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WO1994021284A1 - Formulation et methode therapeutiques - Google Patents

Formulation et methode therapeutiques Download PDF

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Publication number
WO1994021284A1
WO1994021284A1 PCT/AU1994/000121 AU9400121W WO9421284A1 WO 1994021284 A1 WO1994021284 A1 WO 1994021284A1 AU 9400121 W AU9400121 W AU 9400121W WO 9421284 A1 WO9421284 A1 WO 9421284A1
Authority
WO
WIPO (PCT)
Prior art keywords
antibody
treatment
gastrointestinal disease
proteolytic enzyme
animal
Prior art date
Application number
PCT/AU1994/000121
Other languages
English (en)
Inventor
David Spencer Chandler
Benjamin John Reed
Original Assignee
Pharma Pacific Pty. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Pharma Pacific Pty. Ltd. filed Critical Pharma Pacific Pty. Ltd.
Priority to JP6520414A priority Critical patent/JPH08509965A/ja
Priority to EP94910286A priority patent/EP0706400A1/fr
Priority to AU62787/94A priority patent/AU673589B2/en
Publication of WO1994021284A1 publication Critical patent/WO1994021284A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A61K35/744—Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
    • A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/40—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum bacterial
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals

Definitions

  • This invention relates to a method and composition for treatment or prevention of gastrointestinal disease, particularly in neonatal mammals.
  • Gastrointestinal disease is a significant cause of morbidity and mortality in humans and in domestic animals, particularly in the first few weeks of life.
  • a high proportion of hospital admissions of babies results from gastrointestinal infection, which leads to rapid dehydration, and may prove fatal.
  • gastrointestinal infection spreads extremely rapidly, and results in failure to thrive, often leading to death. The effects of these conditions are particularly devastating in the production of pigs and poultry.
  • a protease preparation has been marketed under the trade name "DETACH” by Ciba-Geigy.
  • rotavirus diarrhoea In the case of rotavirus diarrhoea, it is known that the most important protective factor is the presence of specific antibody in the lumen of the small intestine. Protection against rotavirus diarrhoea can be achieved by oral administration of IgG, whether the IgG is homologous or heterologous (Snodgrass D.R. et al, Infect. Immun., 1977 16 268-270; Barnes, G.L. et al, Lancet 1982 1 1371-1373). However, it appeared from these references that it was necessary that the IgG should be purified, or should be present in colostrum rather than in milk.
  • cows that had been immunised with inactive bovine rotavirus conferred passive antibody to their calves via colostrum (Mebus, CA. et al, J. Am. Vet. Med. Assoc, 1973 163 880-883). It was subse ⁇ piently shown that oral administration of bovine colostrum from immunized cows to human infants was effective in protection against rotavirus diarrhoea, (Hilpert H. et al, J. Infect. Dis., 1987 156 158-166; Davidson G.P. et al, Lancet 23 September 1989 709- 712) .
  • Intact colostral antibody has been found efficacious in treatment of Helicobacter pylori infections, which may be associated with gastritis and peptic ulcer disease.
  • J ⁇ e2ico.bacter pylori was formerly known as Campylobacter pylori .
  • This method is the subject of Australian Patent Application Number 80207/91 by Abbott Laboratories, entitled “Method for the treatment of gastric disease", the entire disclosure of which is herein incorporated by reference. Efficacy in this instance was obtained by regular ingestion of intact colostral whey antibody.
  • This specification describes in detail methods for immunisation with Heli ⁇ oJa ⁇ ter pylori, and methods for isolation and concentration of specific antibodies from mammary secretions, including milk and colostral whey, of animals immunised with Helicobacter pylori, and in particular bovine colostrial whey.
  • the Fc region is involved in binding to certain host cell surfaces, usually after conformational changes in the molecule which occur following antigen binding, and in the binding of complement. Fc binding initiates a number of downstream immunological reactions which are ultimately directed towards removal of the antigen from the host body.
  • Fc receptors which bind free Fc regions.
  • the presence of microbial Fc receptors on the cell surface is correlated with pathogenicity and virulence, and also with suppression of the host immune response (Widders, P.R.; Bacterial Immunoglobulin-Binding Proteins, Vol. 1 (Academic Press) 1990 Pages 375-395).
  • the Fc receptors may remain fixed on the microbial surface, or may be sloughed to become "soluble" Fc receptors.
  • the Fc portion of IgM which is a pentamer of the Y-shaped basic units, has been demonstrated to enhance clearance of E. coli strain 055 in new born, pre-colostral piglets (Zikan, J. and Miler, I., Immunochemistry 1975 _12_ 813-815) . Although the presence of Fc receptors was not detected on these bacteria, Fab fragments obtained by pepsin digestion of IgM retained the complement-associated bactericidal activity of the parent molecule, while the Fc fragment retained the ability of the parent molecule to clear E. coli by opsonisation.
  • an improved response may be obtained by combining administration of protease-treated antibody in order to prevent or alleviate gastrointestinal disease.
  • Administration of protease- treated antibody, or protease together with antibody enables each component to exert its separate effects, and also ensures that at least a portion of the specific antibody is affected. This is particularly beneficial in neonates, where gastric and intestinal proteolytic activity is low because of developmental immaturity, (Moughan P.J. et al, In. Nutritional Triggers for Health and in Disease; Simopoulos A.P. (ED) Worlds Rev. Nutr. Diet. Basel, Karger, 67 40-113) and in adults, where gastric stasis may interfere with the maintenance of integrity of ingested antibody.
  • the present invention proposes that an exogenous culture of these organisms, if administered concurrently with the protease-treated antibody, would have an improved chance of colonisation.
  • Cultures of lactobacilli and streptococci are currently used commercially, with limited success, to control diarrhoeal diseases in piglets and other species. These cultures are called probiotics.
  • the main problem with the therapeutic function of probiotics is the difficulty in establishing these strains in the GIT (Cain, C.,1988. Observations of indigenous and non-indigenous lactic acid bacteria as potential probiotic organisms in pigs. Masters Thesis, School of Agriculture, La Trobe University) .
  • the present invention provides a means of improving the likelihood of improving the colonisation of the intestinal tract by probiotic strains, thereby extending the period of disease protection offered by the oral administration of antibody. It is proposed that the use of pepsin-digested antibody in neonates, or undigested antibody in older individuals together with probiotics, may be used to treat both gastric and intestinal infections. The combination of antibody and an appropriate probiotic would greatly reduce the requirement for continuous antibody therapy.
  • the invention therefore provides in one aspect a method of treatment or prevention of gastrointestinal disease in an animal, comprising the step of administration to a mammal in need of such treatment of an effective amount of an antibody which has been pretreated with an appropriate proteolytic enzyme, or of a proteolytic enzyme together with an effective amount of an antibody.
  • the invention is applicable to the treatment of a wide variety of animals, including pigs, cattle, sheep, horses, poultry and humans. It is particularly suitable for the treatment of neonatal animals and humans.
  • the causative organisms of the gastrointestinal disease which may be treated or prevented include, but are not limited to, Helicobacter pylori, Escherichia coli, and rotavirus.
  • the antibody suitable for use in the invention does not have to be purified, and may be derived from immune serum or colostrum, or from yolks of eggs of immunized poultry, or may be a monoclonal antibody or a bioengineered antibody. The only requirement is for antibody specificity against the pathogenic agent. Colostrum from immunised dairy animals, such as cows, sheep or goats, is especially convenient for use in the invention.
  • the antibody may be IgG, IgA or IgM, but is preferably IgG x , and is most preferably bovine IgG ⁇ If the antibody is derived from egg yolk it is preferably Ig ⁇ .
  • Proteolytic enzymes which are suitable for use in the invention include, but are not limited to, pepsin, papain, bromelain, fungal proteases, and trypsin.
  • Pepsin is preferred, because it is easy to control the digestion (cleavage) reaction, and because it is cheap and robust.
  • the concentration of the proteolytic enzyme should not be so high, or the digestion so prolonged, that the antibody is totally degraded; the person skilled in the art will be able to determine a suitable concentration by normal trial and error experimentation.
  • the invention provides a method of treatment or prevention of gastrointestinal disease in an animal, comprising the step of administering to an animal in need of such treatment an effective amount of an antibody which has been pretreated with a proteolytic enzyme, or of a proteolytic enzyme together with an effective amount of an antibody, in conjunction with a probiotic organism.
  • the probiotic organism is suitably an organism indigenous to the species of animal to be treated, although it may be a non-indigenous member of the mucosal flora of healthy individuals of that species.
  • the probiotic organism is a IiactoJa ⁇ illus or Streptococcus. A mixture of two or more probiotic organisms may be used.
  • the method of the invention may be used in conjunction with other treatments, such as antibiotic treatment.
  • further protease may be administered separately, in order to influence mucosal properties which favour chemical interactions between a pathogenic organism and the host.
  • proteolytic enzyme and "protease” are to be taken to be synonymous.
  • the invention is specifically described with reference to gastrointestinal disease, it will be clearly understood that the invention is applicable to the treatment or prevention of disease at other sites which is caused by organisms from the gastrointestinal tract of the animal suffering the disease.
  • the antibody and the protease may have to be delivered separately.
  • the methods of the invention are suitable for treatment of immunocompromised patients or patients particularly prone to infection, such as patients with AIDS-related complex or AIDS, or patients suffering rom extensive burns or scalds, or for the treatment of patients suffering from gastrointestinal malabsorption syndromes.
  • the methods of the invention are also suitable for treatment of patients receiving H 2 -receptor antagonists such as Tagamet, which inhibit acid secretion in the stomach, and have diarrhoea as a frequent side-effect.
  • the invention provides a composition for treatment or prevention of gastrointestinal disease in an animal, comprising either a) an effective amount of an antibody which has been pretreated with a proteolytic enzyme or b) a proteolytic enzyme together with an effective amount of antibody, and optionally a probiotic organism, together with a pharmaceutically-acceptable carrier.
  • the formulation provides a two-part liquid format, in which the protease is enteric coated or buffered, and is suspended in a buffered liquid excipient either separately or together with the antibody.
  • the formulation may comprise a multilayer tablet, optionally enteric coated, in which the enzyme forms the innermost layer and antibody forms an outer layer, preferably isolated from the enzyme.
  • Conventional fillers, granulating agents, and excipients may be present. Variations will be obvious to the person skilled in the art.
  • the invention also provides formulations for use in the aforesaid method. Individual formulations will depend upon the antibody and protease type, and can be devised using known formulation principles and normal trial-and-error experimentation.
  • Piglets in the colostrum replacer group received ReSus (Nufarm Animal Health Pty Ltd) .
  • ReSus is a commercial colostrum replacer containing hyperimmune bovine colostrum from cows immunised against E. coli of types which infect piglets, using a polyvalent whole cell and pilus vaccine.
  • Piglets in the second treatment group received bovine colostral antibody from the same bulk batch of colostrum, but in this case the antibody had been removed from the base colostrum by fat removal and acid casein precipitation.
  • the antibody was then further purified by (NH 4 ) 2 S0 4 precipitation and exhaustive dialysis against distilled water, until no precipitate was evident when the antibody containing solution was added to a BaCl 2 solution.
  • Peptic digestion of the antibody for use with piglets in the third treatment group was conducted at 37°C overnight, using commercial pepsin in the ratio of one part pepsin to fifty parts antibody (Fang, W.D. and Mukkur, T.K.S., Biochem. J., 1976 155 25) . All antibody-containing treatments were adjusted prior to use to have the same titre of blocking activity (equivalent to that found in ReSus) when tested in an ELISA blocking assay. This assay consisted of K88 + E.
  • a fourth (control) group of piglets was given the same volume of commercial milk replacer containing no anti-K88 antibody, according to the same regimen as piglets given the antibiotic treatments.
  • Treatments were given by oro-gastric tube.
  • Commercial milk replacer, at manufacturer's recommended quantity for neonatal piglets, and bacterial challenge doses were also given by oro-gastric tube.
  • Piglets born to three sows were taken at birth, before they had a chance to suckle.
  • the piglets were immediately weighed, ranked by weight and randomly distributed into four weight-matched treatment groups. Piglets were identified individually and by treatment group using individually numbered coloured eartags. They were then allocated randomly to heated cages in approximately weight-matched pairs. At about two hours after birth the piglets were given their first treatment dose, followed thirty minutes later by a bacterial challenge dose, consisting of 10 10 haemolytic K88 + E. coli, strain WG,
  • the TSA was used to assess total bacterial count. Rogosa and TSA counts were similar when incubated aerobically or anaerobically. Lactobacilli numbers were estimated from anaerobically incubated plates. Total counts were estimated from aerobically incubated plates. Statistical Analysis
  • Streptococci and lactobacilli are bacterial populations of the GIT that are generally associated with good health. Counts of these bacteria were higher in all piglets receiving antibody treatments. Table 1 indicates that the purified antibody counts were not significantly improved over commercial colostrum replacer, although there were trends within the results for both lower pathogen counts and higher "desirable flora" counts overall within the GIT, particularly in piglets receiving pepsin-digested antibody.
  • Values marked a and b are not significantly different from any other values marked a or b respectively, and those marked a or b are not significantly different from those marked ab.
  • Table 2 Means of log transformed bacterial count ratios over all GIT sites.
  • LSD 5% is the least significant difference at the 5% confidence level.
  • a formulation according to the invention comprises a capsule shell, containing two types of microcapsules: a) a protease selected from bro elain, pepsin or papain, together with binder agents, present as cores about 750 microns in diameter, and coated with an enteric coating agent; b) antibody such as bovine IgG, in a preferably non-protein base microencapsulated with bovine colostrum; the microcapsules should have a core size of not more than 250 microns.
  • Suitable agents include starch, carboxymethyl cellulose, povidone, lactose and dextrose.
  • Suitable enteric coating agents include cellulose acetate phthalate, with a suitable film softening agent such as triacetin or glycerine.
  • the microspheres are formed using a standard device such as a Rota-processor (Acromatic A.G.) and then the protease microspheres may be coated using an Ultra Coater (Acromatic A.G.).
  • antibody microspheres may be formed in a Rota-processor and the coating of bovine colostrum may be applied by top spray coating.
  • Microcapsules prepared as in this example may be formulated as a tablet in a starch base.
  • Three alternative tablet formations are as follows: a) a core of bromelain, together with starch filler is coated with cellulose acetate phthalate, then with a layer of antibody together with colostrum and egg albumin. b) a core of bromelain, antibody, starch and egg albumin is coated with a layer of colostrum, and then with a layer of cellulose acetate phthalate. c) a core of bromelain, antibody, starch and egg albumin is coated with cellulose acetate phthalate and then with an outer layer of colostrum. EXAMPLE 4
  • the bromelain and antibody may be replaced by antibody which has been pre-treated with a proteolytic enzyme. It will be clearly understood that the invention in its general aspects is not limited to the specific details referred to hereinabove.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Mycology (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Virology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une méthode de traitement ou de prévention d'affections gastro-intestinaux chez un animal. Ladite méthode consiste à administrer à un animal ayant besoin de ce type de traitement une dose efficace d'un anticorps ayant été préalablement prétraité avec un enzyme protéolytique, ou d'un enzyme protéolytique combiné avec une dose efficace d'un anticorps, éventuellement en combinaison avec un organisme probiotique, l'anticorps étant spécifiquement dirigé contre un organisme capable d'induire une affection gastro-intestinale. Ledit anticorps est, de préférence, dérivé du colostrum. L'invention porte également sur des compositions destinées à être utilisées dans ladite méthode.
PCT/AU1994/000121 1993-03-15 1994-03-15 Formulation et methode therapeutiques WO1994021284A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6520414A JPH08509965A (ja) 1993-03-15 1994-03-15 治療剤および治療方法
EP94910286A EP0706400A1 (fr) 1993-03-15 1994-03-15 Formulation et methode therapeutiques
AU62787/94A AU673589B2 (en) 1993-03-15 1994-03-15 Therapeutic formulation and method

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
AUPL7821 1993-03-15
AUPL782193 1993-03-15

Publications (1)

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WO1994021284A1 true WO1994021284A1 (fr) 1994-09-29

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PCT/AU1994/000121 WO1994021284A1 (fr) 1993-03-15 1994-03-15 Formulation et methode therapeutiques

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EP (1) EP0706400A1 (fr)
JP (1) JPH08509965A (fr)
WO (1) WO1994021284A1 (fr)

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997037636A1 (fr) * 1996-04-03 1997-10-16 Elias Hakalehto Lutte contre des microbes nocifs: therapie et prevention
WO1998003081A1 (fr) * 1996-07-22 1998-01-29 Wisconsin Alumni Research Foundation Procede d'amelioration de la croissance d'un animal ou de l'indice de conversion des aliments chez un animal et compositions utilisees selon ce procede
WO1998043610A1 (fr) * 1997-04-03 1998-10-08 Elias Hakalehto Procede de production de produits sucres contenant de la gelee
EP0873755A1 (fr) * 1997-04-23 1998-10-28 Ghen Corporation Prévention et traitement d'infections par les bactéries E.Coli entérohémorrhagique
EP0877032A1 (fr) * 1997-04-11 1998-11-11 Ghen Corporation Anticorps spécifiques pour l'utilisation dans la préparation de compositions pharmaceutiques utiles pour la prévention ou le traitement de gastrites, d'ulcères gastriques et d'ulcères duodénaux
WO1998040474A3 (fr) * 1997-03-12 1999-02-11 Immuno Ag Facteur sanguin active dependant de la vitamine k et procede de preparation dudit facteur
EP0914831A3 (fr) * 1997-11-04 1999-06-30 Medipharm CZ, s.r.o. Produit biologique pour l'administration orale préventive ou thérapeutique contre le parvovirose canin
EP0930316A1 (fr) * 1998-01-19 1999-07-21 Medipharm CZ, s.r.o. Produit oral pour la prévention et le traitement des gastroentérites infectieuses des veaux
EP0725789A4 (fr) * 1993-09-20 1999-07-28 Anadis Ltd Procede d'extraction d'immunoglobulines du colostrum et emploi de ces dernieres dans des preparations pharmaceutiques
EP0955061A1 (fr) * 1998-03-20 1999-11-10 Medipharm CZ, s.r.o. Produit oral pour la prévention et la thérapie des infections gastrointériques porcines
EP1100950A4 (fr) * 1998-07-30 2002-10-16 Wisconsin Alumni Res Found Usines d'anticorps bacteriens gastro-intestinaux
WO2003041512A1 (fr) * 2001-11-12 2003-05-22 Mars, Incorporated Denree alimentaire
WO2005016383A1 (fr) * 2003-08-14 2005-02-24 Merial Limited Compositions et vaccins contenant un(des) antigene(s) de cryptosporidium parvum et d'un autre pathogene
WO2005005481A3 (fr) * 2003-07-10 2005-04-28 Avitek Pharma Inc Therapie combinatoire pour maladies gastro-enteriques provoquees par des micro-organismes
EP1552848A4 (fr) * 2002-06-28 2006-02-08 Gen Corp Kk Compositions dirigees contre la coccidiose du poulet
US7785635B1 (en) 2003-12-19 2010-08-31 The Procter & Gamble Company Methods of use of probiotic lactobacilli for companion animals
US7906112B2 (en) 2003-12-19 2011-03-15 The Procter & Gamble Company Canine probiotic Lactobacilli
US7998473B2 (en) 2003-12-19 2011-08-16 The Procter & Gamble Company Methods of treatment or prevention of gastrointestinal disorders using canine probiotic bifidobacterium
US8034601B2 (en) 2005-05-31 2011-10-11 The Procter & Gamble Company Feline probiotic bifidobacteria
US20120177650A1 (en) * 2009-09-23 2012-07-12 Borody Thomas J Therapy for enteric infections
US8563522B2 (en) 1997-07-08 2013-10-22 The Iams Company Method of maintaining and/or attenuating a decline in quality of life
US8809035B2 (en) 2003-12-19 2014-08-19 The Iams Company Canine probiotic Bifidobacterium
US8877178B2 (en) 2003-12-19 2014-11-04 The Iams Company Methods of use of probiotic bifidobacteria for companion animals
US9192177B2 (en) 2005-05-31 2015-11-24 The Iams Company Feline probiotic Lactobacilli
US9415083B2 (en) 2004-05-10 2016-08-16 Mars, Incorporated Method for decreasing inflammation and stress in a mammal
US9771199B2 (en) 2008-07-07 2017-09-26 Mars, Incorporated Probiotic supplement, process for making, and packaging
US10104903B2 (en) 2009-07-31 2018-10-23 Mars, Incorporated Animal food and its appearance

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JPH021553A (ja) * 1988-02-19 1990-01-05 Fuji Yakuhin Kogyo Kk ヒトｉｖ型コラーゲンのサンドイッチ酵素免疫学的定量法
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JPH021553A (ja) * 1988-02-19 1990-01-05 Fuji Yakuhin Kogyo Kk ヒトｉｖ型コラーゲンのサンドイッチ酵素免疫学的定量法
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Title
CHEMICAL ABSTRACTS, Volume 107, No. 15, issued 12 October 1987 (12.10.87), Columbus, Ohio, USA, SHIMAZAKY et al., Susceptibility of bovine colostral and serum IgG to proteolytic enzymes as analyzed via gel filtration chromatographic behaviour, page 554, column 1, the abstact No. 132267e, Nippon Chikusan Gakkaiho 1987, 58(4), 324-32 (Japan) abstract. *
PATENT ABSTRACTS OF JAPAN; & JP,A,02 001 553 (FUJI YAKUHIN KOGYO KK), 5 January 1990 (05.01.90), abstract. *

Cited By (42)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0725789A4 (fr) * 1993-09-20 1999-07-28 Anadis Ltd Procede d'extraction d'immunoglobulines du colostrum et emploi de ces dernieres dans des preparations pharmaceutiques
WO1997037636A1 (fr) * 1996-04-03 1997-10-16 Elias Hakalehto Lutte contre des microbes nocifs: therapie et prevention
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WO1998003081A1 (fr) * 1996-07-22 1998-01-29 Wisconsin Alumni Research Foundation Procede d'amelioration de la croissance d'un animal ou de l'indice de conversion des aliments chez un animal et compositions utilisees selon ce procede
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