US20060275253A1 - Beta hydroxy short to medium chain fatty acid polymer - Google Patents

Beta hydroxy short to medium chain fatty acid polymer Download PDF

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US20060275253A1
US20060275253A1 US10/570,133 US57013306A US2006275253A1 US 20060275253 A1 US20060275253 A1 US 20060275253A1 US 57013306 A US57013306 A US 57013306A US 2006275253 A1 US2006275253 A1 US 2006275253A1
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chain fatty
fatty acid
medium chain
short
acid
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Kazunari Ushida
Masaki Kuriyama
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Earthus Inc
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Earthus Inc
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Assigned to EARTHUS, INC. reassignment EARTHUS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KURIYAMA, MASAKI, USHIDA, KAZUNARI
Publication of US20060275253A1 publication Critical patent/US20060275253A1/en
Priority to US12/591,209 priority Critical patent/US9649332B2/en
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    • 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
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof
    • 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
    • A23K20/158—Fatty acids; Fats; Products containing oils or fats
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A23L33/12—Fatty acids or derivatives thereof
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
    • A61K8/85—Polyesters
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A61K9/204—Polyesters, e.g. poly(lactide-co-glycolide)
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)

Definitions

  • the present invention relates to a method for delivering a ⁇ -hydroxy short-medium chain fatty acid monomer or an oligomer thereof to the large intestine by means of oral administration or a procedure parallel to oral administration.
  • the present invention further relates to a composition which is used for delivering a ⁇ -hydroxy short-medium chain fatty acid monomer or an oligomer thereof to the large intestine of a subject by means of oral administration or a procedure parallel to oral administration.
  • the invention relates to a novel animal feeding stuff.
  • the invention relates to a pharmaceutical composition and a functional food product useful for keeping or improving physiologic function, for treating or preventing inflammatory bowel disease and for treating or preventing large intestine cancer.
  • the invention relates to a coating composition useful for delivering an active ingredient to the large intestine of a subject and releasing the ingredient there.
  • Adjusts endocrine secretion including promotes insulin secretion and prevents catabolic hormone secretion.
  • Affects on the bacterial flora in the large intestine including stimulates growth of lactic acid fermentation bacteria and suppress growth of escherichia colis.
  • the short chain fatty acids When the short chain fatty acids are orally administered, almost all of the administered acids are absorbed from stomach and small intestine and the acids hardly get to the large intestine. Accordingly, in the conventional studies, oral administration of various resistant starches or water soluble dietary fibers; and enema administration of short chain fatty acids have been employed for delivering the short chain fatty acids to the large intestine.
  • the orally administered resistant starches or water soluble dietary fibers pass through the gastrointestinal tract without being digested, reach to the large intestine, and in the large intestine, part of them are easily digested into short chain fatty acids by the fermentation action of bacterial flora in the large intestine.
  • non-patent references 1-3 disclose effects of short chain fatty acids on inflammatory bowel disease, diarrhea, colon cancer and the like.
  • a short chain fatty acid is useful for treating inflammatory bowel disease including ulcerative colitis, Crohn's disease, pouchitis, ischemic colitis, diversion colitis, and radiation proctitis.
  • the short chain fatty acid is effective for treating large bowel cancer because of its apoptosis inducing effect on tumor cells (see non-patent references 4-7).
  • Non-patent reference 27 proposes the mechanism as follows: the resistant starch is fermented and absorbed in the large intestine, the stimulation is transmitted to the short intestine and the release of fatty acid from the short intestine to the circulation system is suppressed.
  • Some other effects of a short chain fatty acid such as inhibiting tumor cell growth, promoting cell differentiation and inducing apoptosis have also been reported and based on those effects, many people have tried to use some short chain fatty acids for preventing or treating large bowel cancer such as colon cancer and rectal cancer.
  • many studies on the administration of various dietary fibers for reducing the risk of or preventing the onset of large bowel cancer have been reported. Relationship between the amount of generated short chain fatty acids and the cancer inhibitory effect has been reported and the role of the short chain fatty acids on inhibiting cancer is suggested (non-patent references 28 and 29). Effect of short chain fatty acids enema for preventing onset of cancer has also been reported (non-patent reference 30).
  • the short chain fatty acid affects differently on different stages of developing tumor from normal epithelial cells thorough adenoma cells. That is, it promotes growth of normal cells and induces apoptosis of adenoma cells. In addition, on the tumor cells, it has been reported to suppress growth, induce apoptosis and promote histone hyperacetylation. The mechanism of the same has been elucidated.
  • 5-fluorourasil which is metabolized into butyric acid, and ester derivatives, such as glycerides or sugar ester, of short chain fatty acids have been proposed for treating breast cancer, prostate cancer or leukemia.
  • ester derivatives such as glycerides or sugar ester
  • the art employed oral administration of various resistant starches or water soluble dietary fibers or enema administration of short chain fatty acid in order to apply the short chain fatty acids to the large intestine.
  • all of thus administrated resistant carbohydrates are not necessarily converted to short chain fatty acids. Some may be converted to carbon dioxide gas, some may be used for bacterial body and some may be converted to the other organic acids such as lactic acid and succinic acid.
  • the short chain fatty acid production efficiency from the resistant carbohydrates are generally low.
  • the fermentation speed of the resistant carbohydrates is greatly affected by the manner of intake or the existence form of the same in the food.
  • the production ratio between the short chain fatty acids and the other organic acids could vary greatly, for example, if the fermentation speed increases, the amount of the other organic acids can increase.
  • the other organic acids may affect badly. For example, production or accumulation of a large amount of lactic acid may cause diarrhea.
  • short chain fatty acid may be applied directly to the large intestine by means of intestinal infusion such as enema.
  • intestinal infusion such as enema.
  • poly( ⁇ -hydroxybutyric acid) As a polymer of hydroxy fatty acid, poly( ⁇ -hydroxybutyric acid) was firstly found by Lemoigne et al and then, the structure of the polymer and the function as energy storage product and as nutrient or energy source in microorganisms were revealed. After the discovery of copolymer of ⁇ -hydroxybutyric acid and ⁇ -hydroxyvaleric acid from natural bacteria by Wallen et al, many studies on hydroxy fatty acid polymers have been conducted by the art. (non patent reference 36). Accordingly, it was found that microorganisms produce various hydroxy fatty acid polymers. Hydroxy fatty acid polymers are thermoplastic and proposed to be used for manufacturing biologically degradable plastics.
  • Patent reference 1 discloses to use emulsion of polyhydroxyalkanoate having particle size of 0.1-10 ⁇ m as fat or cream substitutes based on their texture. This reference is silent about the digestion or metabolite energy of the polymer.
  • Patent reference 2 discloses animal nutrition composition comprising polyhydroxyalkanoate. This reference discloses that polyhydroxyalkanoate or hydroxy fatty acid polymer increases metabolizable energy content of the food and focused on the energy upon intake the same. However, it is silent about the metabolizing mechanism or metabolizing ratio of the polymer in the animal body. Many microorganisms have enzymes capable of depolymerizing poly(hydroxy fatty acids) (non patent reference 37), but there is no report that an animal produces such a depolymerase.
  • Patent reference 3 discloses orally administrative polyhydroxycarboxylic acid which is used for lowering pH in the intestinal tract by oral administration of the same. This reference discloses various effect of the polymer and all of them are those predicted from the pH lowering effect. According this reference, ⁇ -hydroxycarboxylic acids, especially lactic acid are preferable and polylactic acid was used in the working example. It does not mention ⁇ -hydroxy short-medium chain carboxylic acid.
  • Non-patent reference 38 is a report of a study on microorganism proteins for feeding animals and the reference discloses the effect of poly( ⁇ -hydroxybutyric acid) produced by the microorganisms as bi-product on the animals.
  • About 65% of poly( ⁇ -hydroxybutyric acid) taken by a pig was recovered from the feces and no residual polymer was found in the organs such as liver, kidney or muscle. Accordingly, about 35% of the polymer was speculated as metabolized in the intestine.
  • Non-patent reference 39 discloses a study employing a copolymer of ⁇ -hydroxybutyric acid and ⁇ -hydroxyvaleric acid as metabolizable energy. Said copolymer was hardly metabolized in pigs but the water soluble hydrolysates of the polymer obtained with sodium hydroxide could be metabolized. The reference suggests that the metabolism of the copolymer could vary depending on particle size or crystalline form of the copolymer.
  • Non-patent references 40 and 41 disclose that copolymers of ⁇ -hydroxybutyric acid and ⁇ -hydroxyvaleric acid could hardly be metabolized in sheep but copolymers having smaller particle size or hydrolysates of the copolymers could be metabolized. However, they are silent about physiological effects of the copolymer on the sheep.
  • compositions having mono- or multiple layer coating or capsulated compositions comprising the active ingredient which are obtainable by coating the ingredient with film or capsule of a polymer that dissolves under specific pH range, such as methacrylic acid copolymer, or a polymer that is digested by bacterial flora in the large intestine, such as chitosan or aromatic azo moiety comprising polymers have been proposed(patent references 4-7).
  • a polymer that dissolves under specific pH range such as methacrylic acid copolymer
  • a polymer that is digested by bacterial flora in the large intestine such as chitosan or aromatic azo moiety comprising polymers
  • those coatings might be degraded in the small intestine or excreted without being degraded in the large intestine.
  • there are some problems in manufacturing the coatings due to the poor solubility of the used polymers in the less-residual volatile organic solvent.
  • patent reference 8 Orally or enterally administerable immune modulator, which is to be absorbed by macrophage phagocytosis, comprising microsphere matrix made of poly(hydroxybutyric acid) has been proposed (patent reference 8).
  • the reference discloses microsphares having particle distribution range of 1-15 ⁇ m so that macrophages can phagocytize the same.
  • the reference does not mention to use the polymer for delivering a drug to the large intestine utilizing the property of the polymer being degraded by bacterial flora in the large intestine.
  • An object of the present invention is to provide a composition used for delivering a physiologically active ⁇ -hydroxy short-medium chain fatty acid or a oligomer thereof to the large intestine.
  • Another object of the present invention is to provide a method for delivering a ⁇ -hydroxy short-medium chain fatty acid or an oligomer thereof to the large intestine by means of oral administration or a procedure parallel to oral administration.
  • Yet another object of the present invention is to provide a novel animal feeding stuff composition.
  • Still another object of the present invention is to provide a composition useful for treating cancer or inflammatory diseases in the large intestine or for maintaining or improving the intestine function.
  • Further object of the present invention is to provide a large intestine degradable coating composition, which enables to deliver an active ingredient to the large intestine by means of oral administration or a procedure parallel to oral administration.
  • the inventors have discovered that when a poly( ⁇ -hydroxy short-medium chain fatty acid) is administered orally to a subject, the polymer reaches the large intestine without being fully digested at stomach or short intestine and degraded by the bacterial flora in the large intestine. Further, inventors have also discovered that a monomer or oligomer of ⁇ -hydroxy short-medium chain fatty acid, produced by the bacterial flora degradation of the polymer in the large intestine, exhibits various physiological effects including similar effects as those known in short-medium chain fatty acids and completed the invention.
  • the present invention provides a composition for delivering a ⁇ -hydroxy short-medium chain fatty acid or a oligomer thereof to the large intestine, which comprises a polymer of the ⁇ -hydroxy short-medium chain fatty acid.
  • the invention also provides a method for delivering a ⁇ -hydroxy short-medium chain fatty acid or an oligomer thereof to the large intestine of an animal including human, which comprises administering orally a polymer of the ⁇ -hydroxy short-medium chain fatty acid to the animal.
  • the present invention provides use of a polymer of a ⁇ -hydroxy short-medium chain fatty acid, for manufacturing a composition for delivering the ⁇ -hydroxy short-medium chain fatty acid or a oligomer thereof to the large intestine.
  • the polymer obtained by polycondensing ⁇ -hydroxy short-medium chain fatty acid will not be fully degraded in the stomach or short intestine and the large part of the administered polymer will be delivered to the large intestine.
  • the polymer in the large intestine will be degraded by the bacterial flora there to give water soluble monomer or oligomer of the ⁇ -hydroxy short-medium chain fatty acid, the monomer or oligomer will be absorbed from the large intestine and exhibit the physiological activity.
  • ⁇ -hydroxy short-medium chain fatty acid represents saturated fatty acid having 3-12 carbon atoms.
  • Preferred examples may include ⁇ -hydroxy-butyric acid, ⁇ -hydroxypropionic acid, ⁇ -hydroxyvaleric acid, ⁇ -hydroxycaproic acid, ⁇ -hydroxycaprylic acid and ⁇ -hydroxycapric acid.
  • polymer of a ⁇ -hydroxy short-medium chain fatty acid or “poly( ⁇ -hydroxy short-medium chain fatty acid)” may be either a monopolymer of a monomer as above or a copolymer of two or more ⁇ -hydroxy short-medium chain fatty acids.
  • monopolymer of ⁇ -hydroxybutyric acid or a copolymer of ⁇ -hydroxybutyric acid and one or more of the other ⁇ -hydroxy short-medium chain fatty acid monomers may preferably be used.
  • copolymers a copolymer of ⁇ -hydroxybutyric acid and ⁇ -hydroxyvaleric acid is preferably used.
  • the poly( ⁇ -hydroxy short-medium chain fatty acid) may comprise any monomer unit other than ⁇ -hydroxy short-medium chain fatty acid as long as said monomer unit impair the physiological property of monomer or oligomer of the ⁇ -hydroxy short-medium chain fatty acid.
  • the polymerization degree of the poly( ⁇ -hydroxy short-medium chain fatty acid) is not limited as long as the polymer is insoluble to water.
  • the orally administered polymer will be absorbed as it is or after hydrolyzed under the acid or alkaline condition in the stomach or small intestine before the polymer reaches the large intestine.
  • Polymers of a ⁇ -hydroxy short-medium chain fatty acid with about 10 or more degree of polymerization are water insoluble.
  • polymers having 1000 or more weight-average molecular weight are preferably used.
  • the upper limit of the molecular weight of the polymer is not limited and any polymers which can be prepared may be used in the present invention.
  • Appl. Microbiol, Biotechnol., 47, 140-143 discloses that poly( ⁇ -hydroxy butyric acid) having weight average molecular weight of 20,000,000 or more was obtained.
  • the poly( ⁇ -hydroxy short-medium chain fatty acids) with polymerization degree of 20-100,000, especially 20-20,000 are preferably used.
  • oligomer of ⁇ -hydroxy short-medium chain fatty acid represents a water soluble oligomer unless otherwise indicated.
  • preferred oligomers are those with a polymerization degree of less than 10, more preferably less than 6 and especially less than 3.
  • composition of the present invention is useful for treating or preventing various diseases.
  • diseases include large bowel cancer such as rectal cancer and colon cancer, inflammatory bowel disease such as ulcerative colitis, Crohn's disease, pouchitis, diversion colitis, radiation proctitis and ischemic colitis.
  • composition of the present invention is also useful for treating or preventing diarrhea including diarrhea associated with dysentery or cholera, constipation and irritable bowel disease.
  • the composition When administered orally or via a route parallel to the oral administration, the composition decreases the neutral fat in the blood and therefore, the composition can be used for preventing or treating hyperlipidemia.
  • the composition of the present invention has further effect of promoting fat mobilization for utilizing the fat for energy in fasting or starvation. According to this effect, the composition can reduce fat in the body and may be applied for the purpose of losing weight or improving meat quality in livestock animals.
  • composition of the present invention will relieve stress of the subject.
  • composition of the present invention is very safe and long term administration of the same will not cause problems.
  • a composition comprising a ⁇ -hydroxy short-medium chain fatty acid, an oligomer thereof, or a physiologically acceptable derivatives thereof in a manner that the component is delivered to the large intestine.
  • physiologically acceptable derivative may include acceptable salts and physiologically hydrolyzable derivatives, such as esters and amides, of the ⁇ -hydroxy short-medium chain fatty acid or its oligomer and phosphorylated compounds wherein the hydroxy groups are phosphorylated.
  • Salts may be those with an inorganic ion or an organic base.
  • inorganic ions may include cations of alkali metals, alkali earth metals and transition metals, for example sodium, potassium, magnesium, calcium, zinc, iron and manganese cations.
  • organic bases may include trimethyl amine, triethyl amine, ethanol amine, diethanol amine, triethanol amine, and basic amino acids such as arginine, lysine, and ornithine.
  • esters may include alkyl esters such as methyl ester, ethyl ester and isopropyl ester, and hydroxyalkyl esters such as hydroxyethyl ester.
  • esters with saccharides such as mono saccharides and oligo-saccharides and those with polyols such as glycol, glycerol, polyethylene glycol and polypropylene glycol are also used preferably in the invention.
  • phosphate esters with a phosphoric acid such as nucleotides may also be used preferably.
  • alkyl amides such as diethyl amide and amides with oligopeptides are preferably used.
  • ⁇ -hydroxy short-medium chain fatty acids or oligomers thereof are absorbed from stomach or small intestine.
  • the acid or oligomer thereof can be delivered to the large intestine and exert the physiological effect there.
  • the composition comprising the ⁇ -hydroxy short-medium chain fatty acid, an oligomer thereof or a physiologically acceptable derivative thereof in a manner that the component can be delivered to the large intestine will have similar effect as of the above described composition of the present invention comprising a polymer of the ⁇ -hydroxy short-medium chain fatty acid.
  • a large intestine degradable coating composition comprising a poly( ⁇ -hydroxy short-medium chain fatty acid) is also provided.
  • the poly( ⁇ -hydroxy short-medium chain fatty acids) used for this embodiment may be the same as above described.
  • large intestine degradable coating composition represents a coating composition which can provide a dosage form by coating an active ingredient with the composition, wherein the dosage form can deliver the ingredient to the large intestine by means of oral administration or procedure parallel to oral administration of the same without being dissolved in the stomach or short intestine.
  • oral administration or procedure parallel to oral administration include administration via transnasal tube, gastric administration such as administration directly to stomach or infusion directly to the large intestine in addition to oral administration.
  • the “animal” represent not only mammals including human but also the other vertebrates including fishes and birds.
  • Various bacteria living in the large intestine of vertebrates form the bacterial flora and the bacteria metabolize the food stuff, which are not digested in the stomach or short intestine, by fermentation to give short chain fatty acids and the like.
  • the vertebrates absorb thus generated short chain fatty acids for their energy or nutrition. (J. Exp. Zool. Suppl. 3, 55-60(1980); Physiol. Rev., 78, 393-427 (1998)).
  • Bacterial flora in the large intestine have been studied in various vertebrates including not only mammals such as human, pig and sheep but also birds such as chickens and ducks and fishes such as carps.
  • the vertebrates in general, have been revealed to have bacterial flora in the large intestine.
  • Physiol. Res. 47,259-263(1998); Comp. Biochem. Physiol. A: Mol. Integr. Physiol., 131,657-668(2002); Comp. Biochem. Physiol. A: Mol. Integr. Physiol., 132,333-340(2002); and Appl. Environ. Microbiol., 68,1374-1380(2002), the cited references are herein incorporated by reference.
  • the composition of the present invention is useful for all vertebrates and especially, for mammal, bird and fish.
  • the term “large intestine” represents the digestive tract consisting of cecum, colon and rectum. In some animal species, digestive system is underdifferentiated or underdeveloped and their large and small intestines are indisguishable. In such a case, “large intestine” represents the area where bacterial flora present and fermentation by the bacteria is occurred.
  • the poly( ⁇ -hydroxy short-medium chain fatty acid) may be prepared by any procedure known to the art.
  • ⁇ -hydroxy short-medium chain fatty acid monomer, the starting material may be polycondensed by means of a conventional polyester synthesizing method.
  • poly( ⁇ -hydroxy short-medium chain fatty acid) produced by microorganism or higher organisms may also be used.
  • Ralstonia eutropha and Alcaligenes latus have been known to produce a large amount of poly( ⁇ -hydroxybutyric acid).
  • Ralstonia eutropha cells having high protein content also contains higher amount of amino acids such as serine and glycine, which are added for the purpose of growth promotion, and therefore had been proposed as protein source. Accordingly, this microorganism will be useful not only for providing poly( ⁇ -hydroxybutyric acid) or the like, but also as protein source and are preferable especially for manufacturing animal feeding stuffs or food products.
  • the poly( ⁇ -hydroxy short-medium chain fatty acid) used in the present invention may be those obtained from recombinant microorganisms or plants.
  • the polymer may be isolated from the microorganism or plant before adding to the composition of the invention, or the microorganism or plant per se containing the polymer may be added to the composition.
  • the microorganism comprises at least one trace elements selected from the group consisting of selenium, cobalt, manganese, zinc and copper.
  • the microorganism may be cultured in a medium comprising the desired elements in the form of a suitable salt.
  • the condition and medium used for the culture are well known to the art and may be determined depending on the microorganism to be used.
  • the poly( ⁇ -hydroxy short-medium chain fatty acid) is administered orally, transnasaly using transnasal tube, or by means of direct infusion to the large intestine. Oral administration is more easy and practically preferable.
  • the poly( ⁇ -hydroxy short-medium chain fatty acid) will be degraded by the bacterial flora in the large intestine. Accordingly, when the composition of the present invention is administered orally, the composition will not be digested or absorbed to provide energy in the small intestine, but the polymer will be delivered to the large intestine, degraded there and utilized.
  • the water soluble monomers and oligomers produced by the degradation of the poly( ⁇ -hydroxy short-medium-chain fatty acid) of the present invention are absorbed from the large intestine and exert physiological effects.
  • the poly( ⁇ -hydroxy short-medium chain fatty acid) of the present invention By administering the poly( ⁇ -hydroxy short-medium chain fatty acid) of the present invention, not only the effects known with short-medium chain fatty acids including inhibition of diarrhea or soft feces, decrease of water content in the feces, promotion of growth and decrease of nitrogen excretion in urine, but also the other novel effects including decrease of the water intake and urine amount, alleviation of fecal odor, increase of the stool frequency, relieve of stress, decrease of gastric and large intestinal retention contents, decrease of small intestine, large intestine and kidney weights, increase of nitrogen accumulation rate and decrease of nitrogen excretion rate were observed.
  • the inventors have firstly found the facts that poly( ⁇ -hydroxy short-medium chain fatty acid) is degraded by bacterial flora in the large intestine and exerts various novel effects other than those conventionally known as the effect of short-medium chain fatty acids.
  • a composition which can deliver a ⁇ -hydroxy short-medium chain fatty acid monomer, a oligomer thereof or a physiologically acceptable derivative thereof.
  • the ⁇ -hydroxy short-medium chain fatty acid monomer or oligomer thereof is delivered to the large intestine and exerts the above described effects.
  • composition of the present invention which comprises poly( ⁇ -hydroxy short-medium chain fatty acid) and the composition which can deliver a ⁇ -hydroxy short-medium chain fatty acid, a oligomer thereof or a physiologically acceptable derivative thereof to the large intestine may be administered to vertebrates in general.
  • the composition of the present invention can be used for various uses associated with activating the large intestine functions.
  • the composition of the present invention can reduce or relieve strains on kidney or liver in a patient with renal failure, chronic renal disease or hepatic disease.
  • a monomer or oligomer of a ⁇ -hydroxy fatty acid monomer i.e. the degradation products of the composition of the present invention
  • exhibits tumor cell growth inhibiting activity i.e. the degradation products of the composition of the present invention.
  • the degradation products, ⁇ -hydroxy fatty acid or the oligomer thereof exerts the effect similar to that of the conventionally known short chain fatty acid.
  • the composition of the present invention comprising a poly( ⁇ -hydroxy short-medium chain fatty acid) and the composition comprising a ⁇ -hydroxy short-medium chain fatty acid monomer, oligomer thereof or physiologically acceptable derivative thereof in a manner that the component can be delivered to the large intestine may be added to diet or drinking stuff for raised or cultivated mammals, birds or fishes, or may be formulated as an additives for those feeding or drinking stuffs. That is, the composition of the present invention may preferably be used as an animal feeding stuff or an additive for an animal feeding product for maintaining or improving health, promoting growth, reducing odor of faces and urine and facilitating faces and urine disposal of livestock animals, birds, fishes and companion animals.
  • the composition of the present invention may also be used as functional food product for keeping and controlling the health state and for preventing diseases.
  • the term “functional food product” may include supplements, enteral nutritional product, component nutrition product, medical food product, post operative diet and additives thereto.
  • the functional food product may be not only for human but also for animals other than human such as companion animals and livestock animals.
  • the composition of the present invention may also be used as pharmaceutical composition for preventing or treating constipation and diarrhea, and also for preventing or treating a disease which can be relieved or arrested by means of the various effect of the composition of the present invention.
  • composition of the present invention is provided as a pharmaceutical composition for treating a specific disease, as functional food product for preventing specific diseases or general health maintenance in animals including human and as additive for food or animal feeding product are also in the scope of the present invention.
  • composition of the present invention When the composition of the present invention is provided as pharmaceutical composition or functional food product for an animal including human, it may be formulated as a dosage form suitable for oral administration such as powder, granule, tablet, capsule, sublingual tablet, troche, chewable tablet, dispersion and the like.
  • the dosage form may be manufactured in a conventional manner.
  • the composition of the present invention may be incorporated in food and/or beverage and administered orally.
  • composition of the present invention may further comprise a pharmaceutically acceptable additive.
  • Additives are not limited and may be selected from those discloses in general reference books on drug formulation such as excipient, diluent, expander, solvent, lubricant, adjuvant, binder, disintegrating agent, coating agent, capsulating agent, emulsifier, dispersant, suspending agent, thickener, tonicity agent, buffering agent, soothing agent, preservative, antioxidant, corrigent, flavor and colorant based on the requirement.
  • composition of the present invention may further comprise the other pharmaceutically active ingredient as long as it will not impair the object of the present invention.
  • the formulation of the composition is not limited and may be prepared by adding the poly( ⁇ -hydroxy short-medium chain fatty acid) or ⁇ -hydroxy short-medium chain fatty acid monomer, oligomer thereof or physiologically acceptable derivative thereof formulated in a manner that the component can be delivered to the large intestine, to a conventional feeding stuff product.
  • the feeding stuff according to the present invention may comprise further physiologically active ingredient unless it will not impair the object of the present invention.
  • composition of the present invention may also be formulated as an additive for animal feeding stuff.
  • the composition of the present invention may comprise whole microorganisms containing the poly( ⁇ -hydroxy short-medium chain fatty acid) therein.
  • the composition comprises the whole microorganism, the microorganism per se will be utilized as protein source.
  • microorganisms may be prepared with incorporating some essential trace elements in the microorganisms by a conventional procedure simultaneously with producing the poly( ⁇ -hydroxy shot-medium chain fatty acid), and thus obtained microorganisms may preferably be added to the composition since not only the protein but also the trace elements from the microorganism can be utilized.
  • the amount of the ⁇ -hydroxy short-medium chain fatty acid, oligomer thereof or physiologically acceptable derivative thereof in the composition is not limited and may be determined depending on the species, body weight, sex, health condition of the subject to be administered, object of the administration and the like. In general, the amount may be 1 mg-500 mg/kg body weight.
  • the composition of the present invention may be administered all at once or in two or more divided doses. Alternatively, 0.01-5 wt % of the composition may be added to the feeding, drinking or food stuff and administered the stuff to the subject. The amount may be increased or decreased according to the object of the administration.
  • the present invention further provides a large intestine degradable coating composition, comprising poly( ⁇ -hydroxy short-medium chain fatty acid).
  • the coating composition of the invention may be in the form that conventionally used in the pharmaceutical field, such as matrix material for microspheres, coating agent for solid preparation such as tablets, granules, pills and capsules, embedding sheet material for embedding drugs therein or materials for capsules.
  • the composition degradable in the large intestine may be poly( ⁇ -hydroxy short-medium chain fatty acid) which is consisting only of short-medium chain fatty acid or copolymer comprising the other monomer unless said monomer impair the object of the present invention.
  • additives which are conventionally used in manufacturing medicaments may be added to he composition. Examples of the additives may include aggregation inhibitor, disintegrating agent, lubricant and colorlant. Preferable procedure for manufacturing poly( ⁇ -hydroxy short-medium chain fatty acid) is the same as above.
  • the active ingredient to be delivered to the large intestine is coated with the coating composition of the invention.
  • the coating may be conducted by any of conventionally known procedures, for example, solid or capsule formulation containing the active ingredient may be coated by means pan coating or fluid bed coating, or those active ingredients may be coated by film obtained by a conventional method such as extrusion.
  • the capsule may be manufactured by means of a conventional method such as vacuum or pressure forming using a sheet of the composition obtained by extrusion, or by applying and drying the composition to the die.
  • Microspheres may be obtained by means of a conventional method such as drying the polymer in the liquid or spray drying.
  • the thickness of the coating matrix or the like obtained with the large intestine degradable coating composition can be adjusted by means of any procedure well known to the art based on the object of the administration of the formulation or the kind of the active ingredient.
  • the active ingredient to be coated by the coating composition of the present invention is not limited and may be any component desired to be delivered to the large intestine.
  • Non limited examples may include protein or peptide compound, which will be inactivated by gastrointestinal enzyme or having an activity similar to insulin which will be absorbed effectively from the large intestine, and various medicaments for the treatment of various diseases in the large intestine.
  • i Ralstonia eutropha preculture was inoculated in 30 L culture medium shown below and incubated under aeration and agitation at 30° C. During the incubation, the pH was adjusted to 6.8 with aqueous ammonia and the consumed glucose was added accordingly. When the predetermined cell concentration was obtained, aqueous sodium hydrate was added instead of aqueous ammonium to start deposition of the polymer. The culture was incubated for total 3 days with keeping the addition of glucose to provide cells containing poly( ⁇ -hydroxybutyric acid). The cells were collected with centrifugation and treated with protease and then with aqueous hydrogen peroxide to isolate the polymer. The polymer was collected, washed with water and dried.
  • the same medium used in reference example 1 2000 L was used and the same microorganism was cultured in the same manner as reference example 1 except for using a mixture of glucose and propionic acid (9:1) in stead of glucose as carbon source for the deposition of the polymer added after the culture reached to the predetermined cell concentration.
  • copolymer was analyzed by NMR and confirmed to comprise 5.4 mol % of ⁇ -hydroxyvaleric acid monomer unit.
  • the weight average molecular weight determined with GPC was 737,000 and the yield was 49.8 g/L medium.
  • Poly( ⁇ -hydroxybutyric acid) was obtained in the same manner as Reference example 1 except for the incubation period was shortened.
  • the polymer was confirmed by NMR and the weight average molecular weight determined with GPC was 869,000.
  • the obtained cells contained 23.6 wt % of the polymer and the dry yield of the cells was 105.4 g/L medium.
  • the nutrition analysis of thus obtained cells are shown in Table 1.
  • the microorganism containing poly( ⁇ -hydroxy short-medium chain fatty acid) is also useful as protein source.
  • TABLE 1 Nutrition Analysis of the cells comprising poly( ⁇ - hydroxybutyric acid). Analyzed Item Content (%) water content 1.8 crude protein 64.2 (Conversion Factor: 6.25) crude lipid 0.8 crude fiber 0 crude ash 3.9 soluble nitrogen content 29.3 100-the above 5 members
  • Cecal fluid of a pig was obtained via cecum cannula, diluted 5 fold with Pipes buffer (pH 6.5) and filtered with gauze. Thus obtained cecal fluid 50 ml was added with the test sample 0.5 g and the mixture was incubated for 24 hours at 37° C. under anaerobic condition (nitrogen 80% and carbon dioxide 20%). After the incubation was completed, the resulting fluid was analyzed by ion chromatography.
  • the powdery poly( ⁇ -hydroxy butyric acid) obtained in the reference example 1 and dried cells of Ralstronia eutropha containing poly( ⁇ -hydroxy-butyric acid) obtained in the reference example 3 were used.
  • the degradation ratios of the poly( ⁇ -hydroxy-butyric acid) samples which were determined based on the concentrations of the degraded products calculated from the peak areas, were about 30% for the powdery polymer of reference example 1 and about 50% for the dried cells of reference example 3. The difference might be caused from the different surface areas of the poly( ⁇ -hydroxybutyric acid) samples based on the different particle sizes,
  • each polymers was weighted and added to 50 ml of the each aqueous enzyme solution containing 0.1 wt % of the enzyme and adjusted to the pH mimicking the stomach or small intestine environment.
  • the mixture was shaken at 37° C. for the predetermined time, i.e. 6 hours for mimicking the stomach digestion and 10 hours for mimicking the short intestine digestion, and then, filtered and collected.
  • the feces was dried for 48 hours at 80° C. and crushed and about 1 g of which was weighted.
  • the dried feces was extracted with 1,2-dichloroethan under heat and reflux, the extract was added with 3 volume of n-hexane to precipitate and collect poly( ⁇ -hydroxybutyric acid) and weighted the same.
  • the degradation ratio of the poly( ⁇ -hydroxybutyric acid) in the large intestine was calculated from the amount of the polymer remained in the feces.
  • odor measurement ammonium, volatile fatty acid, hydrogen sulfide and total mercaptan contained in the feces were measured once a week. The measurement was carried out as follows: one day's feces of each group was collected, put in a plastic bucket and stood for one day without covering the top. After that, 1 kg of the feces was spread on a tray, put the tray in 100 L plastic bag with non-smelled air and kept for 1 hour. Then, the concentration of the respective element in the head space of the bag was measured with a gas detecting tube.
  • Example 4 The body weight of the animals was increased from around 10 kg at the start to around 25 kg.
  • the test was conducted with weanling pigs during the rapid growth period and there was no significant difference in the test and control groups.
  • the feed conversion ratio in the test group was better than the control group in several per cent (table 3).
  • the retention of the ingested materials in the gastrointestinal tract could be decreased also in the test group pigs. This suggests that the substantial body weight including muscle amount and the like might be increased in the test group and caused in the substantial difference in the feed conversion ratio.
  • the odor of the control group was more irritate than that of the test group.
  • Each odorous component are shown in Table 4 below. The declining trend and significant decline of the odor from the excretory substance were confirmed. That is, in the test group, the volatile fatty acid was decreased by about 25% and both hydrogen sulfide and total mercaptan were decreased by more than 40% from those of the control group (Table 4).
  • Example 5 each four male pigs were selected for the test and control groups so that pigs of the two groups have approximately the same body weights and housed individually in the metabolic cage. After the 3 days acclimatization period with ad libitum feeding of the same diet, the effect on the feces and urine amount and nitrogen metabolism were examined.
  • the amount of the copolymer in the collected feces was determined in the same manner as Example 1.
  • the diet intake was significantly decreased.
  • the diet intake per day was about 1.4 kg, whereas the diet intake of the control group was decreased by more than 20% in about two days (average, 1.75 days) during the metabolic cage feeding period.
  • no decrease in diet intake was observed.
  • the decrease in diet intake observed in the control group is suggested being caused by the stress due to the small space of the metabolic cage.
  • the diet intake of the test group was not decreased and the effect of the composition of the present invention as a stress reliever was confirmed.
  • the average stool frequency observed in the test group of 32.5 was significantly larger (+30%) than that of the control group of 25. This supports the effect of the invention to activate the intestinal movement and provide better excretion.
  • the urination frequency in both groups was about 40 and there were no significant difference between the groups.
  • the average amount of the urine in the test group of 3,946 g was non-significantly lower ( ⁇ 11%) than that in the control group of 4,452 g, Further, the average water content in the feces of the test group of 62.6% was significantly lower ( ⁇ 10%) than that in the control group of 69.4%.
  • the nitrogen balance was calculated based on the nitrogen amount in the feces and urine determined by the Kjeldahl method, dried ratio of the diet (89.5%), CP value of the diet (26.0%) and the nitrogen amount conversion factor (6.25). Results are summarized in Table 6.
  • composition of the present invention is effective for improving feed conversion ratio and increasing muscle amount as well as decreasing urine disposal cost. It is more difficult to treat nitrogen contents in the urine than those in the feces.
  • SD Nitrogen Balance Test in Pigs test group control group
  • fecal nitrogen (g) 19.5(0.8) 19.4(1.1) urinary nitrogen (g) 43.7(4.0) 47.1(3.5) *p ⁇ 0.1 **: p ⁇ 0.05
  • the poly( ⁇ -hydroxybutyric acid) used herein was that obtained in Reference Example 1.
  • Example 7 At the date when bloody stools were observed two successive days, the animals were divided into control and test groups and fed with the respective diet shown in table 8 for 7 days. After that, all animals were sacrificed and subjected to autopsy. Each organ was weighted and visually observed. In addition, tissue slice of the large intestine was prepared and the tissue was observed with optical microscope. The histopathological evaluation of the inflammatory was made in the same manner as Example 7.
  • the animals were fed with commercially available pelletized feeding stuff, Labo MR stock, Nosan Corporation Kanagawa, Japan for 3 days of acclimatization. After that, the animals were fed with the basic diet shown in Table 10 twice a day, between 9 and 10 o'clock, and between 21 and 22 o'clock, for 4 days of acclimatization. After the acclimation period was terminated, the animals were divided into two groups. The test and control groups were fed with the respective diet twice a day for 2 weeks. The control group was fed with the basic diet in an amount 95 wt % of the average intake amount of the test group so that there is no difference between the control and test groups in terms of the intake of the ingredient in the basic diet (pair feeding design).
  • Cell line HT-29 derived from colon tumor was inoculated into McCoy's SA medium supplemented with 10% fetal calf serum comprising penicillin 50 U/ml, streptomycin 50 ⁇ g/ml and HEPES 10 mM on 96-well cell culture plate (7,500 cells/well). The cells were pre-incubated in an atmosphere of 95% air and 5% carbon dioxide at 37° C. for 24 hours. Then, various amount of butyric acid, which has been known to have differentiation and apoptosis inducing effects, was added as a positive control.
  • R( ⁇ )- ⁇ -hydroxy-butyric acid, S(+)- ⁇ -hydroxybutyric acid and dimer of R( ⁇ )- ⁇ -hydroxybutyric acid were added (all were in the form of sodium salt).
  • the R( ⁇ )- ⁇ -hydroxybutyric acid dimer was prepared by purification of oligomers of R( ⁇ )- ⁇ -hydroxy-butyric acid, which was prepared according to Eur. J. Biochen., 118, 177-182(1981)(the cited reference is herein incorporated by reference), by column chromatography. The plate was incubated further 72 hours. The cell number in the each well was determined by the MTT method based on the difference of the optical density.
  • Fluid bed coating machine (Freund Corporation, Tokyo, Japan) was used.
  • Granular food dye Red No.102 of approximately 0.5 mm diameter was coated using 2 w/v % solution of the copolymer obtained in Reference Example 2 in methylene chloride by spraying the solution to the granule for 1 hour.
  • the obtained coated food dye had 40 wt % of coating ratio and about 30 ⁇ m of calculated coating thickness.
  • the coating ratio represents the ratio of the weight of coating composition to that of the food dye.
  • the coated food dye was put in the gastric juice and small intestinal juice mimetic solutions used in Example 3 at 37° C. and stirred gently. The dye leakage from the coated food dye was observed visually over time.
  • Example 2 the cecal fluid of pig, which was diluted 5 fold with Pipes buffer pH 6.5 used in Example 2 was used.
  • the coated food dye was added to the cecal fluid at 37° C. and stirred gently under anaerobic condition. The dye leakage from the coated food dye was observed visually over time.

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