a period in which the product is not administered to the animal, may induce beneficial changes in the intestine of treated animals that is maintained beyond the actual course of the therapy. Accordingly, the methods of the invention encompass periodic administration of the non-enteric C. lechleri proanthocyanidin polymer or C.
  • lechleri botanical extract product to an animal, such that an initial treatment may be given, followed by a time period, e.g., a lag of several days or even weeks, such as 1, 2, 3, 4, or more weeks, before another treatment, if any, is administered to the animal.
  • a time period e.g., a lag of several days or even weeks, such as 1, 2, 3, 4, or more weeks, before another treatment, if any, is administered to the animal.
  • the disclosed methods and C. lechleri-derived proanthocyanidin polymer and botanical extract products, without an enteric coat or formulation, used in the methods provide several advantages in the treatment of diarrhea in neonatal, pre-weaned non-human animals, e.g., bovine calves and equine foals. Such advantages include more rapid and effective treatment effects, reduced medication, labor and veterinary costs, which result in earlier weaning of animals and heavier weaning weights.
  • the treatment of pre-weaned animals in accordance with the methods and products of the invention may also reduce the quantity of electrolytes used in standard of care to treat diarrhea-related dehydration and other symptoms, which is also of economic and commercial benefit.
  • FIG. 1 shows the results of a responder analysis and presents the percentages of animals that responded to treatment with a non-enteric paste formulation comprising the SB 300 product relative to placebo.
  • Responders are defined as animals (foals) that achieved a formed stool (i.e., a fecal score of 1 or 2) in the overall study scheme at the time of analysis.
  • FIG. 2 shows the results of a resolution of diarrhea analysis reflecting the percentages of animals (foals) whose diarrhea had resolved following treatment with a non- enteric paste formulation comprising the SB 300 product relative to placebo.
  • Resolution of diarrhea was defined as an animal (foal) that produced a formed stool (i.e., a fecal score of 1 or 2) at any point during the reported period at the time of analysis.
  • FIG. 3 shows fecal score responder analysis and non-inferiority of the non-enteric
  • SB 300 product following treatment of animals (foals) with a non-enteric paste formulation comprising the SB 300 product compared with treatment of animals (foals) with an enteric paste formulation comprising the SB 300 product.
  • Responders are as for FIG. 1.
  • FIG. 4 shows the results of a resolution of diarrhea analysis reflecting the percentages of animals (foals) whose diarrhea had resolved following treatment with a non- enteric paste formulation comprising the SB 300 product compared with treatment of animals (foals) with an enteric paste formulation comprising the SB 300 product. Resolution of diarrhea is as for FIG. 2.
  • the invention provides treatment methods effective for reducing and/or alleviating diarrhea in neonatal non-human animals, particularly unweaned or pre-weaned animals, in need thereof.
  • the methods are directed to the treatment of diarrhea, particularly secretory/watery diarrhea, or episodic diarrhea, caused by a variety of etiological agents and/or environmental factors in neonatal and young (juvenile, non-adult) animals, particularly where scourges of diarrhea in such immature animals can have a profound economic impact for animal husbandry, including the animal agriculture, food, recreation and health industries.
  • the invention further provides formulations and compositions suitable for treating diarrhea in neonatal and young animals.
  • animal herein denotes non-human, warm-blooded mammals of a number of different species.
  • the terms "young”, non-adult”, “immature” and “juvenile” are used synonymously herein and generally refer to animals under one year of age.
  • the animals are pre-weaned or have the bulk of their diet as milk or a milk substance.
  • the methods of the invention provide a solution to a significant need for the animal industry, e.g., the beef and dairy industries worldwide, in which neonatal calf diarrhea presents one of the largest health challenges, as well as economic losses.
  • the methods of the invention provide a solution to the common problem of watery or secretory diarrhea, including episodic diarrhea, that frequently afflicts horse farms, particularly, horse foals.
  • the methods and treatments of the invention improve gastrointestinal/gut health and normalize stool formation in young animals suffering from diarrheal conditions, including, by way of example, watery diarrhea in horse foals and bovine calves, as well as other pre-weaned, non-human animals.
  • the methods and treatments of the invention are particularly suitable for treating animals of a young age.
  • the animals are neonatal (or newborn), unweaned or pre-weaned, non-adult animals that are born, bred, raised and/or maintained in a domesticated and/or agricultural setting, e.g., as livestock and farm animals, for commodities such as food, labor, sport, or other commercial or non-commercial agricultural husbandry capacity.
  • Nonlimiting examples of animals affected by diarrhea and treatable by the methods and formulations of the invention include, without limitation, neonatal and young cattle (calves), young bison or buffalo, pigs (piglets), sheep (lambs), goats (kids), horses (foals) and camels (calves), as further described herein.
  • the neonatal or young animals are domestic, companion animals, such as, without limitation, dogs and cats of any species.
  • "young" animals are generally under one year of age.
  • “Neonatal” animals are generally two to three weeks of age, or less.
  • the present invention relates to treating diarrhea in neonatal, unweaned or pre- weaned and young animals with physiologically and pharmaceutically acceptable, non-enteric formulations and compositions comprising a therapeutically effective amount of an antidiarrheal agent comprising a proanthocyanidin polymer obtained from a Croton spp., preferably Croton lechleri.
  • the animals are on a diet that is solely or predominantly milk or milk replacer.
  • the proanthocyanidin polymer composition can also be obtained from a Calophyllum spp., in particular Calophyllum inophylum.
  • the pharmaceutically acceptable, non-enteric composition comprises a proanthocyanidin polymer from Croton lechleri.
  • the pharmaceutically acceptable, non-enteric composition comprises a botanical extract derived from Croton lechleri.
  • treating can refer to ameliorating, preventing, inhibiting, reversing, attenuating, alleviating, abrogating, minimizing, suppressing, reducing, decreasing, diminishing, stabilizing, eradicating, curing, or eliminating the deleterious effects of a disease or condition, or the progression or worsening of the disease or condition.
  • successful treatment may involve alleviating one or more symptoms of a disease or condition, although not necessarily all of the symptoms, of the disease or condition, or attenuating the symptoms or progression of the disease or condition. Curing or eliminating the disease or condition from the animal is an optimal outcome of the practice of the methods of the invention.
  • treatment of an animal in need thereof typically involves the use or administration of an effective amount or a therapeutically effective amount of a proanthocyanidin polymer or a proanthocyanidin polymer composition preferably from a Croton spp., particularly C. lechleri, provided in a non-enteric form or as a non-enteric product.
  • Effective amount refers to the quantity (amount) of the composition, and the like, that induces a desired response in the animal subject upon administration or delivery to the animal.
  • an effective amount produces a therapeutic effect in the absence of, or with little or virtually no, adverse effects or cytotoxicity in the animal.
  • any adverse effects associated with an effective amount are optimally outweighed by the therapeutic benefit achieved.
  • the treatment methods are directed to ameliorating, preventing, inhibiting, reversing, attenuating, alleviating, abrogating, minimizing, suppressing, reducing, decreasing, diminishing, stabilizing, eradicating, curing, or eliminating diarrhea and/or its associated symptoms caused by a variety of different agents or environmental factors and influences that adversely affect the health, growth and survivability of neonatal and young animals.
  • the diarrhea is secretory/watery diarrhea.
  • Such diarrhea can be a clinical sign of gastrointestinal (GI) disease in an animal; it can also reflect primary disorders outside of the digestive system, such as disorders affecting the large bowel or the small bowel.
  • GI gastrointestinal
  • the methods described herein are suitable for treating diarrhea resulting from different mechanisms involved in the pathogenesis of the disorders, for example, osmotic diarrhea, secretory diarrhea, episodic diarrhea, or inflammatory and infectious diarrhea.
  • the neonatal or young animal can suffer from diarrhea associated with inflammation of the lining of the colon, such as colitis, or acute colitis, which can be caused by infection or inflammation of the bowel.
  • Osmotic diarrhea is associated with absorption of water in the intestines, which depends upon adequate absorption of solutes. If excessive amounts of solutes are retained in the intestinal lumen, water will not be absorbed and diarrhea results. Osmotic diarrhea typically results from ingestion of a poorly absorbed substrate, for example, a carbohydrate or divalent ion or from malabsorption of any type, such as an inability to absorb certain carbohydrates. Secretory diarrhea occurs when the secretion of water into the lumen of the intestine exceed absorption. Under normal conditions, large volumes of water are secreted into the small intestinal lumen, but a large portion of this water is efficiently absorbed before reaching the large intestine.
  • Secretory diarrhea can result from exposure of an animal to toxins (enterotoxins) from certain types of bacteria, such as cholera toxin of Vibrio cholerae and heat-labile toxin of E. coli.
  • Massive diarrhea is induced from such microorganisms as a consequence of their toxins strongly activating adenylyl cyclase, which causes a prolonged increase in the intracellular concentration of cyclic AMP within crypt enterocytes. This increase, in turn, results in prolonged opening of the chloride channels that contributes to secretion of water from the crypts, thereby allowing uncontrolled secretion of water.
  • bacterial toxins can also affect the enteric nervous system, resulting in an independent stimulus of water secretion.
  • Inflammatory and infectious diarrhea can be caused by the disruption of the epithelium of the intestine due to microbial or viral pathogens.
  • the epithelium of the digestive tube is protected from insult by a number of mechanisms that constitute the gastrointestinal barrier.
  • the gastrointestinal barrier can be breached and result in diarrhea.
  • Destruction of the epithelium results not only in leaking of serum and blood into the lumen but also is often associated with significant destruction of adsorptive epithelium. When this occurs, the absorption of water becomes highly inefficient and diarrhea results.
  • the pathogenic culprits frequently associated with infectious diarrhea include bacteria, such as E.
  • coli Campylobacter and Salmonella viruses, such as rotaviruses, coronaviruses, parvoviruses and norovirus; and protozoa, such as coccidia species, Cryptosporium and Giardia.
  • Activated white blood cells are stimulated to produce and secrete inflammatory mediators and cytokines that stimulate secretion.
  • An secretory component is thus imposed upon and exacerbates an inflammatory diarrhea.
  • reactive oxygen species produced by leukocytes can damage or destroy intestinal epithelial cells, which are replaced with immature cells that are generally lacking in the brush border enzymes and transporters necessary for the absorption of nutrients and water.
  • components of an osmotic (malabsorption) diarrhea provide additional pathology and problems for an afflicted animal.
  • the diarrhea to be treated is caused by infection or invasion of the animals by pathogens, including bacteria, e.g., Escherichia coli, Salmonella spp., Clostridium spp., such as C perfringens, C difficile, etc.; viruses, e.g., coronaviruses, rotaviruses, bovine virus diarrhea (BVD) virus, infectious bovine rhinotracheitis (IBR) virus, etc.; protozoa, e.g., Cryptosporidium, coccidia, etc.; as well as yeasts and molds.
  • diarrhea can be caused by a single infectious microorganism; however, mixed infections, such as caused by, e.g., E. coli plus Cryptosporidium, or Coronavirus plus Salmonella spp., are also not uncommon.
  • the gram-negative bacterium Escherichia coli is normally found in the intestines of most animals. Although most E. coli are nonpathogenic, some are able to cause intestinal and extraintestinal infections. Large numbers of E. coli are present in the farm environment as a result of fecal contamination. Initial exposure to pathogenic E. coli may occur in contaminated calving pens, but systemic infection usually requires predisposing environmental factors, inadequate transfer of passive immunity or compromised immune system by other infection. The most common type of colibacillosis in young animals is caused by the noninvasive Enterotoxigenic E.
  • ETEC coli coli
  • Treatment of neonatal and young animals according to the methods of the invention is of particular importance, because such immature animals are most susceptible to infection by numerous pathogens of many types; resistance to infection develops with increasing age of the animal.
  • younger animals experience more severe clinical illness as a result of infection and resulting diarrhea.
  • young animals (lambs) at one to five days of age experienced more severe infection by enteric cryptospores, causing protracted diarrhea, wasting and death, while young lambs at thirty days of age, which had become infected, did not exhibit severe signs of clinical disease.
  • due to the anatomy of the gastrointestinal tract of adult animals such as horses, conditions affecting the large intestine and cecum typically cause diarrhea.
  • a foal is an equine, particularly a horse, that is one year old or younger in age.
  • the diarrhea to be treated results from noninfectious causes, for example, without limitation, inadequate nutrition and/or insufficient attention of the neonate or young animal on the part of the mother, exposure to severe environment, or a combination of these events.
  • diarrhea results from a combination of the invasion of infectious microorganisms and noninfectious factors.
  • noninfectious causes of diarrhea in young animals are considered to be factors that predispose or contribute to an animal's susceptibility to infectious agents and causes of diarrhea.
  • the cause of diarrhea in animals is infectious or noninfectious (e.g., environmental)
  • the absorption of fluids from the intestine is altered and life-threatening electrolyte imbalances can occur.
  • the affected animals lose fluids, rapidly dehydrate and suffer from electrolyte loss and acidosis.
  • infectious agents may cause an initial damage to the animal's intestine, actual death from diarrhea (serious diarrhea) in animals usually is a consequence of dehydration, acidosis and loss of electrolytes, which may be difficult to replenish in adequate amount and time.
  • the methods and formulations of the invention are suitable for treating diarrhea and the symptoms of diarrhea, such as dehydration, weight loss, and electrolyte loss, in an effort to prevent more severe dehydration and animal death.
  • Neonatal and young animals acquire antibodies from colostrum, which is optimally received by the animals before they are two to four hours old. As young animals grow older, they rapidly lose their ability to absorb colostral antibodies. Thus, for example, colostrum provided to calves that are more than 24 to 36 hours old will likely not be effective, as antibodies are infrequently absorbed following this time in the animal's life.
  • prophylactic administration of the C. lechleri proanthocyanidin polymer composition can reduce the incidence of diarrheal disease in neonatal animals, improving health, weight gain and survivability in populations of neonatal animals.
  • the treatment of young non-human animals, such as pre- weaned foals, with a non-enteric C. lechleri proanthocyanidin polymer, composition, or botanical extract according to the present methods shows beneficial efficacy in resolving diarrhea and reducing accompanying symptoms, such as dehydration, in animals within a relatively short time period, e.g., within about 24-48 hours, after the animals have undergone treatment.
  • Such treatment efficacy of the non-enteric compositions and products of the invention demonstrates that the C. lechleri proanthocyanidin polymer, composition, or botanical extract is not destroyed in the pH environment of the treated animal's stomach and can reach the active site.
  • the treatment method involves the oral administration of a non-enteric C. lechleri proanthocyanidin polymer, composition, or botanical extract, e.g., SB 300, particularly a paste formulation, in an amount of 4 mg/kg to 10 mg/kg, or in an amount of 4 mg/kg to 8 mg/kg, twice a day for three days (six treatments), to pre-weaned foals having diarrhea.
  • the non-enteric product is administered in dose range of 8-24 mg/kg per dose, or 1600 mg per animal (foal) per dose, or 17-48 mg/kg BID.
  • an antacid such as a proton pump inhibitor, for example omeprazole or lansoprazole
  • a proton pump inhibitor for example omeprazole or lansoprazole
  • the animals are also administered a probiotic and/or one or more antibiotics according to the standard of care.
  • the treatment methods involving the oral administration of a non-enteric C. lechleri proanthocyanidin polymer, composition, or botanical extract, particularly as a paste formulation may be used to resolve diarrhea and achieve formed stool in pre-weaned animals that have previously been treated for diarrhea with another anti-diarrheal product or agent or method, which had failed to resolve the diarrhea in the animals, or which had not completely resolved the animals' diarrhea, at the end of a given treatment period.
  • a non-enteric form of a C may be used to resolve diarrhea and achieve formed stool in pre-weaned animals that have previously been treated for diarrhea with another anti-diarrheal product or agent or method, which had failed to resolve the diarrhea in the animals, or which had not completely resolved the animals' diarrhea, at the end of a given treatment period.
  • lechleri proanthocyanidin polymer, composition, or botanical extract product may advantageously afford a follow-on treatment that is administered to a pre-weaned animal who had received a first treatment that did not successfully or completely treat the diarrheal condition in the animal.
  • the treatment methods involving a non-enteric C. lechleri proanthocyanidin polymer, composition, or botanical extract according to the invention, administered, for example, as an oral paste formulation not only provides a first line treatment for diarrhea in pre-weaned animals in need thereof, but it also provides a potential second line treatment that may be given to successfully resolve and treat diarrhea in animals after another treatment has failed to completely resolve the diarrheic condition in the animals.
  • Proanthocyanidins are types of condensed tannins, which are found in a large number of plants and are classified as hydrolyzable or condensed. Tannins and, in particular, proanthocyanidins are contained in many plants used in traditional medicine as treatment or prophylaxis for diarrhea (See, e.g., Yoshida et al., 1993, Phytochemistry, 32: 1033; Yoshida et al., 1992, Chem. Pharm. Bull, 40: 1997; Tamaka et al., 1992, Chem. Pharm. Bull, 40:2092).
  • Proanthocyanidins are comprised of at least two or more monomer units that may be of the same or different monomelic structure.
  • the monomer units (generally termed “leucoanthocyanidins") are generally monomelic flavonoids which include catechins, epicatechins, gallocatechins, galloepicatechins, flavanols, flavonols, flavan-3,4-diols, leucocyanidins and anthocyanidins.
  • the polymer chains are thus based on different structural units, creating a wide variation of polymeric proanthocyanidins and a large number of possible isomers (Hemingway et al., 1982, J. C. S.
  • Proanthocyanidin polymers and proanthocyanidin are found in a wide variety of plants, especially those having a woody habit of growth ⁇ e.g., Croton spp.. and Calophyllum spp.).
  • a number of different Croton tree species including Croton sakutaris, Croton gossypifolius, Croton palanostima, Croton lechleri, Croton erythrochilus and Croton dmconoides, which are endemic to South America, produce a red viscous latex sap called Sangre de Drago or "Dragon's Blood".
  • the red viscous latex is known for its medicinal properties.
  • 5,211,944 describes the isolation of an aqueous soluble proanthocyanidin polymer composition from Croton spp. See also, Ubillas et al., 1994, Phytomedicine, 1 :77. The isolation of an aqueous soluble proanthocyanidin polymer composition from Calophyllum inophylum and the use of this composition as an antiviral agent are also described in U.S. Patent No. 5,211,944.
  • a proanthocyanidin polymer from C. lechleri, or a composition thereof is crofelemer.
  • Crofelemer (CAS 148465-45-6) is an oligomeric proanthocyanidin of varying chain lengths derived from the Dragon's Blood of Croton lechleri, a tree of the family Euphorbiaceae , which is sustainably harvested under fair trade work practices in the Amazon. It has an average molecular weight of approximately 1900 Da to approximately 2700 Da.
  • the monomers comprising crofelemer comprise catechin, epicatechin, gallocatechin, and epigallocatechin.
  • the chain length of crofelemer ranges from about 3 to about 30 units with an average chain length of about 8 units.
  • Crofelemer has the chemical formula: and a molecular mass of 860-9100 g/mol.
  • the antisecretory mechanism of action of crofelemer involves the targeting and inhibition of two, distinct intestinal chloride channels, namely, the cystic fibrosis transmembrane regulator conductance (CFTR) channel, which is a cAMP- stimulated CI " channel, and the calcium-activated chloride channel (CaCC), as reported, for example, by Tradtrantip, L et al., 2010, "Crofelemer, an Antisecretory Antidiarrheal Proanthocyanidin Oligomer Extracted from Croton lechleri, Targets Two Distinct Intestinal Chloride Channels", Mol.
  • CFTR cystic fibrosis transmembrane regulator conductance
  • CaCC calcium-activated chloride channel
  • crofelemer or a pharmaceutically acceptable formulation or composition comprising crofelemer, is employed in the treatment methods as the proanthocyanidin polymer from Croton lechleri.
  • SP 303 an oligomeric proanthocyanidin from Croton lechleri
  • SP-303 (R. Ubillas et al., 1994, Phytomedicine, 1 :77-106) is largely composed of purified proanthocyanidin oligomers (-)-galloepicatechin and (+)-gallocatechin,(-)-epicatechin and (+)-catechin and is suitable for use in the non-enteric formulations and compositions for administration in the treatment methods described herein.
  • the C. lechleri proanthocyanidin may also be isolated according to example 2 of patent application publication US2007/0254050 or in patent application publication US2005/0019389, which are both incorporated by reference herein in their entirety.
  • SB 300 is the proanthocyanidin polymer from Croton lechleri, or a pharmaceutically acceptable formulation or composition comprising SB 300, which is suitable for use in the treatment methods of the invention.
  • SB 300 as described, for example, by Fischer, H. et al., (2004, J. Ethnopharmacol., 93(2-3):351-357) is a natural product extract, i.e., a purified botanical extract of Croton lechleri, that is particularly amenable for non-enteric formulations and compositions used in the present methods, and is highly functional and cost- effective in the treatment methods described herein.
  • a pharmaceutically acceptable composition comprising a proanthocyanidin polymer from Croton lechleri and employed in the treatment methods of the invention can be obtained from C lechleri, e.g., as described in WO 00/47062 to Shaman Pharmaceuticals, Inc., the contents of which are incorporated by reference herein, and formulated as a food or dietary supplement or nutraceutical formulation.
  • compositions useful in the methods of the invention comprise a raw latex obtained from a Croton species or a Calophyllum species, or an extract obtained from a Croton species or a Calophyllum species, which are not specifically polymeric proanthocyanidin polymer compositions.
  • Exemplary extracts are described in Persinos et al., 1979, J. Pharma. Sci., 68: 124 and Sethi, 1977, Canadian J. Pharm. Sci., 12:7 ' .
  • the proanthocyanidin polymer from Croton lechleri is formulated without an enteric coating or matrix.
  • Non-enteric forms of the proanthocyanidin polymer from Croton lechleri, for example, SB 300, are intended for use in the methods of the present invention.
  • the proanthocyanidin polymer composition effective for treating secretory diarrhea according to the invention, is comprised of monomelic units of leucoanthocyanidins. More particularly, the composition is comprised of proanthocyanidin polymers of 2 to 30 flavonoid units, preferably 2 to 15 flavonoid units, more preferably 2 to 11 flavonoid units and most preferably an average of 7 to 8 flavonoid units with a number average molecular weight of approximately 2500 Da.
  • the proanthocyanidin polymer composition is preferably soluble in an aqueous solution. Preferred for use in the methods according to the invention is a proanthocyanidin polymer from C.
  • proanthocyanidin polymeric compositions useful in the present invention are preferably isolated or purified from a Croton spp., namely, Croton lechleri, or Calophyllum spp. by any method known in the art.
  • the proanthocyanidin polymer composition may be isolated from a Croton spp. or Calophylum spp. by the method disclosed in U.S. Pat. No. 5,211,944 or in Ubillas et al.
  • the proanthocyanidin polymer composition may be generally isolated by the following process, such as provided in U.S. Patent No. 7,341,744.
  • Latex collected from Croton lechleri plants is mixed with purified water (preferably one part latex to two parts purified water). Any insoluble material in the latex solution is allowed to settle, e.g., by leaving the mixture at 4°C overnight (12 hours).
  • the supernatant is pumped away from the residue and is extracted with a short chain alcohol, such as n-butanol.
  • the extraction is preferably performed multiple times, such as three times. After each extraction, the alcohol phase is discarded and the aqueous phase is retained.
  • the aqueous phase is concentrated, for example, using an ultrafiltration device with a 1 kD cut-off membrane.
  • This membrane can be a low protein binding cellulose membrane, or, alternatively, a polypropylene, teflon or nylon membrane can be used.
  • the membrane used should be compatible with acetone.
  • the purpose of the ultrafiltration is to remove the water from the material.
  • the retentate from the ultrafiltration is then concentrated to dryness, for example using tray-dryers at approximately 37°C ( ⁇ 2°C).
  • the dried material is subsequently dissolved in water and is then chromatographed on a cation exchange column (e.g., a CM-Sepharose column) and a size exclusion column (e.g., an LH-20 column).
  • a cation exchange column e.g., a CM-Sepharose column
  • a size exclusion column e.g., an LH-20 column.
  • material is run over a CM-Sepharose and then an LH-20 column in a series. Specifically, the dissolved material is loaded onto the cation exchange column and is then washed with purified water.
  • the proanthocyanidin polymer material is eluted from the cation exchange column with an aqueous acetone solution (preferably 30% acetone), thereby loading the proanthocyanidin polymer material onto the sizing column.
  • the sizing column is disconnected from the cation exchange column and the material is then eluted off of the sizing column with an aqueous acetone solution (preferably 45% acetone).
  • the fractions are collected and monitored with a UV detector, e.g., at a wavelength of 460 nm.
  • Fractions containing the proanthocyanidin polymer material are combined and concentrated, for example, by ultrafiltration using, e.g., a 1 kD cut-off membrane (as described above for the ultrafiltration step prior to the chromatography steps).
  • the retentate may then be concentrated to dryness using a suitable drying method, such as, but not limited to, a rotary evaporator, at a temperature of approximately 37°C ( ⁇ 2°C).
  • suitable drying methodologies include, but are not limited to, tray drying and spray drying.
  • Example 10 of U.S. Patent No. 7,341,744 provides additional, non-limiting, methodology for preparing a composition comprising proanthocyanidin polymer, which can be used according to the invention.
  • a detailed protocol for isolating an enriched proanthocyanidin polymer extract suitable for use in the methods of the invention is described in WO 00/47062 as noted herein above.
  • the invention is directed to methods of treating diarrhea associated with pathogenic infection and non-pathogenic causes, particularly in pre-weaned, neonatal and young animals, comprising administering to an animal in need of such treatment, a pharmaceutically acceptable, non-enteric composition comprising a proanthocyanidin polymer from a Croton species or Calophyllum species in an amount effective to treat the diarrhea.
  • a pharmaceutically acceptable, non-enteric composition comprising a proanthocyanidin polymer from a Croton species or Calophyllum species in an amount effective to treat the diarrhea.
  • the proanthocyanidin polymer is from a Croton species, namely, Croton lechleri. Treating the diarrhea can involve reducing the severity and duration of the diarrhea in the animal.
  • Treating the diarrhea can also involve increasing the survivability, vigor and weight of the animal, and reducing dehydration and its detrimental effects in the animal, particularly a neonatal or young animal undergoing treatment.
  • the diarrhea is secretory or watery diarrhea.
  • the methods of the invention relate to the treatment of non-human animals, notably, but not limited to, the newborns and young of livestock, domestic and farm animals, including grazing animals, which are oftentimes relatively large in size.
  • the immature animals to which treatment with the non-enterically coated proanthocyanidin polymer from Croton lechleri is administered are neonatal (newborn) or infant animals, for example, one to ten hours after birth, one to fifteen hours after birth, twelve to twenty-four hours after birth, twenty-four to thirty-six hours after birth, one to three days after birth, one to four days after birth, one to six days after birth, or one to seven days after birth or up to two weeks after birth.
  • Neonatal animals are generally those being those under two weeks of age.
  • the animals are treated between day one and day four after birth.
  • the neonatal or young animals are treated one to five days of age, less than one week of age, or only a few weeks of age.
  • treatment occurs during the first weeks of life, for example, one to six weeks of age.
  • the animals are from two to ten weeks of age, for example, less than one, two, three, four, five, six, seven, eight, nine, or ten weeks of age.
  • the animals undergoing treatment may also be from one to four weeks of age, from one to six weeks of age, or from two to four weeks of age.
  • the animals are one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, twenty, twenty-one, twenty-two, twenty-three, twenty-four, twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, or thirty days old. In other embodiments, the animals are thirty to forty days old. In other embodiments, the animals are young animals, generally up to one year in age. In many cases, the animals are not weaned (unweaned), i.e., they are still drinking milk and, in certain embodiments, have a diet that is solely or predominantly milk or milk replacer.
  • dairy calves are generally weaned at 60 to 80 days while beef cattle may be weaned at 3 to 8 months of age, pigs at 3 weeks of age, dogs at 7 to 8 weeks, and horses at 4 to 6 months of age.
  • neonatal is synonymous with unweaned or pre-weaned.
  • Such young animals are also highly susceptible to becoming afflicted with diarrhea from various infectious, non-infectious and/or environmental causes.
  • the neonatal and young animals can be treated with a non-enterically coated proanthocyanidin polymer from C. lechleri, e.g., SB 300, or a botanical extract derived from C. lechleri, for one, two, three, four, five, six, seven, eight, nine, or ten days, etc.
  • the C. lechleri proanthocyanidin polymer can be administered to the animal on consecutive days or intermittently, such as every other day, every two days, every three days, every four days, and the like.
  • the C. lechleri proanthocyanidin polymer, which is not enterically coated is administered to the animals for three consecutive days.
  • the C. lechleri proanthocyanidin polymer which is not enterically coated, is administered to the animals for three consecutive days.
  • lechleri proanthocyanidin polymer which is not enterically coated, is administered to neonatal animals between one and four days after birth for three consecutive days.
  • environmental, e.g., farm, conditions surrounding the neonatal and young animals may dictate the start and course of a treatment regimen such that the administration of the C. lechleri proanthocyanidin polymer, which is not enterically coated, occurs earlier in the animal's life and for a longer duration, especially since diarrheal disease typically affects neonatal and young animals in about the first seven days of life, or between about day one or day four of life.
  • the animals may be bovine or camel calves, or equine foals.
  • the animals are also treated with a proton pump inhibitor product such as omeprazole, e.g., in an amount of 4 mg/kg, according to standard of care veterinary methods.
  • a non-enteric formulation or composition comprising a botanical extract derived from C. lechleri, SB 300, or SP 303, is provided in the form of a gel or paste formulation that is orally administered to the neonatal or young animal, such as a horse foal, twice daily for three days, preferably, three consecutive days.
  • the twice daily doses are orally administered to the animal twelve hours apart.
  • the non-enteric paste formulation is particularly suitable as a product that acts locally in the gut and is minimally absorbed systemically.
  • the non-enteric paste product specifically addresses the normalization of stool formation and ion and water flow in the intestinal lumen of neonatal and young animals, such as horse foals, and does not alter gastrointestinal motility, i.e., is not constipating.
  • the paste formulation can be placed in the roof of the animal's mouth.
  • the non-enteric paste product comprising SB 300 is orally administered to a foal at a dose of 4 mg/kg to 8 mg/kg twice daily for three days.
  • the non-enteric paste product comprising SB 300 is orally administered to a foal at in a dose range of 8 mg/kg to 24 mg/kg per dose twice daily for three days, or in a daily dose of 17-48 mg/kg (BID).
  • the amount per dose of SB 300 or other proanthocyanidin polymer composition of the invention is 1600 mg, or may be 800 mg, 1000 mg, 1200 mg, 1400 mg, 1800 mg or 2000 mg.
  • the formulation is especially suitable for the normalization of stool formation in a short time period, e.g., within one day, two days, three days, less than a week, or less than two weeks; for mitigation of dehydration and weight loss; and reduction in supportive care costs, rehydration therapies, such as oral rehydration, in a young animal afflicted with diarrhea and undergoing treatment.
  • non-human animals for which the treatment methods are suitable are not particularly limited as to animal type, genus, or species.
  • neonatal or young farm animals, food-source animals, livestock animals, animals bred or kept for various purposes, such as sport (e.g., racing, riding), transport, domestic, companion, industrial uses (e.g. hauling, pulling, plowing), and the like, are particularly amenable to treatment according to the methods of the invention.
  • Neonatal or young exotic animals such as cows (calves), cattle or steer (calves), camels (calves), rams and sheep (lambs), horses (foals), pigs (piglets), goats (kids), bison/buffalo (calves), llamas, donkeys, mules, yaks, etc.
  • Neonatal or young exotic animals such as zoo animals of various species, are also embraced by the treatments of the invention.
  • the animals are grazing animals.
  • the treatment of diarrhea in neonates and unweaned animals for example, calves (bovine, camel, buffalo/bison), lambs, piglets, and foals (equine) is particularly embraced by the described methods.
  • the non-enteric C. lechleri proanthocyanidin polymer composition reduces chloride flux across intestinal epithelial cells and reduces fluid movement into the intestinal lumen, which results in fluid loss and dehydration associated with secretory diarrhea. Therefore, the pharmaceutically acceptable, non-enteric formulations and methods of the invention are useful in prophylactic and therapeutic applications in the treatment of secretory diarrhea, especially in preventing the dehydration and electrolyte loss that accompanies secretory/watery diarrhea in young animals. In an embodiment, the methods of the invention may be useful in treating diarrhea resulting from infection by the Salmonella spp.
  • the young animals treated by the methods of the invention are two to four weeks of age.
  • the animals are two to four week old calves, e.g., without limitation, bovine or camel calves, having diarrhea caused by infection with Salmonella, or crytosporidia or a combination thereof.
  • the animals are two to four week old calves, e.g., without limitation, bovine or camel calves, having undifferentiated diarrhea of unknown origin.
  • the animals are horse foals suffering from diarrhea associated with certain adverse environmental conditions and/or infection.
  • the animals treated by the methods of the invention are approximately 3 to 1000 kg in weight; or approximately 5 to 900 kg in weight, or approximately 10 to 350 kg in weight; or approximately 35 kg to 200 kg in weight, or approximately 15 to 150 kg in weight; or approximately 25 to 70 kg in weight, or approximately 30 to 50 kg in weight, or approximately 30 to 40 kg in weight.
  • the young animal being treated for diarrhea is a bovine calf of approximately 20 to 40 kg in weight.
  • the young animal being treated for diarrhea is a camel calf of approximately 30 to 50 kg in weight.
  • the young animal being treated for diarrhea is an equine foal of approximately 35 kg to approximately 200 kg, or approximately 70 kg to approximately 200 kg, in weight.
  • neonatal and young animals are treated prophylactically with a
  • C. lechleri proanthocyanidin polymer composition such as SB 300 or SP 303, in non-enterically protected form, to prevent or reduce the risk or severity of the debilitating effects of diarrheal disease and its associated symptoms, e.g., dehydration and weight loss, in neonatal and young animals.
  • a non-enteric C. lechleri proanthocyanidin polymer composition is administered to neonatal and young animals at a suitable time after birth to protect the animals from diarrhea outbreaks typically caused by infections and adverse environmental conditions.
  • lechleri proanthocyanidin polymer composition to neonatal and young animals can also serve to ameliorate or reduce the risk of the animals' suffering from a more serious or severe form of diarrhea relative to animals that are not provided with the non-enteric C. lechleri proanthocyanidin polymer composition prior to an outbreak of disease or infection.
  • the non-enteric C. lechleri proanthocyanidin polymer composition can be, for example, SB 300 or SP 303.
  • the dose and regimen of non-enteric C. lechleri proanthocyanidin polymer composition administration are within the skill of the practitioner to determine and will depend on the environmental conditions and health of the neonatal and young animals to be treated.
  • the animals can be prophylactically treated with a non-enteric C.
  • lechleri proanthocyanidin polymer composition for example and without limitation, one to seven days, one to six days, one to four days, one to three days, or one or two days after birth.
  • the treatment regimen can involve one, two, three, four, five, six, seven or more days, of non-enteric C.
  • the non-enteric paste product comprising SB 300 is orally administered to a foal at in a dose range of 8 mg/kg to 24 mg/kg per dose twice daily for three days, or in a daily dose of 17-48 mg/kg (BID).
  • the amount per dose of SB 300 or other proanthocyanidin polymer composition of the invention is 1600 mg, or may be 800 mg, 1000 mg, 1200 mg, 1400 mg, 1800 mg or 2000 mg.
  • the animals can be regularly observed and monitored for formed stool, health improvements and weight gain.
  • These prophylactic methods of the invention can improve weight gain within the first 15, 20, 25 or 30 days by at least 5%, at least 10%, at least 15%, or even at least 20%.
  • the proanthocyanidin polymer from C. lechleri, or a non-enteric composition thereof can be provided in any physiologically, pharmaceutically, or therapeutically acceptable form.
  • the pharmaceutically acceptable composition can be formulated for oral administration as, illustratively, but without limitation, powders; crystals; granules; small particles, including microparticles; particles sized on the order of micrometers, e.g., microspheres and microcapsules; particles sized on the order of millimeters, particles sized on the order of nanometers, e.g., nanoparticles; beads; microbeads; pellets; pills; tablets; microtablets; compressed tablets or tablet triturates; molded tablets or tablet triturates; and in capsules, which are either hard or soft and contain the composition as a powder, particle, bead, solution or suspension.
  • the pharmaceutically acceptable non-enteric composition can also be formulated for oral administration as a solution or suspension in an aqueous liquid, as a liquid incorporated into a gel capsule, as a gel, as a paste or gel paste, a powder, or as any other convenient formulation for administration.
  • the non-enteric composition can be formulated for rectal administration, as a suppository, enema or other convenient form.
  • the composition can be formulated as a dietary supplement or food supplement, e.g., as described in WO 00/47062, for administration to an animal in need thereof according to the present invention.
  • a non-enteric formulation or composition comprising a botanical extract derived from C. lechleri, SB 300, or SP 303, is provided in the form of a gel or paste formulation that is orally administered to an animal, in need, twice daily for three days, preferably, three consecutive days.
  • the twice daily doses are administered to the animal twelve hours apart.
  • the paste formulation is particularly suitable as a product that acts locally in the gut and is minimally absorbed systemically.
  • the paste product specifically addresses the normalization of stool formation and ion and water flow in the intestinal lumen of the treated animals and does not alter gastrointestinal motility, i.e., is not constipating.
  • the paste formulation can be placed in the roof of the animal's mouth.
  • the non-enteric paste formulation comprising SB 300 is orally administered to an animal, e.g., a foal, in need at a dose of 4 mg/kg to 8 mg/kg twice daily for three days.
  • the non-enteric formulation is especially suitable for the normalization of stool formation in a short time period, e.g., within a day or two, less than a week or less than two weeks; in animals afflicted with diarrhea and undergoing treatment.
  • the non-enteric pharmaceutical formulation can also include any type of pharmaceutically acceptable excipients, additives, carriers, or vehicles.
  • diluents or fillers such as dextrates, dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, sorbitol, sucrose, inositol, powdered sugar, bentonite, microcrystalline cellulose, or hydroxypropylmethylcellulose can be added to the proanthocyanidin polymer composition to increase the bulk of the composition.
  • binders such as, but not limited to, starch, gelatin, sucrose, glucose, dextrose, molasses, lactose, acacia gum, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapgol husks, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, Veegum and starch arabogalactan, polyethylene glycol, ethylcellulose, and waxes, can be added to the formulation to increase its cohesive qualities.
  • lubricants such as, but not limited to, talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, carbowax, sodium lauryl sulfate and magnesium lauryl sulfate can be added to the formulation.
  • glidants such as, but not limited to, colloidal silicon dioxide or talc can be added to improve the flow characteristics of a powdered formulation.
  • Disintegrants such as, but not limited to, starches, clays, celluloses, algins, gums, crosslinked polymers (e.g., croscarmelose, crospovidone, and sodium starch glycolate), Veegum, methylcellulose, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, carboxymethylcellulose, or sodium lauryl sulfate with starch can also be added to facilitate disintegration of the formulation in the intestine.
  • crosslinked polymers e.g., croscarmelose, crospovidone, and sodium starch glycolate
  • Veegum methylcellulose
  • agar bentonite
  • cellulose and wood products natural sponge
  • cation-exchange resins alginic acid, guar gum, citrus pulp, carboxymethylcellulose, or sodium lauryl sulfate with starch
  • the non-enteric pharmaceutically acceptable formulations contain the proanthocyanidin polymer composition without an enteric coating, in addition to another pharmaceutically acceptable vehicle.
  • such non-enteric formulations do not require the inclusion of a substance, such as an enteric coating, that protects the C. lechleri proanthocyanidin polymer and/or the polymer or extract composition from the stomach environment.
  • the non-enteric proanthocyanidin polymer composition can be directly-compressed into a tablet.
  • the tablet can be without excipients and of pharmaceutically acceptable hardness and friability, optionally, with a lubricant, e.g., without limitation, magnesium stearate, and enteric coated.
  • a lubricant e.g., without limitation, magnesium stearate, and enteric coated.
  • the pharmaceutically acceptable, non-enteric compositions containing the proanthocyanidin polymer composition or product may also include one or more exogenous substances that either neutralize stomach acid and/or enzymes or are active to prevent secretion of stomach acid.
  • formulations can be prepared by methods known in the art (see, e.g., methods described in Remington's "The Science and Practice of Pharmacy," 22nd Edition, Editor-in-Chief: Lloyd V. Allen, Jr., Pharmaceutically acceptable Press, Royal Pharmaceutically acceptable Society, London, UK, 2013).
  • the pharmaceutically acceptable composition of the proanthocyanidin polymer composition is formulated as non-enteric coated granules or powder (e.g., microspheres with a diameter of 300-500 microns) provided in either hard shell gelatin capsules or suspended in an oral solution.
  • the non-enteric coated proanthocyanidin polymer composition powder or granules can also be mixed with food, particularly for administration to neonatal or young animals. Such preparations may be prepared using techniques well known in the art.
  • non-enteric coated proanthocyanidin polymer composition granules and powder can be prepared using any method known in the art, such as, but not limited to, crystallization, spray-drying or any method of comminution, preferably using a high speed mixer/granulator, as described, for example and without limitation, in U.S. Patent No. 7,323,195, incorporated herein by reference.
  • the non-enteric proanthocyanidin polymer composition is in the form of an aqueous suspension in admixture with suitable excipients.
  • suitable excipients include suspending agents, for example, methylcellulose, sodium carboxymethylcellulose, hydroxy- propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents, which may be a naturally-occurring phosphatide, e.g., lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g., heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol, for example, polyoxyethylene sorbionate, a naturally-occurring phosphatide, e.g., le
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, e.g., sucrose, saccharin or aspartame.
  • Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the non-enteric proanthocyanidin polymer composition in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent, suspending agent and one or more preservatives are exemplified by those stated above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present.
  • the non-enteric proanthocyanidin polymer composition is a gel or gel formulation.
  • the non-enteric proanthocyanidin polymer composition is a paste or paste formulation.
  • the paste formulation contains a purified botanical extract derived from C. lechleri.
  • the paste formulation contains non-enterically coated beads comprising SB 300 or SP 303.
  • the gel or paste is contained or preloaded in a delivery device, such as a syringe, e.g., a needle-less syringe, or other type of applicator or delivery system, especially for oral delivery.
  • a gel or paste formulation is particularly suited for administration to Salmonella spp.
  • the gel or paste is not contained in a delivery device, but is administered to the roof of the mouth of the animal, particularly one that is too incapacitated or ill to eat or drink, thereby eschewing an oral or other mode of administration.
  • Processes for generating granules and particles comprising the C. lechleri botanical extract, a non-enteric proanthocyanidin polymer composition, or a compressible form thereof are as known and practiced in the art.
  • gels are prepared for oral delivery and contain surfactants and copolymers, such as poloxamers and Pluronics of different types, e.g., Pluronic F.
  • the non-enteric proanthocyanidin polymer composition is in a paste formulation, preferably for oral administration.
  • an oral paste may comprise, without limitation, an oily vehicle or excipient, such as a hydrophobic oily vehicle, a basifying agent, a flavoring agent and a coloring agent.
  • hydrophobic oily vehicles include vegetable oil, triglyceride or polypropylene glycol, as well as a thickening agent, e.g., aluminum stearate.
  • Flavoring agents can include, for example, fruit flavors, mint flavors, honey flavor, and other natural and organic flavorings known to those skilled in the art.
  • Coloring agents can include, for example, iron oxide or titanium dioxide.
  • the oily vehicle can be liquid paraffin or other suitable waxes, including a thickening agent.
  • Oily suspensions may be formulated by suspending the C. lechleri proanthocyanidin polymer as active ingredient in a vegetable oil, e.g., arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil, such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, e.g., beeswax, hard paraffin or cetyl alcohol.
  • Oral preparations can include sweetening agents as mentioned above and flavoring agents to improve palatability.
  • Pharmaceutically acceptable preservatives for example, an anti-oxidant such as ascorbic acid, can also be added to such compositions.
  • the non-enteric C. lechleri proanthocyanidin polymer pharmaceutical compositions used in the methods of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil such as olive oil or arachis oil, or a mineral oil such as liquid paraffin or mixtures of these oils.
  • emulsifying agents include, without limitation, naturally-occurring phosphatides, e.g., soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, e.g., sorbitan monooleate, and condensation products of partial esters with ethylene oxide, e.g., polyoxyethylene sorbitan monooleate.
  • phosphatides e.g., soy bean, lecithin
  • esters or partial esters derived from fatty acids and hexitol anhydrides e.g., sorbitan monooleate
  • condensation products of partial esters with ethylene oxide e.g., polyoxyethylene sorbitan monooleate.
  • Sweetening, coloring and flavoring agents can be included in the emulsions.
  • Syrups and elixirs containing the C. lechleri proanthocyanidin polymer may also can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such non-enteric formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the non-enteric pharmaceutical compositions may be in the form of a sterile, orally deliverable or administrable aqueous or oleagenous suspension. This suspension may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents, such as those mentioned above.
  • the sterile pharmaceutical preparation may also be a sterile solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, a solution in 1,3-butane diol.
  • a non-toxic parenterally-acceptable diluent or solvent for example, a solution in 1,3-butane diol.
  • acceptable vehicles and solvents that may be used in the preparations include water, Ringer's solution and isotonic sodium chloride solution. Co-solvents, e.g., ethanol, propylene glycol or polyethylene glycols, may also be included.
  • sterile, fixed oils e.g., any bland, fixed oil such as synthetic mono- or diglycerides, are conventionally employed as solvents or suspending media and may be used.
  • fatty acids such as oleic acid and the like, may be used in injectable preparations.
  • the non-enteric proanthocyanidin polymer composition is in powder, e.g., reconstitutable powder, form.
  • the neonates are less than one week in age.
  • the neonatal animals are equine foals.
  • the neonatal animals are bovine calves or camel calves.
  • the neonatal animals are afflicted with E. co/z ' -induced secretory diarrhea.
  • the E. coli causative agent is E.
  • the animal in addition to infection with E. coli, the animal experiences involvement of a viral infection by rotavirus and/or coronavirus, whose mechanism of action involves infection and subsequent destruction of the cells lining the intestinal tract. Such cells are involved in the digestion and absorption of milk in the animal's gut.
  • the methods of the invention also provide the means for the cellular damage in the intestines of the treated neonates and young non-human animals to be repaired.
  • the powder form of the non-enteric proanthocyanidin polymer composition used for treatment is reconstituted or mixed with liquid, such as oral electrolytes, milk or a milk replacer, water, physiological saline, to produce a liquid form or suspension.
  • liquid such as oral electrolytes, milk or a milk replacer, water, physiological saline, to produce a liquid form or suspension.
  • Milk replacer is generally a source of protein from different origins (for example, milk from a different species, soy, or eggs) and energy (lactose and fat) given to the calf, foal, or other animals to replace milk from the mother.
  • the powder form of the non-enteric proanthocyanidin polymer composition is provided in the form of individual dosages in packets, e.g., packaged dosage forms, wherein some number of individual packets are provided for use in a treatment regimen.
  • the number of individual doses that can be packaged and provided together is not intended to be limiting, and can include, for example, one to twenty packaged doses; one to ten packaged doses; two, four, six, eight, ten, or more packaged doses, as well as numbers of packaged doses in-between the foregoing, for efficiency of use, handling and for commercial efficacy.
  • SB 300 generally has about 67% by weight of the proanthocyanidin polymer composition while SP-303 has higher purity, for example 99-100%.
  • the non-enteric powder form of the proanthocyanidin polymer composition is provided in a container, such as a bag, box, bucket, or pail (e.g., 5 lb. to 25 lb. pails), in which the powder can be in an amount of, for example, 100 grams (g) or more, and can optionally include a measuring device, such as a scoop, cup, spoon, trowel, dipper, or ladle.
  • a container encompass, for example, an individual daily dose of the non-enteric proanthocyanidin polymer composition; or an amount suitable for multiple treatments, e.g., a two-day treatment, three-day treatment, four day treatment, etc.
  • An effective amount of the powder can also be mixed with feed for consumption by the young animals, e.g., calves, in need thereof.
  • Dosages may be 400 to 4000 mg per day. In preferred embodiments, the dosages are 1600 mg per day or, preferably, 3200 mg per day.
  • the non-enteric proanthocyanidin polymer composition is administered or delivered to a neonatal animal afflicted with diarrhea and in need thereof by providing the compound as a bolus.
  • the proanthocyanidin polymer composition formulated as bolus i.e., a pill, capsule, or tablet, is orally administered to the neonatal animals afflicted with diarrhea or symptoms thereof, e.g., calves, foals, lambs and kids, directly in the mouth.
  • the treatment regimen comprises administering a dose of 4-10 mg/kg or 4-8 mg/kg of the non-enteric product, or 8-24 mg/kg per dose, or 1600 mg per animal (foal) per dose, for a determined time period, for example, for one, two, or three or more days, preferably three days.
  • the product can be provided to an animal in need thereof in portions of the complete dose, in which the portions are administered one or two or more times per day.
  • the complete dose can be administered to an animal in need thereof one or two or more times per day.
  • the treatment encompasses a dose of 250 mg given two times a day.
  • the treatment encompasses an oral dose of 250 mg given two times a day for 3 days.
  • the dose is the Croton lechleri proanthocyanidin polymer composition, SB 300, in non-enteric form, e.g., a reconstituted, non-enteric powder form.
  • the proanthocyanidin polymer composition is in a non-enteric gel or gel formulation.
  • the gel is contained or preloaded in a delivery device, such as a syringe or other type of injector or delivery system, especially for oral delivery.
  • the gel comprises polymeric particles, such as microparticles or nanoparticles.
  • a gel formulation is particularly suited for administration to neonatal and young, unweaned foals, but also is applicable for other neonatal and unweaned young animals, such as those described herein.
  • the gel is not contained in a delivery device, but is administered to the roof of the mouth of the animal, particularly one that is too incapacitated or ill to eat or drink, thereby eschewing an oral or other mode of administration.
  • gels are prepared for oral delivery. Processes for generating granules and particles comprising the proanthocyanidin polymer composition or a compressible form thereof are as known and practiced in the art, and as provided, for example, in U.S. Patent No. 7,341,744, the contents of which are incorporated by reference herein.
  • the proanthocyanidin polymer composition is in a non- enteric paste formulation, preferably for oral administration.
  • an oral paste may comprise, without limitation, an oily vehicle or excipient, such as a hydrophobic oily vehicle, a basifying agent, a flavoring agent and a coloring agent.
  • hydrophobic oily vehicles include vegetable oil, triglyceride or polypropylene glycol, as well as a thickening agent, e.g., aluminum stearate.
  • Flavoring agents can include, for example, fruit flavors, mint flavors, honey flavor, and other natural and organic flavorings known to those skilled in the art.
  • Coloring agents can include, for example, iron oxide or titanium dioxide.
  • the oily vehicle can be liquid paraffin or other suitable waxes, including a thickening agent.
  • the non-enteric paste formulation contains SB 300 or SP 303, which is administered to an animal, such as a horse foal, at a dose of 4 mg/kg to 10 mg/ml, includes incremental mg/ml doses therebetween. More particularly, the non-enteric paste formulation containing SB 300 is administered to the foal at a dose of 4 mg/kg to 8 mg/kg, twice a day for three days. In an embodiment, the paste containing non-enteric protected SB 300 is administered twice a day at twelve hour intervals for greater than two days, such as for three days, or for four days, or longer, preferably three days.
  • administration can be via any suitable, convenient or preferred route of administration including oral, buccal, dental, periodontal, via food source (animal feed), nutrition source, or libation source, otic, inhalation, endocervical, intramuscular, subcutaneous, intradermal, intracranial, intralymphatic, intraocular, intraperitoneal, intrapleural, intrathecal, intratracheal, intrauterine, intravascular, intravenous, intravesical, intranasal, ophthalmic, biliary perfusion, cardiac perfusion, spinal, sublingual, topical, transdermal, intravaginal, rectal, ureteral, or urethral.
  • oral, buccal, and food and/or drink supplements are particularly suitable routes.
  • the product is an aqueous formulation and is provided to the animal as a drench or directly from a ready-to-use (RTU) bottle directed to the esophageal cavity so as to more effectively reach the animal's intestine/gut for optimal activity.
  • administration can also be by inclusion in the regular or special diet of the animal, such as in a functional food for the animals or companion animals.
  • Dosage forms can include, without limitation, oral, injectable, transdermal, aerosol including metered aerosol, chewable products or pellets, capsules, capsule containing coated particles, nanoparticles, or pellets, capsule containing delayed release particles, capsule containing extended release particles, concentrates, creams and augmented creams, suppository creams, discs, dressings, elixirs, emulsions, enemas, extended release films or fibers, gases, gels, metered gels, granules, delayed release granules, effervescent granules, implants, inhalants, injectable lipid complexes, injectable liposomes, inserts or devices, extended release inserts, intrauterine devices, jellys, liquids, extended release liquids, lotions, augmented lotions, oils, ointments, augmented ointments, pastes, pastilles, pellets, powders, reconstituted powders, extended release powders, metered powders, solutions,
  • the dosages can be provided as non-enteric formulations, compositions, pharmaceutically acceptable formulations and compositions, physiologically acceptable formulations and compositions, including pharmaceutically and physiologically acceptable carrier, excipients, diluents, or vehicles as known and used in the art.
  • the C. lechleri proanthocyanidin polymer product, or a non-enteric composition thereof is preferably encapsulated and formulated with suitable carriers, and the like, in solid dosage forms.
  • suitable carriers, excipients, diluents and vehicles include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, gelatin, syrup, methyl cellulose, methyl- and propylhydroxybenzoates, talc, magnesium, stearate, water, mineral oil, edible oils, and the like.
  • the formulations can also include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavoring agents.
  • the compositions can be formulated to provide rapid, sustained, extended, or delayed release of the active ingredient after administration to the animal by employing protocols and methods well known in the art.
  • the non-enteric formulations can also include compounds or substances that reduce proteolytic degradation and promote absorption such as, for example, surface active agents.
  • the specific dose can be calculated according to the approximate body weight, body mass, or body surface area of the animal, or the volume of body space or mass to be occupied. The dose also depends on the particular route of administration selected by the practitioner. Further refinement of the calculations necessary to determine an appropriate dosage for treatment is routinely made by those of ordinary skill in the art, for example, using appropriate assays and analytical procedures, such as has been described for certain compounds (e.g., Howitz et al., Nature, 425: 191-196, 2003). Exact dosages can be determined based on standard dose-response studies. Therapeutically effective doses for treatment of diarrhea-afflicted animals can be determined, by titrating the amount of the active product given to the animal to arrive at the desired therapeutic effect, while minimizing side effects.
  • a therapeutically acceptable form of the non-enteric C. lechleri proanthocyanidin polymer composition including a C. lechleri botanical extract, is administered, particularly orally administered, in an amount ranging from 0.1 to 100 mg/kg per day, once, twice or more daily.
  • the amount can range from about 0.1 to about 10 mg/kg, once, twice or more daily; or from about 0.1 to about 25 mg/kg, once, twice or more daily; or from about 0.1 to about 30 mg/kg, once, twice or more daily; or from about 0.1 to about 40 mg/kg, once, twice or more daily.
  • the daily dose can be 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 6 mg/kg, 7 mg/kg, 8 mg/kg, 9 mg/kg, 10 mg/kg, 14 mg/kg, 18 mg/kg, 20 mg/kg, etc., as well as incremental dose amounts in between, once, twice or more daily.
  • the amount can range from about 1 to about 10 mg/kg/day once, twice or more daily; or from about 1 to about 5 mg/kg/day, from about 1 to about 8 mg/kg/day, from about 1 to about 10 mg/kg/day, or from about 4 to about 8 mg/kg once, twice or more daily.
  • the amount of the non-enteric C. lechleri proanthocyanidin polymer composition for administration is 4 mg/kg to 8 mg/kg two times a day.
  • the 4 mg/kg to 8 mg/kg dose is administered twice a day for three days.
  • a non- enteric formulation of SB 300 in a paste is orally administered to a pre-weaned animal, e.g. a horse foal, at a dose of 8 mg/kg to 24 mg/kg per dose, or at a total daily dose of 17 mg/kg to 48 mg/kg, administered in two dose per day for three days.
  • the foregoing amounts of the non-enteric C. lechleri proanthocyanidin polymer composition are administered, for example, twice daily, three times daily, four times daily, or more than four times daily, rather than once per day.
  • Higher doses e.g., 15, 20, 25, 30, 35, 40, 45, 50, or 100 mg/kg per day or twice or more daily, may be required, as necessary, to treat diarrhea and accompanying dehydration in the neonatal and young animals.
  • a suitable dose for the non- enteric C. lechleri proanthocyanidin polymer product or composition may range from about 1 mg to about 2000 mg, either daily or multiple times per day, such as twice daily.
  • a suitable dose may range from about 10 mg to about 1800 mg, either daily or multiple times per day, particularly twice daily.
  • a suitable dose may be 1600 mg per animal twice daily.
  • a suitable dose may range from about 30 mg to about 800 mg, either daily or multiple times per day, particularly twice daily. It will be understood that the ranges include the lower and higher amounts specified, as well as amounts in between.
  • the doses administered multiple times per day can be given for consecutive days, e.g., two days, three days, four days, five days, six, days, seven days, or more, in some embodiments.
  • a dose administered multiple times per day may embrace two, three, four, five, six, or more times per day.
  • Other dosing schedules such as every other day, or every third day, every fourth day, etc. are embraced by the invention.
  • doses and amounts administered to the animal can vary, given the wide range of weights of the animals undergoing treatment, as well as the animal species and type of digestive system, e.g., ruminant or non-ruminant.
  • the C. lechleri proanthocyanidin polymer is SB 300 in a non-enteric form.
  • daily doses including multiple daily doses, e.g., twice or three times a day, of the non-enteric C. lechleri proanthocyanidin polymer product may be 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg., 100 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 500 mg (or mg amounts in between) per animal. Administration schedules may also be altered to achieve a therapeutically effective concentration of the C. lechleri proanthocyanidin polymer in non-enteric form to treat the diarrhea and its symptoms as described herein.
  • a suitable dosage amount for use in the methods according to the invention is 1600 mg administered once or twice daily.
  • the compound may be administered once per day, twice per day, 3 times per day, 4 times per day, 5 times per day, 7 times per day or 10 times per day.
  • the dosage is divided into equal parts administered throughout the day, however in some embodiments related to treating more severe or entrenched symptoms, it may be useful to tailor the dosage administration schedule so that most of the daily treatment is administered at a predetermined time of the day, e.g., the beginning half of the day. In some embodiments, about 50% 60%), 70%) or 80%> of the dosage is administered in the first half of the day. In other embodiments, it may be more appropriate to administer most of the dosage in the latter half of the day so that about 50%, 60%>, 70% or 80%> of the dosage is administered in the latter half of the day.
  • the dose amount actually administered can be determined by the practitioner, in the light of the relevant circumstances, including the severity of the disease, condition, or symptoms thereof being treated, the form of the product to be administered, the age, weight, and response of the individual animal receiving treatment, as well as the chosen route of administration.
  • the methods of the invention further embrace the administration of pharmaceutically acceptable non-enteric formulations of the proanthocyanidin polymer composition either alone or in combination with other supplements or agents for treatment or amelioration of the symptoms of secretory diarrhea, such as rehydration agents, electrolytes (e.g., sodium, potassium, magnesium, chloride and formulations thereof), antibiotics, gut-lining protectants, such as kaolin, pectin, or bismuth liquid, and fluid adsorbents, such as attapulgite.
  • pharmaceutically acceptable non-enteric formulations of the proanthocyanidin polymer composition either alone or in combination with other supplements or agents for treatment or amelioration of the symptoms of secretory diarrhea, such as rehydration agents, electrolytes (e.g., sodium, potassium, magnesium, chloride and formulations thereof), antibiotics, gut-lining protectants, such as kaolin, pectin, or bismuth liquid, and fluid adsorbents, such as attapulgite.
  • electrolytes e.
  • Other agents may include anti-motility agents, although because many of the microorganisms and pathogens that are associated with diarrhea induction in neonatal and young animals concomitantly decrease gut motility, the use of anti-motility drugs may be contraindicated.
  • Natural biological products e.g., Lactobacillus, Bifidobacterium, or Streptococcus faecium, other bacteria and yeast microorganisms, or other probiotics, may also be employed as additives to restore the natural balance of intestinal flora in the affected neonatal animals.
  • Such natural biological products, e.g., probiotics as known in the art are commercially available and may be administered in conjunction with the non-enteric C.
  • lechleri proanthocyanidin polymer or composition thereof for example, prior to, at the same time as, or after the administration of the non-enteric proanthocyanidin polymer or composition to a non-human animal.
  • a reconstituted C. lechleri proanthocyanidin polymer or composition, without enteric coating, thereof may include probiotics in accordance with the present invention.
  • the invention provides the use of a non-enteric composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri or a botanical extract thereof in treating diarrhea in a pre-weaned non-human animal, wherein the composition is formulated as a non-enterically coated, pharmaceutically acceptable bolus or reconstituted powder and is orally administered to the pre-weaned non-human animal in an amount of 4 mg/kg to 10 mg/kg per day, preferably in an amount of 4 mg/kg to 8 mg/kg, twice a day for two or more consecutive days, preferably for three days.
  • the non-enteric product is orally administered in an amount of 4 mg/kg to 10 mg/kg per dose, preferably in an amount of 4 mg/kg to 8 mg/kg, four times a day for two or more consecutive days, preferably for three days.
  • the non-enteric product, such as non-enteric SB 300 is orally administered in an amount of 8 mg/kg to 24 mg/kg per dose per foal.
  • the non-enteric product, such as non-enteric SB 300 is orally administered in a daily dose of 17 mg/kg to 48 mg/kg (BID).
  • the pre-weaned animal is selected from the group consisting of a bovine calf, a camel calf, a buffalo calf, a bison calf, a lamb, a kid, a foal and a piglet.
  • the pre-weaned animal is an equine foal.
  • the pre-weaned animal is characterized as being one or more of: less than three months of age; 8 days to 3 months of age; and/or approximately 35 to 200 kg in weight.
  • the pre-weaned animal is preferably on a primarily or solely milk or mild replacer based diet. In other embodiments, the C.
  • lechleri proanthocyanidin polymer composition is orally administered in a non-enteric coated form (i) as a powder reconstituted with oral electrolytes, milk or a milk substitute, physiological saline, or water; (ii) as a bolus; or (iii) as a paste.
  • the non-enteric C. lechleri proanthocyanidin polymer composition is administered for at least three consecutive days.
  • the non-enteric C. lechleri proanthocyanidin polymer composition is administered twice daily for at least three consecutive days.
  • the non-enteric composition is administered to the pre- weaned animal in an amount of 500 mg to 1800 mg, or in an amount of 800 mg to 1600 mg, per dose.
  • the invention further provides the use of a composition comprising a non-enteric aqueous soluble proanthocyanidin polymer from Croton lechleri, or a latex or botanical extract form thereof, in treating or preventing diarrhea in a pre- weaned equine foal, wherein the composition is formulated as a non-enteric, pharmaceutically acceptable paste and is orally administered to the foal in an amount of 4 mg/kg to 8 mg/kg per day two times per day for three consecutive days.
  • the non-enteric product such as non-enteric SB 300
  • the paste is administered two times a day, twelve hours apart, for three consecutive days.
  • the paste is contained in a delivery device, which is optionally a syringe.
  • oral administration comprises applying the paste to the roof of the foal's mouth.
  • the non-enteric composition comprising the C. lechleri proanthocyanidin polymer is SB 300, SP 303, or crofelemer.
  • the non-enteric composition comprising the C. lechleri proanthocyanidin polymer is a non-enteric SB 300 product.
  • the pre-weaned animal is administered 4 mg/kg omeprazole, once daily.
  • the pre-weaned foal responds to treatment with the non-enteric pharmaceutical composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri as determined by a fecal score of 1 or 2 within about 48 hours following oral administration of the non-enteric composition.
  • about 65% of pre-weaned foals treated with the non-enteric pharmaceutical composition comprising an aqueous soluble proanthocyanidin polymer from Croton lechleri respond to treatment within about 48 hours following oral administration compared with foals treated with a placebo, which is absent the non-enteric composition comprising an aqueous soluble Croton lechleri-derived proanthocyanidin polymer.
  • a successful treatment response refers to the animals' having a fecal score of 1 or 2 at the time of analysis or assessment.
  • This Example describes the results of a study in accordance with the present invention in which a non-enteric paste formulation containing SB 300 was administered to young, pre-weaned equine foals as an anti-secretory product for the treatment of diarrheal disease.
  • the study was conducted to assess the safety, tolerability, and efficacy of a non-enteric- coated form of SB 300, with no added probiotic, to treat watery/secretory diarrhea in the foals.
  • the non-enteric product called EONORM TM FOAL, comprises SB 300, a standardized botanical extract derived from the Croton lechleri tree, which is sustainably harvested.
  • Diarrhea in young equines is very common and there are many causative agents and conditions (e.g., viral, bacterial, protozoa, drugs and toxins) that manifest clinical signs of watery diarrhea (secretory) in the foals. These agents and conditions trigger the pathophysiological mechanisms of secretory diarrhea caused by abnormal ion transport in intestinal epithelial cells. The presence of such abnormal mediators result in changes in intracellular cyclic adenosine monophosphate (cAMP), cyclic guanosine monophosphate (cGMP) calcium and/or protein kinases, which, in turn, cause an increase in chloride secretion. Water follows the chloride ions.
  • Secretory diarrhea in afflicted foals is due to abnormal stimulation of the intestinal epithelium with a concomitant increase in the rate of intestinal secretion that overwhelms the absorptive capacity. Study animals, treatments and procedures
  • This six-day, multi-site study involved 20 foals, aged between 8 days and 3 months, suffering from secretory or watery diarrhea, all of which were placed into one treatment group.
  • the foals ranged from 70 kg to 200 kg in weight.
  • non-enteric-coated paste formulation of EONORM TM FOAL was administered orally to the foals, twice daily for six treatments at 4-8 mg/kg per foal (BID x 3 days).
  • the non-enteric SB 300 active (investigational veterinary product or IVP) was orally administered in an amount of 8 mg/kg-24 mg/kg per dose; or a daily dose of 17 mg/kg-48 mg/kg (BID); i.e., in an amount of 1600 mg per foal per dose.
  • the treatment period was followed by a 72-hour (3 day) observation period.
  • the animals were also administered approximately 4 mg/kg omeprazole, once daily. Fecal scoring was conducted every six hours during both the treatment and observation periods. The study took place in Argentina during foaling season.
  • the inclusion criteria for animal subjects to be treated included the following: (i) pre-weaned foals between birth and 16 weeks of age; (ii) baseline fecal scores of 3 or 4 (described further below); and (iii) male or female foals of any breed.
  • the exclusion criteria for the study were as follows: (i) foals suffering from non-gastrointestinal disease or unsuitable to be enrolled in the study in the opinion of the Investigator; (ii) foals > 16 weeks of age; (iii) fecal Score of ⁇ 3 or >4; (iv) weaned foals; (v) uncomplicated (absence of fever, or other clinical signs or otherwise healthy) foal heat diarrhea; (vi) treatment with oral anti-diarrheals within 7 days of the first dose administration; (vii) orphaned foals; and (viii) foals with hemorrhagic diarrhea.
  • Medications prohibited for the study included probiotics, oral electrolytes (IV fluids allowed), oral anti-diarrheal treatments (within 7 days of the first dose administration and while on study).
  • a representative paste composition of the present invention which comprises the active SB 300 in a non-enteric coated form, exemplifies the paste used in this example.
  • the non-enteric SB 300 paste composition was contained in a syringe.
  • the paste formulation containing non-enteric SB 300 for use in the study contains the following components: Component % w/w g/syringe
  • Titanium dioxide 1.10 0.7
  • a fecal score of 1 or 2 was indicative of a responder subject and resolution of diarrhea in the subject.
  • a fecal score of 3, 4, or 5 was indicative of diarrhea.
  • a clinical responder was any animal (foal) that developed formed stool or had no stool (Fecal Score of ⁇ 3), and maintained formed stool or no stool (i.e., no Fecal Score of 4, 5 or 6) for a minimum of 16 consecutive hours within a 24 hour time period during the 72-hour Treatment Period (T 0h r - T 72h r)- Resolution of diarrhea was defined as a Fecal Score of ⁇ 3 (formed stool) at any post-baseline assessment.
  • Descriptive statistics (number of subjects, mean, standard deviation, minimum, median and maximum values) were presented for continuous variables by treatment group and time point. For categorical parameters, the number and percentage per category were presented for each treatment group.
  • the models included fixed terms for treatment group, time point, treatment group by time point interaction with site and treatment group by site interaction as random effects.
  • the baseline value is included in the model as a covariate.
  • the mean value for each 24 hour treatment block was plotted by treatment group.
  • TLUS was calculated from the date of the first dose to the last time of an unformed stool score (3, 4 or 5). Animals not achieving a formed stool / fecal score of 1 or 2 were censored to the time of the last evaluation. The log-rank test was utilized to compare treatment groups. The 25 th quartile, mean time, median time and 75 th quartile were presented, if available.
  • SB 300 paste formulation (Non-enteric, Active BID) within the first 24 hours of the treatment period, with a p-value of 0.7013. (FIG. 2, 0-24 h).
  • resolution of diarrhea was defined as a foal that produced a formed stool (fecal score of 1 or 2) at any point during the reported period.
  • resolution of diarrhea was attained in 65% of foals treated with the non-enteric SB 300 paste formulation (Non-enteric, Active BID), with a p-value of 0.0202. (FIG. 2, 0-48 h).
  • the placebo comparator comprised a paste formulation without SB 300 and without other components such as probiotics; the placebo was administered QID in an amount of 6 mg/kg to 17 mg/kg per dose to pre-weaned foals.
  • the study results demonstrate that a non-enteric formulation of SB 300, a C. lechleri derived botanical extract, showed efficacy in resolving diarrhea and successfully treated diarrhea in foals, based on the fecal score and response analyses.
  • the non-enteric SB 300 product resulted in a higher percentage of treated foals having a fecal score of 1 or 2 (Responders) compared with the percentage of foals treated with placebo in the 0-48 h time period of the study. This trend of higher percentages of non-enteric SB 300 product-treated foals showing response and resolution of diarrhea compared with placebo-treated foals continued to the end of the study and during the observation periods.
  • results indicate that the non-enteric coated product administered to foals evades destruction in the stomach of the treated animals and reaches the active site to reduce diarrhea and improve fecal scores in the treated animals.
  • 85% of the foals treated with non-enteric SB 300 had responded to treatment and had resolution of diarrhea.
  • non-enteric SB 300 paste formulation was not inferior compared with an enteric form of the active, i.e., an enteric coated SB 300 paste formulation, in treating and resolving diarrhea in pre- weaned foals.
  • the active enteric SB 300 comparator was administered BID in an amount of 6 mg/kg to 17 mg/kg per dose, or a daily dose of 11 mg/kg to 32 mg/kg to pre-weaned foals (800 mg per dose per foal); the foals receiving enteric SB 300 generally weighed less than the foals receiving non-enteric SB 300. Therefore, the doses of enteric coated SB 300 were adjusted according to the body weight of the foals treated with the enteric active.

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Abstract

L'invention concerne des méthodes de traitement d'animaux non humains nouveau-nés et jeunes, particulièrement des animaux avant le sevrage, atteints de diarrhée et/ou de symptômes associés, lesdites méthodes consistant à administrer à un animal en ayant besoin une composition à base de polymères de proanthocyanidine isolée à partir d'une plante de l'espèce Croton ou Calophyllum en l'absence d'un enrobage entérique. En particulier, les animaux avant sevrage, nouveau-nés et jeunes comprennent des poulains, qui souffrent fréquemment de diarrhée de diverses étiologies, et la composition de polymère de proanthocyanidine administrée est isolée de Croton lechleri et se présente sous forme non gastro-résistante. La composition gastro-résistante peut se présenter sous forme soluble aqueuse et peut être administrée par voie orale aux animaux nouveau-nés et jeunes touchés.
PCT/US2016/066083 2015-12-16 2016-12-12 Méthodes de traitement de la diarrhée chez des animaux non humains avant le sevrage, nouveau-nés et jeunes WO2017106074A1 (fr)

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Publication number Priority date Publication date Assignee Title
EP3772984B1 (fr) * 2018-03-29 2022-02-16 FARM@NUTRITION, besloten vennootschap met beperkte aansprakelijkheid Composition d'additif alimentaire pour animaux et procédé pour administrer l'additif

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015184111A1 (fr) * 2014-05-29 2015-12-03 Jaguar Animal Health, Inc. Procédés de traitement de la diarrhée induite par la salmonelle chez les primates non humains
WO2015184101A1 (fr) * 2014-05-29 2015-12-03 Jaguar Animal Health, Inc. Méthodes de traitement de la diarrhée chez des animaux non humains nouveau-nés et jeunes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015184111A1 (fr) * 2014-05-29 2015-12-03 Jaguar Animal Health, Inc. Procédés de traitement de la diarrhée induite par la salmonelle chez les primates non humains
WO2015184101A1 (fr) * 2014-05-29 2015-12-03 Jaguar Animal Health, Inc. Méthodes de traitement de la diarrhée chez des animaux non humains nouveau-nés et jeunes

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3772984B1 (fr) * 2018-03-29 2022-02-16 FARM@NUTRITION, besloten vennootschap met beperkte aansprakelijkheid Composition d'additif alimentaire pour animaux et procédé pour administrer l'additif

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