WO2014184655A1 - Procédés d'utilisation de complexes phospholipide-peptide-protéine de crustacés - Google Patents

Procédés d'utilisation de complexes phospholipide-peptide-protéine de crustacés Download PDF

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Publication number
WO2014184655A1
WO2014184655A1 PCT/IB2014/001068 IB2014001068W WO2014184655A1 WO 2014184655 A1 WO2014184655 A1 WO 2014184655A1 IB 2014001068 W IB2014001068 W IB 2014001068W WO 2014184655 A1 WO2014184655 A1 WO 2014184655A1
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WIPO (PCT)
Prior art keywords
krill
ppc
formulation
meal
composition
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PCT/IB2014/001068
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English (en)
Inventor
Inge Bruheim
Mikko Griinari
Stig Rune REMOY
Even REMOY
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Olympic Seafood As
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Publication of WO2014184655A1 publication Critical patent/WO2014184655A1/fr

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    • 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
    • A61K35/56—Materials from animals other than mammals
    • A61K35/612—Crustaceans, e.g. crabs, lobsters, shrimps, krill or crayfish; Barnacles
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L17/00—Food-from-the-sea products; Fish products; Fish meal; Fish-egg substitutes; Preparation or treatment thereof
    • A23L17/40—Shell-fish
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils

Definitions

  • the present invention is related to high quality crustacean phospholipid-peptide- protein (PPC) compositions for use as nutritional supplements, cosmetic products, pharmaceuticals and clinical nutrition.
  • PPC crustacean phospholipid-peptide- protein
  • the use of crustacean PPC compositions can treat medical disorders and/or to improve mental and/or physical performance.
  • PPC may comprise a phospholipid-peptide-protein complex or a de-oiled phospholipid-peptide-protein complex.
  • such crustacean PPC compositions can improve symptoms of various medical disorders.
  • Krill are marine crustaceans (Class Malacostraca, Order Euphausiacea) comprising approximately 86 species, a majority of which are free swimming, and are considered plankton (Everson 2000). Krill sometimes form dense swarms that can extend over several square kilometers and represent a biomass of thousands or even millions of tons (Nicol and Endo 1999).
  • compositions and formulations in where most of the nutrients and the bioactive components from krill are kept intact and where both lipid soluble and lipid insoluble micronutrients which are required can be in mixed in a feasible way.
  • the present invention is related to high quality crustacean phospholipid-peptide- protein (PPC) compositions for use as nutritional supplements, cosmetic products, pharmaceuticals and clinical nutrition.
  • PPC crustacean phospholipid-peptide- protein
  • the use of cmstacean PPC compositions can treat medical disorders and/or to improve mental and/or physical performance.
  • PPC may comprise a phospholipid-peptide-protein complex or a de-oiled phospholipid-peptide-protein complex.
  • such crustacean PPC compositions can improve symptoms of various medical disorders.
  • the present invention contemplates a method, comprising: a) providing: i) a patient exhibiting at least one symptom of a medical disorder; ii) a low fluoride crustacean meal formulation; b) administering said composition to said patient under conditions such that said at least one symptom is reduced.
  • the medical disorder comprises an age-related medical disorder.
  • the age-related medical disorder includes, but is not limited to, a lack of homeostatic control, macular degeneration, diabetes, or inflammation.
  • the medical disorder comprises malnutrition, hi one embodiment, the medical disorder comprises an ocular disorder.
  • the medical disorder comprises a cardiovascular disorder.
  • the medical disorder comprises a skeletal medical disorder.
  • the medical disorder comprises a central nervous system disorder. In one embodiment, the medical disorder comprises a muscular disorder. In one embodiment the medical disorder comprises cachexia. In one embodiment, the medical disorder comprises digestive tract medical disorder. In one embodiment, the medical disorder comprises a dyslipidemic medical disorder. In one embodiment, the medical disorder comprises a hair disorder. In one embodiment, the medical disorder comprises a nail disorder. In one embodiment, the medical disorder comprises a skin disorder. In one embodiment, the medical disorder comprises a sexual disorder. In one embodiment, the formulation is a pharmaceutically acceptable formulation. In one embodiment, the crustacean meal formulation is a krill meal formulation. In one embodiment the crustacean meal formulation is a medicament.
  • the meal formulation comprises a low fluoride phospholipid-peptide-protein complex (e.g., for example, Krill Meal 1). In one embodiment, the meal formulation comprises a low fluoride de-oiled phospholipid-protein complex (e.g., for example, Krill Meal 2). In one embodiment, the meal formulation further comprises a low fluoride krill oil. In one embodiment, the meal formulation further comprises a low trimethyl amine krill oil. In one embodiment, the meal formulation further comprises a low fluoride, low trimethyl amine krill oil. hi one embodiment, the meal formulation further comprises a low fluoride extraction residue.
  • a low fluoride phospholipid-peptide-protein complex e.g., for example, Krill Meal 1
  • the meal formulation comprises a low fluoride de-oiled phospholipid-protein complex (e.g., for example, Krill Meal 2).
  • the meal formulation further comprises a low fluoride krill oil. In one embodiment, the meal formulation further comprises a low
  • the meal formulation further comprises an additional ingredient including, but not limited to, minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • the administered composition ranges between 0.005 - 0.50 grams per day per kilogram of said patient's body weight, hi one embodiment, the formulation includes, but is not limited to, a capsule, a gelatin capsule, a flavored capsule, a tablet, coated tablets, powders, granulates, solutions, dispersions, suspensions, syrups, emulsions, a liquid nutrition composition and/or a beverage.
  • the formulation includes, but is not limited to a nutritional supplement, a pharmaceutical, a food supplement, a functional food ingredient, a food additive and/or a nutritional supplement preparation.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of an ocular medical disorder; ii) a crustacean meal formulation comprising a low fluoride phospholipid-peptide-protein complex, zinc oxide, vitamin C and vitamin E; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the ocular medical disorder is a retinal disorder.
  • the ocular medical disorder is macular degeneration.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride carstacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 1 -3 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a cardiovascular medical disorder; ii) a crustacean meal formulation comprising a low fluoride phospholipid-peptide-protein complex, phytosterols, phytostarrnols and vitamin D; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the cardiovascular medical disorder is a heart disorder.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil.
  • the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a skeletal medical disorder; ii) a crustacean meal formulation comprising a low fluoride phospholipid-peptide-protein complex, calcium carbonate, vitamin D and vitamin K; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the skeletal medical disorder is oestoporosis.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil.
  • the crustacean meal formulation further comprises a low trmethyl amine crustacean oil.
  • the meal formulation further comprises a low fluoride extraction residue.
  • the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • the administering comprises a daily effective dose ranging between approximately 0.5 - 4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a central nervous system medical disorder; ii) a crustacean meal formulation comprising a low fluoride phospholipid-peptide- protein complex and ubiqinon (e.g., for example, Q10); and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the central nervous system medical disorder is dementia.
  • the central nervous system medical disorder is multiple sclerosis.
  • the central nervous system medical disorder is reduced mental acuity.
  • the centeral nervous system medical disorder is reduced concentration.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation. In one embodiment, the crustacean meal formulation further comprises a low fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 1 -3 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of an ocular medical disorder; ii) a crustacean meal formulation comprising a low fluoride de-oiled phospholipid-peptide complex, zinc oxide, vitamin C, vitamin E, lutein, zeaxanthin and DHA; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the ocular medical disorder is a retinal disorder.
  • the ocular medical disorder is macular degeneration.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 1 -3 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a muscular medical disorder; ii) a crustacean meal formulation comprising a low fluoride de-oiled phospholipid- protein complex and omega-3 fatty acids; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the muscular medical disorder is an anabolic medical disorder.
  • the anabolic medical disorder is a mitochondrial disorder.
  • the formulation is a
  • the crustacean meal formulation is a krill meal formulation. In one embodiment, the crustacean meal formulation further comprises a IOAV fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the admimstering comprises a daily effective dose ranging between approximately 1 -3 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a cachexic medical disorder; ii) a crustacean meal formulation selected from the group consisting of a low fluoride
  • the cachexic medical disorder is cancer. In one embodiment, the cachexic medical disorder is malnutrition. In one embodiment, the cachexic medical disorder is a chronic infectious disease.
  • the formulation is a pharmaceutically acceptable formulation, hi one embodiment, the crustacean meal formulation is a krill meal formulation. In one embodiment, the crustacean meal formulation further comprises a low fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil.
  • the meal formulation further comprises a low fluoride extraction residue.
  • the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • the administering comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a lack of homestatic control; ii) a crustacean meal formulation selected from the group consisting of a low fluoride
  • the formulation is a pharmaceutically acceptable formulation, i one embodiment, the crustacean meal formulation is a krill meal formulation. In one embodiment, the crustacean meal formulation further comprises a low fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue.
  • the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • the adm stering comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of an endocrinologic medical disorder; ii) a crustacean meal formulation selected from the group consisting of a low fluoride phospholipid-pep tide-protein complex and a low fluoride de-oiled phospholipid-protein complex and at least one additional ingredient; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the endocrinologic medical disorder is diabetes.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue, hi one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of an inflammatory medical disorder; ii) a crustacean meal formulation selected from the group consisting of a low fluoride phospholipid-peptide-protein complex and a low fluoride de-oiled phospholipid-protein complex and at least one additional ingredient; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the inflammatory medical disorder is arthritis.
  • the formulation is a pharmaceutically acceptable formulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil.
  • the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a digestive tract medical disorder; ii) a crustacean meal formulation selected from the group consisting of a low fluoride phospholipid-peptide-protein complex and a low fluoride de-oiled phospholipid-protein complex and at least one additional ingredient; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the digestive tract medical disorder is irritable bowel disease.
  • the digestive tract medical disorder is Crohn's disease.
  • the digestive tract medical disorder is ulcerative colitis, i one embodiment, the formulation is a
  • the crustacean meal formulation is a krill meal formulation. In one embodiment, the crustacean meal formulation further comprises a low fluoride crustacean oil. In one embodiment, the crustacean meal formulation further comprises a low trimethyl amine crustacean oil. In one embodiment, the meal formulation further comprises a low fluoride extraction residue. In one embodiment, the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils. In one embodiment, the administering comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the present invention contemplates a method, comprising: a) providing; i) a patient exhibiting at least one symptom of a dyslipidemic medical disorder; ii) a crustacean meal formulation selected from the group consisting of a low fluoride phospholipid-peptide-protein complex and a low fluoride de-oiled phospholipid-protein complex and at least one additional ingredient; and b) administering said formulation to said patient under conditions such that said at least one symptom is reduced.
  • the dyslipidemic medical disorder is elevated low density lipoprotein cholesterol levels
  • hi one embodiment the dyslipidemic medical disorder is reduced high density lipoprotein cholestrol levels
  • hi one embodiment, the dyslipidemic medical disorder is elevated triglyceride levels.
  • the formulation is a pharmaceutically acceptable fonnulation.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil.
  • the crustacean meal formulation further comprises a low trimethyl amine crustacean oil.
  • the meal formulation further comprises a low fluoride extraction residue.
  • the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • the administeiing comprises a daily effective dose ranging between approximately 0.5 -4 grams.
  • the formulation further comprises a lipid insoluble ingredient.
  • the lipid insoluble ingredient comprises a lipid insoluble vitamin.
  • the lipid insoluble vitamin comprises approximately between 5 - 50 wt% of the formulation.
  • the lipid insoluble vitamin includes, but is not limited to, vitamin C, vitamin B12 and/or folate.
  • the lipid insoluble ingredient comprises cognitive health protecting substances.
  • the cognitive health protecting substances include, but are not limited to, resveratrol, astaxanthin or ubiquinone.
  • the lipid insoluble ingredient comprises cartilage protecting substances.
  • the cartilage protecting substances are glucosamine and chondroitin.
  • the lipid insoluble ingredients are selected from the group consisting of glucosamine hydrochloride, glucosamine sulfate, glucosamine potassium, glucosamine sodium, N-acetyl d-glucosamine, chondroitin, chondroitin sulfate, curcumin, ascorbic acid, hyaluronic acid, green lipped mussel powder, creatine, L-carnitine, ascorbic acid, manganese, manganese proteinate, zinc, zinc proteinate, copper, copper proteinate, ginseng, green tea extract, ginger, garlic, vincamine, grape seed extract, grape seed meal, dimethyl glycine, whey protein, brewer's yeast, St.
  • the weight ratio of krill meal to lipid insoluble ingredients in the compo sition ranges between approximately 16:1 to 1 : 1.
  • the formulation further comprises a lipid soluble vitamin.
  • the lipid soluble vitamin includes, but is not limited to, vitamin E, vitamin A and/or vitamin D.
  • the lipid soluble vitamin comprises approximately between 5 - 50 wt% of the formulation.
  • the lipid soluble ingredient is selected from the group consisting of vitamin A, vitamin D, vitamin E, alpha lipoic acid, lutein, and natural carotenoids.
  • the composition comprises 10 - 90 % (w/w) krill meal, 10 - 90 % (w/w) lipid insoluble mgredient(s), and 0 - 80 % (w/w) excipients.
  • the formulation further comprises a nutritionally essential mineral.
  • the nutritionally essential mineral includes, but is not limited to, zinc, calcium, magnesium and/or zinc oxide.
  • the nutritionally essential mineral comprises approximately between 0.001 - 50 wt% of the formulation.
  • the formulation further comprises a bioactive health ingredient.
  • the bioactive health ingredient includes, but is not limited to, zeaxanthin, resveratrol and/or ubiquinon.
  • the bioactive health ingredient comprises approximately between 0.001 - 50 wt% of the formulation.
  • the formulation further comprises an omega-3 enriched marine oil.
  • the omega-3 enriched marme oil includes, but is not limited to, fish oil and/or squid oil.
  • the omega-3 enriched marine oil is microencapsulated.
  • the omega-3 enriched marine oil comprises approximately between 5 - 95 wt% of the formulation.
  • the omega-3 oil is in a form including, but not limited to, an ethylester, a triglyceride and/or a phospholipid.
  • the formulation further comprises a DHA enriched marine oil.
  • the DHA enriched marine oil includes, but is not limited to, fish oil and/or squid oil.
  • the DHA enriched marine oil is microencapsulated.
  • the DHA enriched marine oil comprises between approximately 5 - 95 wt% of the formulation.
  • the formulation further comprises an EPA enriched marine oil.
  • the EPA enriched marine oil includes, but is not limited to, fish oil and/or squid oil.
  • the EPA enriched marine oil is microencapsulated.
  • the EPA enriched marine oil comprises bteween approximately 5 - 95 wt% of the formulation.
  • the formulation further comprises conventional excipients including, but not limited to, solvents, diluents, binders, sweeteners, aromas, pH modifiers, viscosity modifiers, antioxidants, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, tartaric acid, water, ethanol, glycerol, sorbitol, and/or carboxymethyl cellulose.
  • the excipient is selected from the group consisting of, fillers, granulating agents, adhesives, disintegrants, lubricants, antiadherants, glidants, wetting agents, dissolution retardants, enhancers, adsorbents, buffers, chelating agents, preservatives, colours, flavours, sweeteners, starch, pregelatinized starch, malto dextrin, monohydrous dextrose, alginic acid, sorbitol, mannitol, magnesium stearate, stearic acid, talc, silic, cellulose, microcrystalline cellulose, methyl cellulose,
  • polyvinylpyrrolidone and - commercial products such as Aerosil ® , Kollidon ® and Explotab ® .
  • the administering comprises an effective daily dose of the formulation between approximately 100 mg - 100 gram. In one embodiment, the duration of the administration comprised at least two weeks.
  • the present invention contemplates a method, comprising: a) providing: i) an animal exhibiting at least one symptom of a degenerative joint disease; ii) a veterinary supplement comprising a crustacean meal formulation selected from the group consisting of a low fluoride phospholipid-peptide-protein complex and a low fluoride de- oiled phospholipid-protein complex and at least one additional ingredient; b) administering said composition to said animal under conditions such that said at least one symptom is reduced.
  • the composition is homogenous.
  • the crustacean meal formulation is a krill meal formulation.
  • the crustacean meal formulation further comprises a low fluoride crustacean oil.
  • the crustacean meal formulation further comprises a low trimethyl amine crustacean oil.
  • the at least one additional ingredient is selected from at least one of the group comprising minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • the at least one symptom comprises pain.
  • the at least one symptom comprises stiffness.
  • the at least one symptom comprises lameness.
  • the at least one symptom comprises mobility.
  • the at least one symptom comprises mood.
  • the at least one symptom comprises activity.
  • the at least one embodiment comprises play.
  • mobility is assessed by a modified Helsinki Chronic Pain Index.
  • the lameness is determined by a deviation of a 60:40 weight distribution between the front legs and the rear legs of said animal.
  • the animal is a quadruped animal.
  • the quadruped animal is selected from at least one of the group comprising a canine, a feline, an equine, a bovine, an ovine, and/or a porcine.
  • the administering comprises a daily effective dose ranging between approximately 0.005 - 0.50 grams per day per kilogram of said animal's body weight.
  • the duration of the administration comprised at least six weeks.
  • the degenerative joint disease comprises osteoarthritis.
  • the crustacean meal further comprises cartilage protecting substances.
  • the cartilage protecting substances are glucosamine and chondroitin.
  • the at least one additional ingredient is selected from the group comprising glucosamine hydrochloride, glucosamine sulfate, glucosamine potassium, glucosamine sodium, N-acetyl d- glucosamine, chondroitin, chondroitin sulfate, curcumin, ascorbic acid, hyaluronic acid, green lipped mussel powder, creatine, L-carnitine, ascorbic acid, manganese, manganese proteinate, zinc, zinc proteinate, copper, copper proteinate, ginseng, green tea extract, ginger, garlic, vincamine, grape seed extract, grape seed meal, dimethyl glycine, whey protein, brewer's yeast, St.
  • the composition comprises a krill meal to lipid insoluble ingredients weight ratio ranging between approximately 16:1 to 1 : 1.
  • the composition further comprises a lipid soluble ingredient.
  • the lipid soluble ingredient is selected from the group consisting of vitamin A, vitamin D, vitamin E, alpha lipoic acid, lutein, and natural carotenoids.
  • the composition comprises 10 - 90 % (w/w) krill meal, 10 - 90 % (w/w) lipid insoluble ingredient(s), and 0 - 80 % (w/w) excipients.
  • the composition comprises a suitable form selected from the group consisting of a tablet, a capsule, a granule, a pellet, a powder, or a pet treat.
  • the capsule comprises a hard gelatin capsule.
  • the hard gelatin capsule is a sprinkle capsule.
  • the pet treat comprises at least one flavor ingredient.
  • the pet treat comprises a filler ingredient.
  • the composition further comprises an excipient.
  • the excipient is selected from the group consisting of diluents, fillers, binders, granulating agents, adhesives, disintegrants, lubricants, antiadherants, glidants, wetting agents, dissolution retardants, enhancers, adsorbents, buffers, chelating agents, preservatives, colours, flavours, sweeteners, starch, pregelatinized starch, maltodextrin, monohydrous dextrose, alginic acid, sorbitol, mannitol, magnesium stearate, stearic acid, talc, silic, cellulose, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone and - commercial products, such as Aerosil ® , Kollidon ® and Explotab ® .
  • the present invention contemplates a method, comprising: a) providing: i) an animal in need of increased food intake; ii) an animal food or feed comprising between approximately 0.01 % (w/w) and 1.0% (w/w) krill meal; b) feeding said animal said food under conditions such that said animal's food intake increases.
  • the krill meal comprises krill oil.
  • the krill oil comprises at least one omega-3 fatty acid.
  • the method further comprises improving the health of said animal.
  • the animal comprises a non-human animal.
  • the non-human animal comprises a dog. Definitions
  • compositions disclosed herein as “optionally comprises excipients” means that the composition may or may not comprise excipients, in other words the composition possibly comprises excipients.
  • patient is a human or animal and need not be hospitalized.
  • out-patients persons in nursing homes are "patients.”
  • a patient may comprise any age of a human or non-human animal and therefore includes both adult and juveniles (i.e., children). It is not intended that the term "patient” connote a need for medical treatment, therefore, a patient may voluntarily or involuntarily be part of experimentation whether clinical or in support of basic science studies.
  • animal means species including but not limited to mammals, fish, crustaceans, amphibians, reptiles etc.
  • a "companion animal” refers to any non-human animal kept by a human as a pet or any animal of a variety of species that have been widely domesticated as pets, such as dogs (Canis familiar is), and cats (Felis domesticus), whether or not the animal is kept solely or partly for companionsl ip.
  • Companion animals also include working animals including but not limited to horses, cows, pigs, goats, sheep, dogs (i.e., for example, livestock herding) and/or cats (i.e., for example, rodent control).
  • symptom refers to any subjective or objective evidence of disease or physical disturbance observed by the patient.
  • subjective evidence is usually based upon patient self-reporting and may include, but is not limited to, pain, headache, visual disturbances, nausea and/or vomiting.
  • objective evidence is usually a result of medical testing including, but not limited to, body temperature, complete blood count, lipid panels, thyroid panels, blood pressure, heart rate, electrocardiogram, tissue and/or body imaging scans.
  • disease refers to any impairment of the normal state of the living animal or plant body or one of its parts that interrupts or modifies the performance of the vital functions. Typically manifested by distinguishing signs and symptoms, it is usually a response to: i) environmental factors (as malnutrition, industrial hazards, or climate); ii) specific infective agents (as worms, bacteria, or viruses); iii) inherent defects of the organism (as genetic anomalies); and/or iv) combinations of these factors
  • the terms “reduce,” “inhibit,” “diminish,” “suppress,” “decrease,” “prevent” and grammatical equivalents when in reference to the expression of any symptom in an untreated subject relative to a treated subject, mean that the quantity and/or magnitude of the symptoms in the treated subject is lower than in the untreated subject by any amount that is recognized as clinically relevant by any medically trained personnel.
  • the quantity and/or magnitude of the symptoms in the treated subject is at least 10% lower than, at least 25% lower than, at least 50% lower than, at least 75%o lower than, and/or at least 90% lower than the quantity and/or magnitude of the symptoms in the untreated subject.
  • drug refers to any pharmacologically active substance capable of being administered which achieves a desired effect.
  • Drugs or compounds can be synthetic or naturally occurring, non-peptide, proteins or peptides, oligonucleotides or nucleotides, polysaccharides or sugars.
  • administering refers to any method of providing a composition to a patient such that the composition has its intended effect on the patient.
  • An exemplary method of administering is by a direct mechanism such as, local tissue administration (i.e., for example, extravascular placement), oral ingestion, transdermal patch, topical, inhalation, suppository etc.
  • At risk for refers to a medical condition or set of medical conditions exhibited by a patient which may predispose the patient to a particular disease or affliction.
  • these conditions may result from influences that include, but are not limited to, behavioral, emotional, chemical, biochemical, or environmental influences.
  • krill meal refers here to any mixture of proteins and lipids derived from krill.
  • the term is not limited to any particular method of making krill meal, but any method known in the art is contemplated.
  • medical disorders refers to any biological condition diagnosed by medically trained personell to require treatment.
  • medical disorders may include, but are not limited to, hair disorders, nail disorders, skin disorders, skeletomuscular disorders, multiple sclerosis, or sexual disorders.
  • improved performance refers to any biological condition, where controlled medical testing measures results that medically trained personnel would considered above the expected norm. For example, improved performance may be measured for physical or mental tests.
  • the term "effective amount” refers to any amount of a supplement that improves the palatability of the food or feed.
  • composition refers to any composition can be formulated to a suitable form, such as a tablet, a granule, a pellet or powder.
  • suitable form such as a tablet, a granule, a pellet or powder.
  • the composition may be formulated also to a pet treat or a hard gelatin capsule (sprinkle capsule) can be filled with the composition.
  • krill meal refers here to any mixture of proteins and lipids derived from krill.
  • the term is not limited to any particular method of making krill meal, but any method known in the art is contemplated.
  • omega-3 fatty acid refers to fatty acids which have the final double bond between the third and the fourth carbon atom counting from the methyl end of the carbon chain.
  • Omega-3 fatty acids mainly concerned in this disclosure are the long chain polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docospentaenoic acid (DHA) as well as the minor omega-3 fatty acids including eicosatetraenoic acid (ETA) and
  • DPA docosapentaenoic acid
  • lipid insoluble ingredient refers to any compound not soluble in a lipophilic solvent such as chloroform, n-hexane and toluene.
  • a lipophilic solvent such as chloroform, n-hexane and toluene.
  • lipid insoluble ingredient refers to any compound not soluble in a lipophilic solvent such as chloroform, n-hexane and toluene.
  • such compounds are St. John's wort, creatine, dimethyl glycine, ginko biloba, ginseng, betaglucan, mannaoligosaccharides, vincamine, whey protein, vinpocetine, zinc, zinc proteinate, copper, copper proteinate.
  • More preferably such compounds are grape seed extract, grape seed meal, ginger, garlic, aloe vera and green lipped mussel powder and brewer ' s yeast.
  • Even more preferably such compounds are L-carnitine, hyaluronic acid and green tea
  • glucosamine hydrochloride glucosamine sulfate
  • glucosamine potassium glucosamine sodium
  • N-acetyl d-glucosamine glucosamine sodium
  • chondroitin sulfate chondroitin sulfate
  • curcumin ascorbic acid
  • manganese and manganese proteinate are glucosamine hydrochloride, glucosamine sulfate, glucosamine potassium, glucosamine sodium, N-acetyl d-glucosamine, chondroitin sulfate, curcumin, ascorbic acid, manganese and manganese proteinate.
  • glucosamine refers to 2-Amino-2-deoxy-D-glucose chitosamine or any derivative thereof.
  • chondroitin refers to chondroitin sulfate, which is a sulfated glycosaminoglycan composed of a chain of alternating sugars (N- acetylgalactosamine and glucuronic acid) or any derivative thereof including low molecular weight forms.
  • lipid insoluble ingredients may also comprise any combination of the above mentioned substances.
  • one lipid insoluble ingredient comprises cartilage protecting substances such as glucosamine and/or chondroitin.
  • lipid insoluble vitamins refers to vitamins or
  • micronutrients that are not soluble in a lipophilic solvent such as chloroform, n-hexane and toluene, but are soluble in aqueous solutions.
  • a lipophilic solvent such as chloroform, n-hexane and toluene
  • vitamins include, but are not limited to, vitamin B and/or vitamin C.
  • essential minerals refers to minerals that are essential for the body to work and stay healthy.
  • essential minerals are zinc, magnesium, phosphorus, manganese, selenium, calcium, copper, iodine.
  • lipid insoluble ingredients may also comprise any combination of the above mentioned substances.
  • lipid soluble vitamins refers to vitamins or micronutrients that are soluble in a lipophilic solvent such as chloroform, n-hexane and toluene.
  • a lipophilic solvent such as chloroform, n-hexane and toluene.
  • vitamins include, but are not limited to, vitamin A vitamin D, vitamin E and/or vitamin K.
  • bioactive health ingredients refers to chemical compounds that are naturally occurring and that have proven biological effects or may have biological significance.
  • bioactive health ingredients are within the groups of carotenoids, flavonoids, isothiocyanates, phytoesterogenes, phytosterols, polyphenols. More preferably such compounds are resveratrol, beta-caroten, lycopene, lutein, zeaxantbin, genistein, curcumin, alpha-lipoic acid, ubiquinone, ubiquinol.
  • excipients refer to any substance needed to formulate the composition to the desired form.
  • suitable excipients include but are not limited to, diluents or fillers, binders or granulating agents or adhesives, disintegrants, lubricants, antiadherants, glidants, wetting agents, dissolution retardants or enhancers, adsorbents, buffers, chelating agents, preservatives, colours, flavours and sweeteners.
  • Typical excipients are for example starch, pregelatinized starch, maltodextrin, monohydrous dextrose, alginic acid, sorbitol and mannitol.
  • the excipient should be selected from non-toxic excipients (EEG, Inactive Ingredient Guide, or GRAS, Generally Regarded as safe, Handbook of Pharmaceutical Excipients).
  • Typical excipients in particular for tableting are for example magnesium stearate, stearic acid, talc, silic, cellulose, microcrystalline cellulose, methyl cellulose, polyvinylpyrrolidone and - commercial products, such as Aerosil ® , Kollidon ® and Explotab ® . Excipients can be added into the direct powder compression formula.
  • clinical nutrition refers to the study, treatment and/or prevention of nutritionally-related medical disorders, including but not limited to
  • Nutritional supplement refers to any formulation of specific ingredients that may be of short supply in routinely provided food.
  • a daily intake of a nutritional supplement is typically ⁇ 1 gram to few grams; the form of a nutritional supplement.
  • “food supplement” refers to any formulation of specific ingredients that may be mixed into a food to improve the food's nutritional value.
  • functional food ingredient refers to any formulation of specific ingredients that may be mixed into a food to provide an additional function, such as health-promotion or disease prevention.
  • functional foods may include, but are not limited to, processed food or foods fortified with health-promoting additives, like "vitamin-enriched” products or fermented foods with Live cultures that would confer probiotic benefits.
  • “food additive” refers to any formulation of specific ingredients that may be mixed into a food for purposes including, but not limited to, preservation, stability, microbial control, color, flavor etc.
  • “pharmaceutical” refers to any formulation of specific ingredients that are used to improve the symptomology of a medical condition.
  • animal feed refers to any mixture of animal feed ingredients providing energy and nutrient requirements (e.g., protein, fat, carbohydrates, minerals and
  • a daily intake of 'animal feed' for companion animals is typically between 1 - 2% of body weight, for example 300 g/d for a 20 kg dog;
  • animal feed ingredient refers to any organic or mineral component added to an animal feed mixture in appreciable amounts (i.e., for example a bulk ingredient).
  • Animal feed ingredients are usually added to animal feed at levels greater than 1% (w/w), preferably 1 to 90 % (w/w), typically 10 to 50 %(w/w);
  • flavor ingredient is typically an organic component added to an animal feed for the purposes of improving feed palatability. Flavor ingredients are usually added to animal feeds at levels preferably less than 1% (w/w), more preferably less than 0.5%, most preferably less than 0.1 % by weight of the animal feed;
  • a daily intake of a nutritional supplement is typically ⁇ 1 gram to few grams; the form of a nutritional supplement for companion animals can be liquid or dry (e.g., pellet, tablet, granule, powder, capsule etc.);
  • treat refers to any nutritional product form given to a companion animal as a reward or a snack between meals. Treats may contain food ingredients and other ingredients that give a special consistency to the treat e.g. chewable treat. Treats are not usually considered important for their nutritional content. Treats may be used as rewards and should be highly palatable. Alternatively, treats may also be used as sources of supplementary nutrition and should have ingredients that improve the overall nutritional balance. For example, 'healthy treats' are a special form of treats that contain specific health promoting ingredients; daily intake of a treat is typically from several grams per day up to 100 g/d for an average sized dog (20 kg body weight).
  • fluoride as used herein interchangeably and refer to any compound containing an organofluoride and/or an inorganic fluoride.
  • high fluoride solid fraction refers to a composition containing the vast majority of a crustacean's exoskeleton following a low g- force (e.g., between approximately 1,000 - 1,800 g) horizontal centrifugation separation of a hydro lyzed and disintegrated crustacean material. This fraction contains small particles of exoskeleton of the crustacean that retains the vast majority of fluoride (i.e., for example, between 50 - 95%) in these organisms.
  • low fluoride may refer to the product of any method and/or process that reduced the fluoride from the original material by approximately one third (i.e., for example, from 1500 ppm to 500 ppm).
  • 'a low fluoride crustacean phospholipid-protein complex' comprises one third of the fluoride luoride than 'ahydrolyzed and disintegrated crustacean material' .
  • low fluoride hydrolyzed material fraction refers to a composition containing the vast majority of a crustacean's fleshy internal material following a low g-force (e.g., between approximately 1,000 - 1,800 g) horizontal centrifugation separation of a hydrolyzed and disintegrated crustacean material.
  • This fraction contains small particles of phospholipids, neutral lipids, proteins and/or peptides that is largely devoid of any fluoride (i.e., for example, between 5% - 50% of the raw hydrolyzed and disintegrated material).
  • a low fluoride phospholipid-peptide complex composition subfraction refers to a low fluoride composition containing the vast majority of lipid material following a high g-force (e.g., between approximately 5,000 - 10,000 g) horizontal centrifugation separation of a low fluoride hydrolyzed material fraction.
  • a high g-force e.g., between approximately 5,000 - 10,000 g
  • concentrated hydrolysate composition subfraction refers to a low fluoride composition containing the vast majority of water soluble peptides and/or lean material following a high g-force (e.g., between approximately 5,000 - 10,000 g) horizontal centrifuge separation of a low fluoride hydrolyzed material fraction.
  • a high g-force e.g., between approximately 5,000 - 10,000 g
  • low fluoride oil refers to a lipid-rich composition created by the extraction of a phospholipid-peptide complex composition subfraction using a selective extraction process, such as with a supercritical carbon dioxide fluid. Such a process removes approximately ten-fold of the fluoride from the raw hydrolyzed and disintegrated crustacean material.
  • de-oiled phospholipid-peptide protein complex refers to a low fluoride composition containing the vast majority of dry matter composition created by the extraction of a phospholipid-peptide protein complex composition subfraction using selective extraction process, such as a supercritical carbon dioxide fluid.
  • phospholipid composition refers to a low fluoride composition comprising a high percentage of polar lipids (e.g., approximately 75%) created by the extraction of a de-oiled phospholipid-peptide complex using a co-solvent, such as ethanol.
  • extraction residue or "protein hydrolysate” as used herein refers to a low fluoride composition comprising a high percentage of protein (e.g., approximately 60 - 90%) created by extraction of lipids from either a phospholipid-peptide protein complex or a de- oiled phospholipid-pep tide-complex using a polar solvent alone or in combination with a non-polar solvent.
  • peptide refers to any of various amides that are derived from two or more amino acids by combination of the amino group of one acid with the carboxyl group of another and are usually obtained by partial hydrolysis of proteins.
  • a peptide comprises amino acids having an order of magnitude with the tens.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • pharmaceutically acceptable carrier includes any and all solvents, or a dispersion medium including, but not limited to, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils, coatings, isotonic and absorption delaying agents, liposome, commercially available cleansers, and the like. Supplementary bioactive ingredients also can be incorporated into such carriers.
  • purified may refer to a peptide composition that has been subjected to treatment (i.e., for example, fractionation) to remove various other components, and which composition substantially retains its expressed biological activity.
  • substantially purified this designation will refer to a composition in which the protein or peptide forms the major component of the composition, such as constituting about 50%, about 60%, about 70%, about 80%, about 90%, about 95% or more of the composition (i.e., for example, weight/weight and/or weight/volume).
  • purified to homogeneity is used to include compositions that have been purified to 'apparent homogeneity” such that there is single protein species (i.e., for example, based upon SDS-PAGE or HPLC analysis).
  • a purified composition is not intended to mean that some trace impurities may remain.
  • substantially purified refers to amino acid sequences, that are removed from their natural environment, isolated or separated, and are at least 60% free, preferably 75% free, and more preferably 90% free from other components with whic they are naturally associated.
  • An "isolated peptide or protein” is therefore a substantially purified peptide or protein.
  • Figure 1 presents a flow diagram of one embodiment of a method to produce a low fluoride crustacean material.
  • Figure 2 present exemplary data showing the extraction efficiencies of two different runs in accordance with one embodiment of the present invention. Detailed Description Of The Invention
  • the present invention is related to high quality crustacean phospholipid-peptide- protein (PPC) compositions for use as nutritional supplements, cosmetic products, pharmaceuticals and clinical nutrition.
  • PPC crustacean phospholipid-peptide- protein
  • the use of crustacean PPC compositions can treat medical disorders and/or to improve mental and/or physical performance.
  • PPC may comprise a phospholipid-peptide-protein complex or a de-oiled phospholipid-pep tide-protein complex.
  • such crustacean PPC compositions can improve symptoms of various medical disorders.
  • One embodiment of the invention provides a composition comprising a crustacean meal (e.g., for example, a krill meal).
  • the crustacean meal comprises a nutritional supplement composition including, but not limited to a phospholipid-peptide complex (PPC).
  • PPC phospholipid-peptide complex
  • the composition may further comprise excipients suitable for consumption by an animal (i.e., for example, a companion animal or a human).
  • the composition is particularly suitable for companion animals, such as dogs or cats.
  • Antarctic krill ⁇ Euphausia Superba is a small shrimp like crustacean which can be found in huge quantities in the Southern Ocean, off the coast of Antarctica.
  • krill has developed a unique survival strategy comprising highly potent digestive enzymes to facilitate complete and rapid breakdown ingested food.
  • these potent digestive enzymes also result in a rapid breakdown of proteins and lipids (proteolysis and lipolysis, respectively) after harvesting of the krill.
  • the nutrient content of krill varies, depending on harvesting area and season.
  • the krill can be frozen or turned into a meal immediately after harvesting (i.e., for example, on board the fishing vessel).
  • the lipids found in krill are rich in phospholipids and especially phosphatidyl choline with high content of long chain omega-3 fatty acids, in addition to the antioxidant astaxanthin.
  • gentle processing methods enable the levels of these nutrients to remain stable throughout the process.
  • krill meal can be obtained by cooking krill, followed by pressing, drying and milling, using the same technology and principles as for making fish meal.
  • the krill can be cooked at two different temperatures, where the majority of the phospholipids are removed at a lower temperature.
  • United States Patent Application Publication Number 2009/0061067 herein incorporated by reference.
  • Other methods of making krill meal have been disclosed, where a dried powdery and granular krill product containing all components of krill was obtained.
  • United States Patent Application Publication Number 2003/0113432 herein incorporated by reference.
  • the production process comprised the steps of lightly dehydrating krill, coarsely crashing the krill, and drying the coarsely crushed krill under heating.
  • Other known methods include the use of freeze drying followed by milling and the use of alcohol to denature the enzymes.
  • a protein rich krill meal can be obtained by enzymatic hydrolysis as previously disclosed.
  • Krill contain high proportions of protein, lipid and pigments which, together with their high abundance, make them an attractive nutritional source both for animal and humans.
  • krill meal has a nutritional value equal to, or surpassing, that of regular fish meals when used as a substitute in the diets of various farmed species, including Atlantic cod, Atlantic salmon and Pacific white shrimp (Yoshitomi et al. 2007; Karlsen et al. 2006; Opstad et al. 2006; Gaber 2005).
  • Krill are believed to contain high levels of the carotenoid antioxidant astaxanthin and omega-3 fatty acid, which both ingredients is shown to have many beneficial health effects.
  • krill deteriorate very rapidly. This spoilage occurs through the rapid leaching of fluoride from the krill exoskeleton into the meat and because of auto lytic digestion by hydrolytic enzymes. Spoilage through autolysis is a major problem in krill fisheries and processing and can result in substantial losses of proteins and lipids via the generation of undesirable free fatty acids.
  • the omega-3 polyunsaturated fatty acids present in krill oxidize quite rapidly under oxygen rich atmosphere.
  • the astaxanthin protects the polyunsaturated fatty acid from oxidation, but as a result the astaxanhtin will be destroyed.
  • Omega-3 polyunsaturated fatty acids in krill meal are more easily oxidized than in krill oil products and it is challenging to make stable protein-oil products.
  • Nutritional needs are known to change as animals (e.g., mammals, such as humans) age. Reasons for these changes include, but are not limited to, decreased absorption of essential nutrients from diet, a more sedentary lifestyle, a decreased appetite and/or a change in metabolism. These nutritional changes occur in both the healthy elderly population and the elderly with exceptional nutritional needs due to health problems or diseases. There is growing scientific documentation that shows that certain essential macro and micro nutrients can prevent the development of certain diseases in the elderly population.
  • novel krill meal compositions can be mixed with both Upid soluble and lipid insoluble ingredients to make stable compositions that are effective in alleviation, prevention or treatment certain diseases in the elderly population or in groups of particular nutritional needs. It has also been surprisingly found that novel krill meal compositions enhance the absorption of some essential minerals and lipid soluble health ingredients and that these krill compositions are effective in prevention and treatment of health conditions related to aging.
  • the present invention contemplates a use of a nutritional supplement composition by administering the composition ranging between approximately 0.005 - 0.50 g krill meal per day per kg of body weight of an animal for the treatment of a degenerative joint disease.
  • the composition is homogenous.
  • the krill meal comprises a krill oil.
  • the composition further comprises at least one omega-3 fatty acid.
  • the composition is stable.
  • the homogeneity of the composition is characterized by a lack of phase separation.
  • the stability of the composition is characterized by, in comparison to krill oil, lower lyso-phospholipids, increased omega-3 levels, lower peroxide, lower p-anisidine, and higher astaxanthin.
  • Aging may be characterized by an inability of tissues to maintain homeostasis.
  • a lack of homeostasis control can lead to an impaired response to stress and, as a consequence, an increased risk of morbidity and mortality.
  • the term sarcopeniais now commonly used to describe the loss of skeletal muscle mass and strength that occurs in concert with biological aging.
  • sarcopenia which may be as high as 30% for those over 60 years, will increase as the percentage of the very old continues to grow in our populations.
  • the link between sarcopenia and disability among elderly men and women highlights the need for continued research into the development of the most effective interventions to prevent or at least partially reverse sarcopenia.
  • the aging process is also believed to be a factor in the age-dependent occurrence of central nervous system disabilities, such as dementia.
  • Glutathione ⁇ -glutamylcysteinylglycine
  • Glutathione plays a central role in antioxidant defenses, and irreversible cell damage supervenes when the cell is unable to maintain intracellular glutathione concentrations.
  • Evidence from several animal and human studies suggests that concentrations of glutathione decline with aging.
  • compositions should also be tested in bioavailability studies to identify if the compounds of interest will be absorbed.
  • Age-related macular degeneration is also a major cause of disability in the elderly. More than 20 million people worldwide are severely affected either by age-related macular degeneration or cataracts. AMD is the leading cause of blindness in people over 55 years of age in the western world. Nearly 30% of Americans over the age of 75 years have early signs of AMD and 7% have late stage disease. There are currently no effective treatment strategies for most patients with AMD, attention has focused on efforts to stop the progression of the disease or to prevent the damage leading to AMD.
  • Type 2 diabetes is the most common chronic metabolic disease in the elderly, affecting ⁇ 30 million individuals 65 years of age or older in developed countries.
  • the estimated economic burden of diabetes in the United States is ⁇ $ 100 billion per year, of which a substantial proportion can be attributed to persons with type 2 diabetes in the elderly age group.
  • Epidemiological studies have shown that the transition from the normal state to overt type 2 diabetes in aging is typically characterized by a deterioration in glucose tolerance that results from impaired insulin-stimulated glucose metabolism in skeletal muscle (Petersen et al, Science, 300(5622): 1140-1142 (2003).
  • Elevated oxidative stress has been linked to chronic inflammation and several aging related illnesses. The ability of a cell to resist oxidant damage is determined by a balance between the generation of reactive oxygen species and the defensive capacity to produce antioxidants.
  • a central problem associated with the assessment of free radical induced oxidative stress in disease development has been the limitation in existing assay methods for in vivo measurement of free radical generation.
  • F2-isoprostanes structural isomers of PGF2a, are formed during free-radical catalysed peroxidation of arachidonic acid.
  • a major F2-isoprostane, 8-iso-PGF2a is now a well-recognised reliable indicator of oxidative stress in vivo (Basu, S. Antioxid. Redox Signal. 10: 1405-1434 (2008)).
  • the transcription factor NF- ⁇ is a component of the cellular response to damage, stress, and inflammation. Numerous studies report increased NF-kB activity with aging, and NF-kB was identified as the transcription factor most associated with mammalian aging based on patterns of gene expression (Adam et al, Genes and Development, 3244 (2007). Chronic activation of NF- ⁇ is observed in numerous age-related diseases including, but not limited to, muscle atrophy, multiplesclerosis, atherosclerosis, heart disease, both type land 2 diabetes , osteoarthritis, dementia, osteoporosis, and cancer (Tilstra, J.S. et al, The Journal of Clinical Investigation, 122(7):2601-2612 (2012).
  • NF- ⁇ DNA binding is increased in skin, liver, kidney, cerebellum, cardiac muscle, and gastric mucosa of old rodents compared with that in young rodents.
  • NF-i B was identified as the transcription factor most associated with mammalian aging, based on patterns of gene expression.
  • chronic activation of NF- ⁇ is observed in numerous age-related diseases, including muscle atrophy, multiple sclerosis, atherosclerosis, heart disease, both type 1 and 2 diabetes, osteoarthritis, dementia, osteoporosis, and cancer.
  • oxidative damage and low grade inflammation are central in the development of many of the age related diseases.
  • the transcription factor NF-kB is a central component for the cellular response to these triggers.
  • a scientific approach to the development of nutritional supplements and drugs for the aging population could be to focus on the development of effective antioxidants to target these central biological mechanisms.
  • the central nervous system is particularly vulnerable to oxidative insult on account of the high rate of 0 2 utilization, the relatively poor concentrations of classical antioxidants and related enzymes, and the high content of polyunsaturated lipids, the biomacromolecules most susceptible to oxidation.
  • oxidative stress is a common discussion point for neurodegenerative disease, where damage to neurons can reflect both an increase in oxidative processes and a decrease in antioxidant defenses.
  • oxidative stress plays a major role in the pathogenesis of multiple sclerosis (MS).
  • Reactive oxygen species leading to OS, generated in excess primarily by macrophages, have been implicated as mediators of demyelization and axonal damage in MS.
  • ROS cause damage to main cellular components such as lipids, proteins and nucleic acids (e.g., R A, DNA), resulting in cell death by necrosis or apoptosis.
  • weakened cellular antioxidant defense systems in the central nervous system (CNS) in MS and its vulnerability to ROS effects may augmented damage.
  • CNS central nervous system
  • Treatment with antioxidants might theoretically prevent propagation of tissue damage and improve both survival and neurological outcome. Miller, E. et al, PolMerkur Lekarski. 27(162):499-502 (2009)
  • Some nutritional remedies have been tried for cataracts, glaucoma, and retinal diseases (macular degeneration, diabetic retinopathy, retinopathy of the newborn, and retinitis pigmentosa). Specifically, some nutritional treatments were given for asthenopia, blepharitis, chalazion, conjunctivitis (including giant papillary conjunctivitis), gyrate atrophy of the choroid and retina, keratoconus, myopia, sicca syndrome (dry eyes), and uveitis. The data suggest that nutritional supplements may play role the further of clinical therapy strategies to ocular disorders. Gaby AR., "Nutritional therapies for ocular disorders: Part Three" Altern Med Rev. 13(3): 191-204 (2008).
  • Functional digestive disorders can be characterized by symptoms related to the digestive tract for which no pathological causes can be found using routine diagnostic techniques.
  • Functional dyspepsia and the irritable bowel syndrome are amongst the most widely recognised functional gastrointestinal disorders.
  • Symptom based diagnostic criteria have been developed and refined for the syndromes (the Rome criteria) and these are now widely applied in clinical research.
  • Both functional dyspepsia and IBS are remarkably prevalent in the general population, affecting approximately 20% and 10% of persons, respectively. The prevalence is stable from year to year because the onset of these disorders is balanced by their disappearance in the population. Clinically useful predictors of the course of these disorders have not been identified. Approximately one third of persons with functional dyspepsia concurrently have IBS.
  • Bone turnover in which cells of the osteoclast lineage resorb bone and cells of the osteoblast lineage deposit bone, normally occurs in a highly regulated manner throughout life. Perturbations to these processes underlie skeletal disorders, such as osteoporosis, which are common, chronic and disabling, and increase with age. On the basis of empirical observations or on understanding of the endocrinology of the skeleton, excellent bone- resorption inhibitors, but few anabolic agents, have been developed as therapeutics for skeletal disorders. Goltzman D., "Discoveries, drugs and skeletal disorders” Nat Rev Drug Discov. 1(10): 784-796 (2002). In some embodiment, the present invention contemplates that crustacean meal compositions and other ingredients are useful in treating these disorders.
  • Notch signaling mediates cell-to-cell interactions that may be involved in embryonic development and tissue renewal.
  • the Notch receptor may be cleaved following ligand binding, resulting in the release and nuclear translocation of the Notch intracellular domain (NICD).
  • NICD induces gene expression by forming a ternary complex with the DNA binding protein CBFl/Rbp-Jk, Suppressor of Hairless, Lagl, and Mastermind-Like (Maml). Hairy Enhancer of Split (Hes) and Hes related with YRPW motif (Hey) are also Notch targets.
  • Notch canonical signaling plays a central role in skeletal development and bone remodeling by suppressing the differentiation of skeletal cells.
  • Dysregulation of Notch signaling is associated with diseases affecting human skeletal development, such as Alagille syndrome, brachydactyly and spondylocostal dysostosis.
  • Notch receptors and ligands are found in tumors of the skeletal system.
  • Overexpression of NOTCH1 is associated with osteosarcoma, and overexpression of NOTCH3 or JAGGED 1 in breast cancer cells favors the formation of osteolytic bone metastasis.
  • Activating mutations in NOTCH2 cause Hajdu-Cheney syndrome, which is characterized by skeletal defects and fractures, and JAGl polymorphisms, are associated with variations in bone mineral density.
  • Notch is a regulator of skeletal development and bone remodeling, and abnormal Notch signaling is associated with developmental and postnatal skeletal disorders. Zanotti et al., "Notch regulation of bone development and remodeling and related skeletal disorders" Calcif Tissue Int. 90(2):69-75 (2012).
  • Genetic disorders involving the skeletal system may arise through disturbances in the complex processes of skeletal development, growth and homeostasis and remain a diagnostic challenge because of their variety.
  • the Nosology and Classification of Genetic Skeletal Disorders provides an overview of recognized diagnostic entities and groups them by clinical and radiographic features and molecular pathogenesis. The aim is to provide the Genetics, Pediatrics and Radiology community with a list of recognized genetic skeletal disorders that can be of help in the diagnosis of individual cases, in the delineation of novel disorders, and in building bridges between clinicians and scientists interested in skeletal biology.
  • 456 conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria.
  • the Nosology is a hybrid between a list of clinically defined disorders, waiting for molecular clarification, and an annotated database documenting the phenotypic spectrum produced by mutations in a given gene.
  • the Nosology should be useful for the diagnosis of patients with genetic skeletal diseases, particularly in view of the information flood expected with the novel sequencing
  • Skeletal muscle is the largest organ in the human body, and plays an important role in body movement and metabolism. Skeletal muscle mass is lost in genetic disorders such as muscular dystrophy, muscle wasting and ageing. Chemicals and proteins that restore muscle mass and function are potential drugs that can improve human health and could be used in the clinic.
  • Myostatin is a muscle-specific member of the transforming growth factor (TGF)-beta superfamily that plays an essential role in the negative regulation of muscle growth. Inhibition of myostatin activity is a promising therapeutic method for restoring muscle mass and strength.
  • TGF transforming growth factor
  • Potential inhibitors of myostatin include follistatin domain-containing proteins, myostatin propeptide, myostatin antibodies and chemical compounds. These inhibitors could be beneficial for the development of clinical drugs for the treatment of muscular disorders.
  • Bone morphogenetic protein plays a significant role in the development of neuromuscular architecture and its proper functions. Modulation of BMP activity could be beneficial for muscle function in muscular disorders. Tsuchida K., "The role of myostatin and bone morpho genetic proteins in muscular disorders” Expert Opin Biol Ther. 6(2): 147-154 (2006).
  • myopathies can present with unusual or atypical clinical features including, but not limited to, myotonia, periodic paralysis, respiratory failure, swallowing difficulties, ptosis, ophtalmoplegia, camptocormia, distal and/or asymmetrical limb muscle weakness.
  • myopathies include, but are not limited to, reducing body myopathy, X-linked myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy, and scapuloperoneal myopathy.
  • oxidized low- density lipoprotein a recognized oxidative stress marker, has been positively associated with central obesity, metabolic syndrome manifestations and subclinical atherosclerosis. Helen Hermana M Hermsdorff, Nutrition & Metabolism 2011, 8:59.
  • the PPC used in the methods of the present invention are created by an industrial method for processing catches of crustaceans comprising a number of steps beginning with a very early and substantially complete removal of the crustacean's exoskeleton (i.e., for example, the crust, carapace and/or shell).
  • the crustacean exoskeleton comprises a vast majority of fluoride in the organism. Consequently, this step thereby results in a substantial removal of fluoride from the crustacean material.
  • the method also uses longitudinal centrifugation techniques that prevents separation problems caused by emulsions when processing a raw material with high content of phospholipids that is initiated immediately after decking a catch of crustacean.
  • this relates to the period from decking the crustacean catch and to the initial disintegration of the crustacean (see infra).
  • This period of time should be kept to a minimum, and should preferably not exceed 60 minutes, more preferred not exceed 30 minutes, even more preferred not exceed 15 minutes, and should include a direct transfer of the krill catch from the trawl bag and/or net to a suitable disintegrator.
  • a disintegrator of the crustacean material may be a conventional pulping, milling, grinding or shredding machine.
  • the crustacean catch is initially loaded into a disintegration appratus where the crustacean catch is subjected to pulping, milling, grinding and/or shredding to create a disintegrated crustacean material.
  • the temperature of the disintegration process is around the ambient temperature of the water, i.e. between -2 and +1° C, preferably around +0° C. to +6° C, and may be performed by any convenient disintegration method.
  • This disintegration process is also conventionally done by the previous known processing methods, and represents one of the obstacles according to the prior art because it produces large amounts of exoskeletal particles from the crustacean mixing in the milled material and producing a disintegrated paste with a high fluoride content.
  • this high fluoride content is one of the reasons why the prior art processed crustacean material has limited applications and is less suitable for food, feed or corresponding food or feed additives compared to other marine raw materials e.g. pelagic fish.
  • the crustacean material may then be divided into a particle size suitable for a further separation step for not interfering with the subsequent processing steps.
  • the disintegrating process is performed continuously and produces particle sizes up to 25 mm, a preferred particle size range is between approximately 0.5-10 mm and a more preferred size range is between approximately 1.0-8 mm.
  • this small particle size distribution represents one of advantages of the present invention because the fluoride has a tendency to leak out of the milled material and mingle with the rest of the raw material.
  • this leaking process takes time and is not rapid enough to negatively impact a subsequent enzymatic hydrolysis step, provided the hydrolysis step is performed within specific parameters with respect to time and optimal, or near-optimal conditions, such as pH and temperature and optionally with the addition of co-factors such as specific ions depending on the used enzymes.
  • the temperature of the disintegrated material may be elevated to a temperature suitable for the subsequent enzymatic hydrolysis.
  • the temperature may be increased within seconds (e.g. 1-300 seconds, more preferred 1-100 seconds, even more preferred 1-60 seconds, most preferred 1-10 seconds) subsequent to the disintegrating step for reducing the processing time and thereby preventing diffusion of fluoride and for preparing the material for the enzymatic hydrolysis.
  • Enzymes may be added directly to the disintegrated material or through the added water or both, before, during or after the disintegration process.
  • Exogenous proteolytic enzymes e.g., alkalase, neutrase, enzymes derived from
  • microorganisms including, but not limited to, Bacillus subtitis and/ 'or Aspergillus niger, and/or or enzymes derived from plant species
  • the added enzyme(s) may be in the form of one single enzyme or a mixture of enzymes.
  • the conditions of the hydrolysis should match the optimal hydrolytic conditions of the added enzyme(s) and the selection of optimal conditions for the selected exogenous hydrolytic enzyme(s) is known to the person skilled in the art.
  • the exogenous enzyme alkalase having a pH optimum of about 8, a temperature optimum of 60° C. and a hydrolysis time of 40-120 minutes.
  • the selected enzymes, or combination of enzymes should also be chosen for reducing emulsions caused by high content of phospholipids in the raw material.
  • An efficient amount of proteolytic enzyme(s) will be set after a process- and product optimization process that depends upon the efficiency of a specific chosen commercial enzyme or mix of enzymes.
  • a typical amount by weight of commercial enzymes, as a ratio of the amount of the weight of the disintegrated raw material, are preferably between 0.5% and 0.05%, more preferably between 0.3% and 0.07% and most preferable between 0.2% and 0.09%).
  • This hydrolysis step is aided by endogenous (natural) enzymes because rapid and uncontrolled autolysis is well known in fresh caught crustaceans.
  • exogenous enzymes The reason for adding exogenous enzymes is to take control of, and guide, the breakdown of the proteinaceous material in the disintegrated substance as well as speeding up/accelerating the hydrolysis of the material to avoid and/or preclude the leaking of fluoride from the shell, carapace and crust as mentioned supra.
  • hydrolytic enzymes or a combination of hydrolytic enzymes, should also be carefully chosen to reduce emulsion in the production process.
  • Enzymes may be selected from exo- and/or endopeptidases. If a mixture of enzymes is used, such a mixture may also include one or more chitinases for subsequently making the chitin-containing fraction(s) more amenable to further downstream processing.
  • chitinases are used, care must be taken for not increasing the leakage of fluoride from the shell/crust/carapace of the crustacean into the other fractions. However, since such fluoride leakage takes time, it is possible to perform such an enzymatic treatment within the time parameters indicated supra.
  • a more convenient alternative to including chitinases in the enzyme mix of the initial hydrolysis step will be to process the separated chitin-containing fraction subsequently to the separation step.
  • the enzymatic hydrolysis step should be finished within a time interval of 100 minutes, preferably within 60 minutes, most preferred within 45 minutes calculated from the addition of the endogenous enzyme(s).
  • the amount of enzyme(s) added is related to the type of enzyme product used. As an example it may be mentioned that the enzyme alkalase may be added in an amount of 0.1-0.5% (w/w) of the raw material. This should be taken into context with the added endogenous enzymes since the addition of more enzymes will reduce the time interval of the hydro lytic step.
  • the time of the hydrolytic step is one of the crucial features of the present process since a short hydrolysis time reduces the diffusion time of fluoride from particles of the exoskeleton.
  • the hydrolytic enzymatic processing step is intended to remove the binding between the soft tissue of the krill to the exoskeleton of the crustacean.
  • the hydrolyzed and distintegraed crustacean material is passed through a particle removal device operating through a gravitational force such as a longitudinal centrifuge (i.e., for example, a decanter).
  • a longitudinal centrifuge i.e., for example, a decanter
  • This first separation step removes the fine particles containing a considerable amount of the fluoride from the hydrolysed or hydrolysing crustacean material to create a solids fraction.
  • the centrifuge is operated with a g force between 1,000 and 1,800 g, more preferably between 1,200 and 1,600 g and most preferably between 1,300 and 1,500 g. Through this particle removal step a substantial amount of fluoride is removed from the proteinaceous crustacean fraction.
  • the enzymatic hydrolysis may be terminated by heating of the hydrolysing material (incubate) to a temperature over 90° C, preferably between 92-98° C. and most preferred between 92-95° C, prior to, during or after the separation step, as long as the hydrolysis duration lies within the above given boundaries.
  • the hydrolysis is terminated before, during, or after the fine particle removal step, most preferred after the fine particle removal step.
  • the temperature of the first centrifugation particle removal step in one embodiment, depend on the optimal activity temperature of the enzyme (in the case where the enzymatic hydrolysis step is terminated by heating after the fine particle separation step).
  • the fluoride content in the prior art processed krill protein material has limited applications and are less suitable for food or feed or corresponding food or feed additives, as mentioned supra but the fluoride content of the removed exoskeletal material is not preventive for further separation/purification of this fraction.
  • materials such as chitin, chitosan and astaxanthin may be isolated from the separated exoskeletal material. Such isolation procedures are known within the art. Steps may also be taken for removing the fluoride from the isolated exoskeletal material e.g. through dialysis, nanofiltration, through electrophoresis or other appropriate technologies.
  • Hydrolytic enzyme(s) deactivation may be performed in different ways, such as adding inhibitors, removing co-factors (e.g., crucial ions through dialysis), through thermal inactivation and/or by any other deactivating means.
  • thermal inactivation is preferred by heating the proteinaceous material to a temperature where the hydrolytic enzymes become denatured and deactivated.
  • other means than heating for deactivating the hydrolytic enzymes should be selected.
  • a first centrifugation forms a de-fluorinated hydrolyzed and disintegrated crustacean material fraction and a solids fraction (e.g., containing high fluoride exoskeleton particles).
  • the low flourine hydrolyzed and disintegrated crustacean material fraction may be subsequently separated (e.g., by a second centrifugation) to form a low fluoride Phospholipid-Peptide Complex (PPC) composition fraction, a lean low fluoride Concentrated Hydrolysate Fraction (CHF) fraction that can be used as a food and/or feed additives, and a lipid fraction mainly consisting of neutral lipids.
  • PPC Phospholipid-Peptide Complex
  • CHF Concentrated Hydrolysate Fraction
  • the PPC composition subfraction is rich in lipids, like a smooth cream with no particles, wherein the lipids are well suspended within the peptide components. This suspension results in small density differences between the different PPC composition components thereby making it difficult to further separate the PPC composition with common centrifugal separators and/or decanters. This is especially accentuated with crustacean catches during the second half of the fishing season.
  • a low fluoride PPC material may be separated into subtractions using a horizontal decanter centrifuge with an extended separation path.
  • Horizontal centrifuges e.g., generating a rotational force in the Z plane
  • a PPC composition subfraction would enter an ordinary decanter from a bowl through a central placed feed pipe in the middle of the separation zone.
  • the PPC composition subfraction enters at the end and at the opposite side of the outlet. This modification provides a significant improvement in the separation process by providing a considerably longer clarification/separation zone than ordinary decanters and utilizes the total available separation length of the machine.
  • the drive is able to impart high g-forces: 10,000 g for small machines and 5,000 to 6,000 g for high capacity machines, facilitating the separation of very fine, slow- settling PPC composition subtractions without the complications of emulsification.
  • the PPC composition subfraction will be subjected to the highest g-force just before entering under the baffle.
  • the different liquid layers separated from PPC composition subfraction are concentrated gradually along the axis of the horizontal centrifuge thereby exiting the machine under baffle by the g force pressure generated by the machine.
  • the separation of the PPC composition subfraction into a layer comprising about 27-30% dry matter makes the downstream processing efficient in terms of operating/robustness and as well economically considering both yield and costs of preparing the dry matter into a meal composition.
  • the PPC composition subfraction separation also creates a layer comprising a lean hydrolysate that can be evaporated into a concentrated hydrolysate of greater than 60%.
  • the present invention contemplates methods using a phospholipid- peptide complex (PPC) composition from a crustacean (i.e., for example, krill) made immediately after the catch has been brought upon on board a boat and/or ship (i.e., for example, a fishing vessel).
  • PPC phospholipid- peptide complex
  • the process of creating the PPC composition comprises disintegrating the crustaceans into a disintegrated material comprising smaller particles (i.e., for example, between approximately 1 - 25 millimeters), adding water, heating the disintegrated material, adding enzyme(s) to hydrolyze the disintegrated material, deactivating the enzyme(s), removing solids (i.e., for example, exoskeleton, shell, and/or carapace) from the enzymatically processed material to reduce the fluoride content of the material, separating and drying the PPC composition.
  • a disintegrated material comprising smaller particles (i.e., for example, between approximately 1 - 25 millimeters)
  • adding water heating the disintegrated material
  • adding enzyme(s) to hydrolyze the disintegrated material
  • deactivating the enzyme(s) deactivating the enzyme(s)
  • solids i.e., for example, exoskeleton, shell, and/or carapace
  • the PPC composition is transferred to an onshore facility (i.e., a fish oil extraction plant) where a low-fluoride crustacean oil is separated from the PPC composition using solvents including, but not limited to, supercritical C0 2 and/or ethanol.
  • solvents including, but not limited to, supercritical C0 2 and/or ethanol.
  • the separation of the crustacean oil from the PCC gives a high quality protein powder with a protein content of >80% with less than 10% lipids including free fatty acids.
  • the present invention contemplates using this protein powder for human use in nutritional supplements or pharmaceuticals either alone or in combination with other nutrients, micronutrients or bioactive phytochemicals.
  • de-oiled PPC compositions Using alternative extractions, de-oiled PPC compositions, phospolipids and/or extraction residue (i.e., for example, a protein hydrolysate) compositions are also separated from the PPC composition.
  • extraction residue i.e., for example, a protein hydrolysate
  • crustacean oil can be separated effectively, almost completely, from the disintegrated crustacean material (e.g., feed material) during the extraction.
  • the feed material comprises a PPC composition.
  • hydrophobic/phosphorylated proteins is broken thus facilitating the extraction of the lipids.
  • PPC Phospholipid-Peptide/Protein Complexes
  • compositions comprising crustacean lipids (e.g., for example, phospholipids, and/or omega-3 fatty acids) in the form of a dried ground meal and non-lipid ingredients overcome a number of technological problems relating to combinations of nutrients that provide a basis for in vivo synergistic effects as a result of the nutrient combination.
  • the data provided herein demonstrate that when a crustacean PPC meal is mixed with other nutritional ingredients, the clinical improvement is unexpectedly superior to that achieved when compared to any one of the ingredients administered individually.
  • a homogenous and stable composition is contemplated which does not separate into different phases over time.
  • the composition is formulated into a product comprising a tablet, a granule, a pellet or a powder.
  • problems of formulation are encountered when simply combining a crustacean PPC meal with other ingredients including, but not limited to, crustacean oil and/or lipid insoluble nutrients such as glucosamine, chondroitin, zinc oxide and/or vitamin C in a capsule. Simple mixing will result in a sequestration of the lipid insoluble nutrients within the capsule.
  • the present invention contemplates a low fluoride phospholipid- peptide-protein complex (PPC) composition comprising proteins and peptides in the range of 40-60 weight % and lipids in the range of 40-60 weight % lipids and less than 500 mg/kg fluoride.
  • the lipids comprise phospholipids.
  • the present invention contemplates a composition comprising approximately 200-250 grams/Kg phospholipids, approximately 50-150 grams/kg Omega-3, less than 500 mg/kg fluoride, approximately 15 grams/kg lysophosphatidic acid, and less than approximately 20 grams/kg free fatty acids.
  • the preparation of a low fluoride PPC is described herein. See, Example 1. 2.
  • the present invention contemplates a high quality de-oiled protein-peptide complex composition comprising approximately 90% protein/peptide, less than 500 mg/kg fluoride and 100 grams/kg lipids.
  • the protein/peptide product results from the separation of oil from PCC.
  • the ratio between the protein fraction and the peptide fraction may range between approximately 20: 1 to 1 :20.
  • Low Fluoride de- oiled crustacean PPC can be made as described herein. See, Example 1.
  • the present invention contemplates a composition comprising a crustacean PPC meal and one or more additional ingredients, either alone or in combination.
  • the additional ingredient may include, but are not limited to, zinc, magnesium, calcium, vitamin C, vitamin D, vitamin E, lutein and/or zeaxanthin.
  • the composition is formulated to form a tablet, a capsule, a granule, or powder.
  • the capsule is filled with the composition.
  • the capsule is a hard gelatin capsule.
  • the hard gelatin capsule is a sprinkle capsule.
  • a sprinkle capsule comprising krill meal and a lipid insoluble ingredient in a powder form.
  • the formulation is high in protein and lipid.
  • the formulation is low in free fatty acids.
  • the formulation is highly stable, as characterized by the low free fatty acid content, low peroxide levels, low anisidine levels and high astaxanthin levels.
  • the present invention contemplates a nutritional supplement comprising a combination of a krill meal phospholipid-pep tide-protein complex formulation (e.g., for example, Krill Meal 1) and a second ingredient including, but not limited to, minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and or omega-3 oils.
  • a krill meal phospholipid-pep tide-protein complex formulation e.g., for example, Krill Meal 1
  • a second ingredient including, but not limited to, minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and or omega-3 oils.
  • the present invention contemplates a nutritional supplement comprising a combination of a krill meal de-oiled phospholipid-protein complex formulation (e.g., for example, Krill Meal II) and a second ingredient including, but not limited to, minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • a krill meal de-oiled phospholipid-protein complex formulation e.g., for example, Krill Meal II
  • a second ingredient including, but not limited to, minerals, lipid soluble vitamins, lipid insoluble vitamins, bioactive health ingredients and/or omega-3 oils.
  • a crustacean meal is a krill meal nutritional supplement composition
  • krill PPC ranges between approximately 10 - 90 % (w/w) of the composition, more preferably ranges between approximately 20 - 60 % (w/w) of the composition, and most preferably ranges between approximately 25 to 50 % (w/w) of the composition.
  • the lipid insoluble ingredients range between approximately 10 - 90 % (w/w) of the composition, more preferably ranges between approximately 20 - 60 % (w/w) of the composition, and most preferably ranges between approximately 25 to 50 %(w/w) of the composition.
  • the omega-3 fatty acids range between approximately at least 1 % (w/w) to at least 5 % (w/w) of the composition, and preferably at least 4 % (w/w) of the composition.
  • the excipients range between approximately 0 - 80 % (w/w) of the composition, more preferably ranging between approximately 0 - 60 % (w/w) of the composition, and most preferably ranging between approximately 0 to 50 % (w/w) of the composition, wherein the composition comprises about 20 % (w/w) excipients.
  • a daily dose of a crustacean PPC meal composition as disclosed herein is between approximately 0.1 - 100 g per day per human individual, more preferably between approximately 0.25 to 50 g/d per human individual, and still more preferably between approximately 0.5 to 25 g/d per human individual.
  • a tablet, granule, powder, pellet or capsule comprising a crustacean PPC meal composition maybe administered in a daily dose of between approximately 0.2 to 20 g/20 kg body weight, more preferably 0.4 to 10 g/20 kg body weight, still more preferably 0.8 to 5.0 g/20 kg body weight.
  • the present invention contemplates a composition comprising a crustacean PPC meal and lipid insoluble ingredients in a weight ratio ranging between approximately 16: 1 to 1 : 1. In one embodiment, the PPC and lipid insoluble ingredient weight ratio is approximately 4: 1. In one embodiment, the present invention contemplates a composition comprising PPC and krill oil in a weight ratio ranging between approximately 4: 1 to 1 :4. In one embodiment, the PPC and krill oil weight ratio is approximately 1: 1.
  • compositions processed further into a tablet, granule, pellet, powder or treat or sprinkle capsules provide additional advantages.
  • Inclusion of crustacean lipids in the form of PPC in tablets and other compacted products provides improved stability of crustacean lipids and this invention discloses reduced degradation of crustacean lipid components including, but not limited to, omega-3 fatty acids, astaxanthin, and phospholipids as compared to previously reported capsulated materials.
  • the present invention contemplates a nutritional supplement composition, characterized in that said composition comprises a crustacean PPC meal, low fluoride crustacean oil, and lipid insoluble ingredients, hi one embodiment, the composition is homogenous.
  • the crustacean oil comprises a krill oil.
  • the composition is stable.
  • the homogeneity of the composition is characterized by a lack of phase separation.
  • the stability of the low fluoride krill oil is characterized by, in comparison to conventional krill oil, lower lyso-phospholipids, increased omega-3 levels, lower peroxide, lower p-anisidine, and higher astaxanthin.
  • Extracting krill oil is generally a difficult process resulting in high cost of the oil and often inferior quality (e.g., lower levels of long chain PUFA omega-3) compared to the oil in the meal.
  • the present invention contemplates a crustacean lipid composition comprising at least 75% phospholipids. In one embodiment, the lipid composition comprises between approximately 75% - 90%
  • the lipid composition comprises between approximately 75% - 80% phospholipids.
  • the present invention contemplates a dried extraction residue (e.g., protein hydrolysate) composition comprising approximately 70 - 80% protein, approximately 1.5 - 3.0% lipids, and approximately 5 -7 % ash.
  • Low fluoride crusteacan oil can be made as described herein. See, Example 2.
  • omega-3 PUFAs are one of the most studied nutrients the last 30 years and there are reported a wide variety of positive health-promoting effects and physiological functions of these omega-3 fatty acids.
  • the two most functionally important omega-3 PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
  • EPA eicosapentaenoic acid
  • DHA docosahexaenoic acid
  • Research and clinical data shown that these fatty acids are implicated in maintaining normal blood pressure, managing inflammation and supporting cognitive health. They are also central in healthy nutrition and in prevention of heart disease.
  • EPA and DHA can be obtained from diet or produced in the human body from their precursor alpha-linolenic acid (ALA).
  • ALA alpha-linolenic acid
  • omega-3 PUFAs Although conversion of v-linolenic acid to omega-3 PUFAs is important to retain constant level of EPA and DHA, emerging evidence suggest that synthesis of EPA and DHA from ALA is relative inefficient. With high age and for some diseases the body's ability to convert ALA to EPA and DHA is reduced to a level which is insufficient to retain a sufficient level in vital organs as brain and retina. Therefore, efficient tissue accretion of omega-3 PUFAs depends on the delivery of EPA and DHA from diet.
  • omega-3 PUFA intake are attributed to their distinct capacities to modulate cellular metabolic functions and gene expression. Variation in distribution of different fatty acids/lipids to different tissues in addition to cell specific lipid metabolism, as well as expression of fatty acid- regulated transcription factors, is likely to play an important role in determining how cells respond to changes in PUFA composition. (Benatti, P et al, J. Am. Coll. Nutr.2004, 23, 281).
  • omega-3 dietary source is fish oil or omega-3 concentrates from fish oil.
  • fish oil the omega-3 is in the form of a triglyceride and the natural content of omega-3 fatty acids is in the range of 20-30%.
  • concentrated formulas the omega-3 fatty acids are found as ethylesters or triglycerids and the content of omega-3 fatty acids are in the range of 50-90%.
  • krill oil the omega-3 fatty acids are mainly found in phospholipids and the content of omega-3 fatty acids is in the range of 15-30%.
  • omega-3 has effects on absorption, distribution and tissue accumulation of the omega-3 fatty acids. This will impact the biological effects of the different omega-3 formulations.
  • polyunsaturated fatty acids given as phospholipids give increased accumulation of PUFAs in brain compared to triglycerids and ethylesters formulations.
  • omega-3 fatty acids present in fish oil are considered beneficial supplementary nutrients for companion animals e.g. dogs.
  • omega-3 fatty acids can be derived from several sources of marine organisms including micro algae, seal, squid, molluscs, krill to name a few.
  • Typical sources of omega-3 fatty acids from marine organisms is the oil extracted from the organism.
  • Lipids extracted from Antarctic krill (Euphausia superba) or krill oil contains omega-3 fatty acids.
  • Krill oil has been used as an ingredient in nutritional supplements with remarkable potential to alleviate the arthritis symptoms in human subjects. Deutch et al. J. Am. Coll. Nutr. 26(l):39-48 (2007). Products involving combinations of krill oil and cartilage protecting supplements, such as Genflex 3 and Omegagen are commercially available for humans. It would be useful to have similar combination products for supplementing the diets of animals, such as dogs or other companion animals suffering from osteoarthritis. The form in which the combination products are presented i.e. in gelatin capsules is not the preferred form for supplementing health promoting nutrients to dogs, as dogs do not willingly eat the capsules.
  • the present invention contemplates a composition comprising one or more krill meal lipid insoluble ingredients, either alone or in combination.
  • the composition further comprises lipid soluble ingredients, for example vitamin A, vitamin D, vitamin E, alpha lipoic acid, lutein and other natural carotenoids.
  • the composition is formulated to form a tablet, a capsule, a granule, a pellet or powder.
  • the capsule is filled with the composition.
  • the capsule is a hard gelatin capsule.
  • Protein is particularly important for maintaining muscle strength and preventing sarcopenia, or age-related loss of muscle mass in the elderly population. While the World Health Organization's recommended daily intake for protein is 0.8 g per kilo of bodyweight a day, many scientists working in the field suggest that 1.2 to 1.3 g/kg/day is needed to prevent sarcopenia.
  • Proteins from fish and other marine species have been shown to influence lipid metabolism in rodent models (Jaques et al 1995; Liaset et al., 2009) as well as reduce inflammation in response to feeding high-fat diets (Pilon et al).
  • the combination of omega-3 fatty acids and marine protein appear to have synergistic effects on plasma lipid lowering (Wergedahl et al, 2009; Hosomi et al, 2011).
  • a fat-free krill powder comprising a hydrolysed protein demonstrated antihypertensive effects in spontaneously hypertensive rats.
  • two peptides with angiotensin I-converting enzyme inhibitory effects were subsequently isolated from this hydrolysed protein (Hanaka et al, 2009).
  • a krill meal product containing lipid and protein demonstrated a broad range of effects in a mouse model of dyslipidemia and chronic inflammation. (Bjorndal et al..)
  • Extraction residue e.g., protein hydro lysate
  • compositions may be prepared as described herein, produced in conjunction with low fluoride de-oiled PPC. See, Example 2.
  • Carotenoids are phytochemicals considered beneficial in the prevention of a variety of major diseases. Carotenoids are classified, according to their chemical structure, into carotenes and xanthophylls.
  • the carotene carotenoids include ⁇ -carotene and lycopene and the xanthophyll carotenoids include, but are not limited to, lutein, canthaxanthin, zeaxanthin, violaxanthin, capsorubin and/or astaxanthin.
  • the marine carotenoid astaxanthin (ASTA) is naturally found in a wide variety of living organisms, such as microalgae, fungi, and crustaceans.
  • the human retina accumulates lutein and zeaxanthin two other carotenoids. The latter predominates at the macula lutea while lutein predominates elsewhere in the retina.
  • AMD age-related macular degeneration
  • antioxidants can be effective in lowering oxidative stress and to prevent or improve health conditions related to oxidative stress. It is important that these antioxidants have the capability to penetrate cell membranes. To have effects in relation to neurodegenerative and eye diseases the antioxidant has to penetrate the blood brain barrier.
  • One antioxidant that has this capability is astaxanthin. Astaxanthin provides cell membranes with potent protection against free radical or other oxidative attack. Experimental studies confirm that this nutrient has a large capacity to neutralize free radical or other oxidant activity in the nonpolar ("hydrophobic") zones of phospholipid aggregates, as well as along their polar (hydrophilic) boundary zones. Kidd, P. Alternative Med. Rev. 2011, 11, 364.
  • Resveratrol is a natural product isolated from most red wines.
  • resveratrol derivatives including its oligomers
  • these compounds are believed to have antioxidant activity.
  • antioxidant activity of resveratrol derivatives may be dependent upon specific structure-activity relationships as evidenced by comparison of resveratrol derivatives (i.e., for example resveratrol oligomers).
  • Others sugggest that resveratrol may also have a potential as therapeutic agents for cerebral and cardiovascular diseases. He et al., "From Resveratrol to Its Derivatives: New Sources of Natural Antioxidant" Curr Med Chem. E-pub Dec 3, 2012.
  • Coenzyme Q10 (CoQIO) widely occurs in organisms and tissues, and is produced and used as both a drug and dietary supplement. Increasing evidence of health benefits of orally administered CoQIO are leading to daily consumption in larger amounts, and this increase justifies research and risk assessment to evaluate the safety. A large number of clinical trials have been conducted using a range of CoQIO doses. Reports of nausea and other adverse gastrointestinal effects of CoQIO cannot be causally related to the active ingredient because there is no dose-response relationship: the adverse effects are no more common at daily intakes of 1200 mg than at a 60 mg.
  • Zinc was recognized to be essential for human health in 1963, and its deficiency affects nearly 2 billion people in the developing world. Growth retardation, immune disorders, and cognitive impairment are major manifestation of zinc deficiency. Prasad et al, J. Lab. Clin. Med, 138(4):250-256 (2001).
  • Calcium is a mineral believed essential for living organisms, in particular in cell physiology, where movement of the calcium ion (Ca + ) into and out of the cytoplasm functions as a signal for many cellular processes.
  • Ca + calcium ion
  • calcium is the most abundant metal by mass in many animals.
  • Calcium supplements are used to prevent and to treat calcium deficiencies. It is currently recommended that supplements be taken with food and that no more than 600 mg should be taken at a time because the percent of calcium absorbed decreases as the amount of calcium in the supplement increases. It is also recommended to spread doses throughout the day. Recommended daily calcium intake for adults ranges from 1000 to 1500 mg. It is recommended to take supplements with food to aid in absorption. Vitamin D is added to some calcium supplements. Proper vitamin D status is important because vitamin D is converted to a hormone in the body, which then induces the synthesis of intestinal proteins responsible for calcium absorption.
  • disorders of calcium are usually linked to magnesium balance and, consequently, are physiologically and clinically challenging.
  • a physiology-based approach to the disorders of hypocalcemia, hypercalcemia and/or hypomagnesemia would suggest that the balance of both minerals are involved.
  • Calcium and, to a lesser extent, magnesium balance is achieved through a complex interplay between the parathyroid gland, bone, the intestine and the kidney.
  • CaSR calcium- sensing receptor
  • the main intestinal and renal transporters for calcium and magnesium namely, the transient receptor potential channels TRPV5, TRPV6 and TRPM6.
  • PTH parathyroid hormone
  • the present invention contemplates a composition comprising an animal food and a crustacean PPC meal food ingredient.
  • the PPC meal food ingredient is less than 5% of the composition.
  • the krill meal composition comprises a pet treat.
  • the pet treat composition includes flavor ingredients. Although it is not necessary to understand the mechanism of an invention, it is believed that such flavor ingredients give the pet treat composition a special appealing flavour.
  • the flavor ingredients are either natural or synthetic.
  • the pet treat compositions further comprise filler ingredients. Although it is not necessary to understand the mechanism of an invention, it is believed that such filler ingredients provide a desirable consistency and bulk to the composition.
  • filler ingredients include but are not limited to, meat meals and extracts, other animal byproducts, fish meal and extracts, plant protein meals, cereal meals or fractions of cereals and various binding agents known in the art.
  • a daily dose of a krill meal composition as disclosed herein is administered as between approximately 0.005 to 0.50 gram (g) krill meal/kilogram (kg) animal body weight, more preferably 0.01 to 0.25 g krill meal/kg animal body weight, and still more preferably 0.02 to 0.125 g krill meal/kg animal body weight.
  • a daily dose of the composition preferably would be between approximately 0.1 - 10 g krill meal per day per animal, more preferably between approximately 0.2 to 5 g/d/animal, still more preferably between approximately 0.4 to 2.5 g/d/animal.
  • animals e.g., companion animals
  • krill meal enhances the palatability of animal food or feed, in particular a companion animal's food or feed (i.e., for example, dog food) at concentrations that are at least an order of magnitude lower than what would be required if krill meal was added to food for its nutritional content (protein, fat, carbohydrate).
  • the present invention contemplates a method for improving the palatability of animal food or feed, characterized in that at least 0.01 % (w/w), but less than 1 % (w/w) krill meal is added to animal food or feed.
  • the present invention contemplates a use of krill meal as a flavor ingredient in the amount of less than 1 % (w/w) in animal food or feed.
  • the present invention contemplates a composition comprising an animal food and a krill meal food ingredient.
  • the krill meal food ingredient comprises a krill oil.
  • the composition further comprises at least one omega-3 fatty acid.
  • the krill meal food ingredient is less than 5% of said composition.
  • the krill meal food ingredient is less than 1% of said composition, hi one embodiment, the hard gelatin capsule is a sprinkle capsule.
  • a sprinkle capsule comprising krill meal and a lipid insoluble ingredient in a powder form.
  • Hard gelatin capsules are especially suitable as they can be opened easily by the companion animal owner and the contents dispensed to the animal, for example by sprinkling the composition on dog food.
  • the present invention contemplates a method for preparing a nutritional supplement composition, characterized in that the method comprises mixing a crustacean PPC meal and lipid insoluble ingredient(s). In one embodiment, the mixing further comprises at least one excipient suitable for food or feed.
  • the present invention contemplates a method for producing a nutritional supplement composition.
  • the method comprises mixing krill meal and lipid insoluble ingredient(s).
  • the method further comprises mixing suitable excipients.
  • the composition is preferably formulated to a desired form by using methods well known for a person skilled in the art.
  • the mixing produces a homogenous composition comprising dry krill meal and lipid insoluble ingredients.
  • the mixing of the dry krill meal includes krill oil.
  • the present invention contemplates a novel method of enhancing the palatability of animal food or feed, in particular dog food by adding low levels of krill meal. Furthermore, the method further comprises increasing the food intake of an animal. Although it is not necessary to understand the mechanism of an invention, it is believed that for some animals, in particular companion animals, such as finicky dogs which commonly do not eat sufficient amounts of food offered, krill meal food supplements may improved food consumption.
  • the method further comprises adding the krill meal composition to an animal food or feed.
  • the amount of krill meal composition added to the animal food or feed is less than 5 %, preferably less than 3 %, more preferably less than 1% (w/w), still more preferably less than 0.5%, most preferably less than 0.1% of the weight of the feed.
  • the amount of krill meal composition added to the animal food or feed ranges between approximately 0.01 - 0.9 % (w/w), more preferably ranging between approximately 0.1 - 0.5 % (w/w).
  • a krill meal food or feed comprises a highly palatable treat used for training of the dogs or other companion animals, where krill meal is used as an animal feed ingredient.
  • the present invention contemplates a nutritional supplement composition comprising krill meal lipids and lipid insoluble components.
  • the nutritional supplement composition comprises a companion animal treat.
  • the nutritional supplement composition comprises a suitable form selected from the group consisting of a tablet, a capsule, a granule, a pellet, or a powder.
  • the capsule comprises a hard gelatin capsule.
  • the hard gelatin capsule is a sprinkle capsule.
  • the present invention contemplates a krill meal nutritional supplement comprising cartilage protecting substances.
  • the cartilage protecting substance comprises chondroitin and/or glucosamine.
  • the nutritional supplement may further comprise a lipid insoluble ingredient.
  • the invention is not limited to any particular lipid insoluble ingredient, but a range of lipid insoluble ingredients are contemplated.
  • Non-limiting examples of such components are: glucosamine hydrochloride, glucosamine sulfate, glucosamine potassium, glucosamine sodium, N-acetyl d-glucosamine, chondroitin, hyaluronic acid, green lipped mussel powder, creatine, L-carnitine, ascorbic acid, manganese, manganese proteinate, zinc, zinc proteinate, copper, copper proteinate, ginseng, green tea extract, ginger, garlic, vincamine, grape seed extract, grape seed meal, dimethyl glycine, whey protein, brewer's yeast, St. John's wort, vinpocetine, aloe vera, ginko biloba, curcumm, betaglucans, mannaoligosaccharides and any combination thereof.
  • the present invention further provides pharmaceutical compositions (e.g., comprising the compounds described above).
  • the pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions and formulations for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets.
  • Thickeners flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable.
  • compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions that may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.
  • compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions maybe generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.
  • the pharmaceutical formulations of the present invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media.
  • Aqueous suspensions may further contain substances that increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • the pharmaceutical compositions may be formulated and used as foams.
  • Pharmaceutical foams include formulations such as, but not hmited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product.
  • cationic lipids such as lipofectin (U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (WO 97/30731), also enhance the cellular uptake of oligonucleotides.
  • compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions.
  • the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.
  • Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved.
  • Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. The administering physician can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC50S found to be effective in in vitro and in vivo animal models or based on the examples described herein.
  • dosage is from 0.01 ⁇ g to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly.
  • the treating physician can estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues.
  • low fluoride crusteacean meal e.g., krill
  • Figure 1 A fresh crustacean catch underwent disintegration and hydrolysis immediately after decking onboard a fishing vessel. Subsequently, the crusteacean exoskeleton was separated from the fleshy proteinaceous/lipid material to form a low fluoride phospholipid-peptide-protein complex (low fluoride PPC), wherein the majority of the fluoride in the organism is retained within the exoskeleton material (e.g., by using a horizontal centrifuge). This low fluuride fleshy proteinaceous/lipid material was then dried and ground into a low fluoride crustacean meal (e.g., for example, Krill Meal 1). An overall analysis of Krill Meal 1 is depicted in Table 1 :
  • Lipid classes g/100g Lipid classes g/100g
  • Krill Meal 1 or a low fluoride PPC, was further subjected to an extraction with a supercritical gas (e.g., carbon dioxide) that created a low fluoride de-oiled phospholipid- protien complex (e.g., low fluoride de-oiled PPC).
  • a supercritical gas e.g., carbon dioxide
  • the low fluoride de-oiled PPC was then dried and ground into Krill Meal 2.
  • An overall analysis of Krill Meal 2 is depicted in Table Table 6: Overall Composition Analysis
  • a feed material such as low fluoride PPC or Krill Meal 1 was prepared in accordance with Example 1, was supplied in a sealed plastic bag containing approximately 25kg. The feed material was kept frozen until used in extractions. The granules have a size distribution typically in the range 2 to 5mm, but a number of fine fragments were also present. The granules are greasy to the touch but still break up under compression rather than smear.
  • the extracted krill oil material was passed through two separation vessels in series, held at 90 bar and 45-50 bar respectively.
  • the final krill oil material collected from both separators was pooled together and the ethanol was evaporated.
  • the residual feed material comprises a de- oiled feed material (e.g., for example, de-oiled PPC) and/or an extraction residue, such as a protein hydrolysate, having a reduced lipid content in comparison to the starting feed material. See, Example IX.
  • krill oil cumulative extraction curves were generated for both Run 1 and Run 2 by independently analyzing each sample taken during the extraction runs. See, Table 11. Table 11 - Progressive krill oil extraction sample points and yields.
  • This method of krill oil production resulted in the near complete extraction of total lipids from the krill meal (e.g., for example, approximately 95% of neutral lipids and 90% of phospholipids.
  • the final yield was similar for both the high and low pressure runs, but neutral lipids were more rapidly extracted at higher pressure.
  • the phospholipid extraction rate was similar under both extraction conditions.
  • the pooled krill oil total lipid had an overall phospholipid level of just over 40 wt% and both phosphatidyl inositol and phosphatidyl serine were poorly extracted.
  • the first column shows the specific phospolipids that were analyzed.
  • the second column show the phospholipid profile of the starting feed material (e.g., a low fluoride PPC prepared as described in Example 1).
  • Columns three - eight show the phospholipid profile of each krill oil sample taken during the extraction process as described above.
  • the last two columns show the phospholipid profile of the residual extracted feed material sampled from either the top and/or the bottom of the phospholipid extraction column (e.g., for example, an extraction residue, protein hydrolysate and/or de-oiled PPC).
  • PC phosphatidyl choline
  • phospholipids including contributions from both alkyl acyl phosphatidyl choline (AAPC) and lyso phosphatidyl cholines (e.g., for example, LPC and/or LAAPC).
  • AAPC alkyl acyl phosphatidyl choline
  • lyso phosphatidyl cholines e.g., for example, LPC and/or LAAPC.
  • Smaller amounts of phosphatidyl ethanolamine (PE) are present in both the feed material (column 1, - 5.3%) and in the krill oil extract samples (columns 3 - 8), ⁇ 3.5 - 4.5%).
  • Alkyl acyl and lyso forms of PE (AAPE, LPE) are also present in the feed material and krill oil extracts.
  • Phosphatidyl inositol (PI) and phosphatidyl serine (PS) are present in the feed material, but because they are poorly soluble in ethanol, these phospholipids are poorly extracted and are therefore concentrated in the extracted feed material residue (e.g., having a higher level in the residual PPC in comparison to the feed material, see columns 9 and 10).
  • the data show: i) a relative absence of free fatty acids (FFAs); ii) less than 2% of sterols; iii)
  • extracted krill oils may comprise between approximately 0.01 - 0.1 % FFA of total lipids.
  • This example demonstrates an exemplary analytical lipid extraction with the Soxhlet method comparing conventional krill meal with a low fluoride krill meal (e.g. low fluoride PPC) as described herein.
  • Soxhlet method is a standard method in quantitative determination of fat content of foods and feeds and thus it can be used as a reference method to determine the extractability of various krill meals.
  • the Soxhlet method may be carried out as below using petroleum ether (boiling point 30-60 °C).
  • Conventional krill meal was prepared as described in US 2008/0274203 (Aker Biomarine ASA, Bruheim et al.) and the low fluoride PPC was prepared according to the present invention.
  • the neutral lipids are often part of large aggregates in storage tissues, from which they are relatively easily extracted.
  • the polar lipids are present as constituents of membranes, where they occur in a close association with proteins and polysaccharides, with which they interact, and therefore are not extracted so readily.
  • the phospholipids are relatively tightly bound with hydrophobic proteins and in particular with the phosphorylated proteins.
  • This example presents one method of determining fluoride content of krill products as fluoride by chemical analysis using an ion selective electrode.
  • a low fluoride PPC (Krill Meal 1) was prepared as described herein and extracted in accordance with Example 2 to create a low fluoride krill oil. Both the meals and the oils were analyzed for fluoride content and compared with conventional preparation processes. Briefly, the method disclosed herein removes, in most part, the krill exoskeleton from the krill meal thereby reducing the fluoride content. In contrast, the krill exoskeleton is included in the conventional krill meal thereby having relatively high levels of fluoride.
  • Conventional processes are, for example, described in WO 2002/102394 (Neptune Technologies &
  • the krill meals analyzed for fluoride content were produced by: i) a low fluoride method of present invention; and ii) a whole krill material produced by a conventional process. See, Table 15.
  • Krill oil has typically a strong red colour arising from the carotenoid astaxanthin present in the oil at levels varying from 50 ppm to 1500 ppm. Color of krill oil can be determined with a LabScan ® XE spectrophotometer (Hunter Associates Laboratory, INC. Resbon, VA, USA) and reported in CIELAB colour scales (L*, a* and b* values). Deviation from the red colour of astaxanthin can occur when the krill biomass is processed at high temperature and under conditions that induce oxidation. Typical oxidation induced deviation in krill oil color is an increase in the brownish hue. Brown color in krill oil arises from oxidation of lipids and formation of secondary and tertiary oxidation products with amino residues. This process is also called non-enzymatic browning.
  • Strecker degradation products and pyrroles are products of non-enzymatic browning that have been characterized in samples of krill oil.
  • polymerization of pyrroles results in formation of brown, melatonin like macromolecules.
  • pyrrole content of krill oil can be determined spectroscopically with absorbance at 570 nm.
  • krill oil produced by the method of the present invention has the lowest level of brown color determined spectrophotometrically by using CIELAB colour scales (L*, a* and b* values) and/or the lowest level of pyrroles determined spectroscopically.
  • Organoleptic quality of krill oil is conventionally determined by chemical analysis of volatile nitrogenous compounds arising from the decomposition of krill proteins and trimethyl amine oxide (TMAO). Nitrogenous compounds analyzed are total volatile nitrogen (TVN) and trimethylamine (TMA). In simplified terms the level of nitrogenous compounds correlate with the level of spoilage in the raw material i.e. krill biomass used for extraction of the oil.
  • TMAO trimethyl amine oxide
  • the sensory properties to be determined include several pre-defined parameters of smell and taste. It is to be found that the novel krill oil has an improved sensory profile compared to the other oils tested.
  • the other oils to be tested include one extracted from frozen krill by a method described in WO 2002/102394 (Neptune Technologies & Bioresources) and one extracted from dried krill meal with ethanol alone as described in US 2008/0274203 (Aker Biomarine ASA).
  • krill oil was prepared by krill meal extraction at 40 bars and 40°C using supercritical dimethyl ether (SC DME).
  • SC DME supercritical dimethyl ether
  • the DME extract composition was dried on a Rotavapor ® and then flushed with nitrogen.
  • the components of the resultant dried composition is listed below. See, Table 18.
  • Table 19 Phospholipids in Low fluoride krill oil analyzed using P NMR.
  • the example presents data showing the lipid compositional analysis of a low fluoride phospholipid-protein complex composition created by the methods described herein.
  • the PPC comprises approximately 46.7 g/100 g (e.g., ⁇ 47%) total fat, 11.8 g/100 g (e.g., ⁇ 12%) eicosapentaenoic Acid (EPA) and 6.7 g/ 100 g (e.g., ⁇ 7%) docosahexaenoic acid (DHA).
  • the total lipid content of the PPC total fat was approximately 87.7 % (w/w) and comprises between approximately 115 - 260 mg/kg astaxanthin and between approximately
  • the example presents data showing the lipid compositional analysis of a low fluoride de-oiled phospholipid-protein complex composition created by the methods described herein. Consequently, it would be expected that the fluoride content of the compositions described below are less than 500 ppm.
  • the de-oiled PPC comprises approximately 35 g/ 100 g (e.g., ⁇ 35%) total fat, 16.6 g/100 g (e.g., ⁇ 17%) eicosapentaenoic Acid (EPA) and 10.0 g/ 100 g (e.g., -10%) docosahexaenoic acid (DHA).
  • the total lipid content of the de-oiled PPC total fat was approximately 87.7 % (w/w) and comprises approximately 115 mg/kg astaxanthin and approximately 35.2% unextracted oil.
  • Table 26 Low Fluoride Krill De-Oiled PPC Fat: Neutral Lipid Content (20.1 % w/w of total
  • the example presents data showing the lipid compositional analysis of a low fluoride phospholipid-protein complex mixed with an extraction residue (protein hydrolysate) composition created by the methods described herein in an approximate 60/40 ratio.
  • Protein was prepared by extraction of lipids from either the PPC or the de-oiled PPC. It would be expected that the fluoride content of the compositions described below are less than 500 ppm.
  • the mixture comprises between approximately 28-30 g/100 g (e.g., ⁇ 30%) total fat, approximately 98 mg/kg astaxantine esters, approximately less than 1 mg/kg astaxanthine, a peroxide level of less than 0.1 %;(mEq/kg) and/or an ananiside level of less than 0.1 % (w/w).
  • Krill meal 1 was mixed with zinc oxide, Vitamin C and vitamin E, wherein the daily effective dose is between approximately 1 - 3 grams. This composition is effective for ocular medical disorders, such as those involving retinal disorders.
  • Krill meal 1 is mixed with zinc oxide, vitamin C, vitamin E, lutein, and zeastaxanthin, wherein the daily effective dose is between approximately 0.5 - 2 grams.
  • This composition is effective for ocular medical disorders, such as those involving retinal disorders.
  • Krill meal 1 was mixed with phytosterols and vitamin D, wherein the daily effective dose is between approximately 0.5 - 4 grams. This composition is effective for cardiovascular medical disorders, such as those involving the heart.
  • Krill meal 1 mixed with calcium, vitamin D and vitamin K, wherein the daily effective dose is approximately between 0.5 - 4 grams.
  • This composition is effective for skeletal medical disorders, such as those involving overall bone health.
  • Krill meal 1 was mixed with Ubiquinone (Q10).
  • the composition is effective for central nervous system disorders, such as those involving the brain.
  • Krill meal 2 was mixed with microencapsulated DHA, lutein, xeastazantin, zinc, and vitamin C. This composition is effective for ocular medical disorders, such as those involving the retina.
  • Krill meal 2 was mixed with microencapusulated omega-3 fatty acids. This composition is effective for muscular medical disorders, such as those involving muscle protein anabolism and/or mitochondrial function. Dysfunctional mitochondria in particular are thought to play a key role in muscle function decline, as the mitochondria are the main producers of both cellular energy and free radicals. Alterations in mitochondria have been noted in aging, including decreased total volume, increased oxidative damage, and reduced oxidative capacity.
  • Hard gelatin capsules are commercially available (e.g., PAG Pharmatech Co., Ltd. SZ China (venue)) and generally have two components a base, or body, and a shorter cap which fits firmly over the base.
  • a variety of capsules sizes are available, wherein the capacity of each size varies according to PPC composition and their apparent densities.
  • Hard gelatin capsules are commercially available as clear gelatin capsules or in a variety of colors. For example, different colored capsules can be used to distinguish two different PPC formulations thereby allowing easy identification.
  • the capsule halves are separated and a predetermined, weighed amount, of PPC composition is placed in each capsule half. The capsule halves are then inserted into each other and stored until use.
  • Hard gelatine capsules are filled with a PPC composition in accordance with Example 1 .
  • Different subsets of the filled capsules are then stored under different environmental conditions, for example, at temperatures ranging between - 10 to +100 ° C for different lengths of time (e.g., ranging between 24 hours - 5 years). It would be expected that little or no changes in PPC composition occurs at the lower temperature and shorter lengths of time, versus d e higher temperatures for longer periods of time.
  • the mixtures of crustacean PPC composition as described herein are used to flavor drinks and/or beverages.
  • Such drinks and/or beverages include, but are not limited to, sport drinks, nutritional drinks, milk drinks (e.g., cow milk, goat milk etc.).
  • the flavoring may be performed on an individual drink were a predetermined, weighed amount, of PPC composition is mixed into the drink.
  • Alternative, on a commercial scale, the flavoring may be performed on a large volume of the drink, (e.g., tens, hundreds or thousands of gallons) by emulsifing the PPC composition into the drink volume.
  • Total antioxidant capacity is measured in different crustacean low fluoride PPC compositions using a Ferric Reducing Antioxidant Power (FRAP) analysis (Vitas AS).
  • FRAP Ferric Reducing Antioxidant Power
  • FRAP ferric reducing antioxidant power
  • ferric tripyridyl triazine (Fe III TPTZ) complex to ferrous form (which has an intense blue colour) can be monitored by measuring the change inabsorption at 593 nm.
  • the reaction is non specific, in that any half reaction that has lower redox potential, under reaction conditions, than that of ferric ferrous half reaction, will drive the ferrous (Fe III to Fe II) ion formation.
  • the change in absorbance is therefore, directly related to the combined or "total" reducing power of the electrondonating antioxidants present in the reaction mixture.
  • a list of primary reagents are:
  • a sample (100 ⁇ ) of a PPC composition is mixed with 3 ml of working FRAP reagent and absorbance (593 nm) is measured at 0 minute after vortexing. Thereafter, samples are placed at 37°0 C in water bath and absorption is again measured after 4 minutes. Ascorbic acid standards (100 ⁇ -1000 ⁇ ) were processed in the same way. The analyzer or spectrophotometer is blanked and the OD of Standard and Test at zero minute is measured at 593 nm.
  • a FRAP value of the sample ( ⁇ ) (Change in absorbance of sample from 0 to 4 minute / Change in absorbance of standard from 0 to 4 minute) X FRAP value of standard (1000 ⁇ ).
  • Krill Meal 1 is prepared in accordance with Example I, flushed with argon and stored at 0°C until use.
  • U937-NE-KB-LUC cells are cultured in RPMI-1640 medium with L-glutamin (2nM), penicillin (50 U/ml), streptomycin (50 mg/ml), hygromycin (75 ug/ml), 10% Fetal Bovine Serum at 37°C and C0 2 .
  • the cells are seeded in 24-well plates wherein 1% Fetal bovin serum is added to the medium.
  • NF-kB activity is induced by lipopolysaccharide (LPS) or human TNF-a. Cell viability was measured by trypan blue staining.
  • Luciferase activity is measured by imaging with a IVIS Imaging system from
  • Luminescence is detected after 1 min. and 5 min after addition of 0.2 mg d-luciferin/ml cell medium. Number of photons in each well/second is calculated using Living Image Software. (Xenogen)
  • the preferred animal model could be either the ApoE-3*Leiden mice or the ApoE-3 *Leiden.CETP mice.
  • the lipid profile of the mice model is similar to humans and the animal respond to omega-3 pufas, sterols, statins. Measurements include, but are not limited to, standard lipid parameters as TG, LDL, HDL but also include some cardiovascular inflammatory parameters as ox-LDL, LP-PLA2 and CRP which are relevant as biomarkers for atherosclerosis. It it is expected that crustacean PPC meal has a greater therapeutic efficacy than ordinary omega-3 products on these parameters.
  • a relevant animal model for inflammation is the NFKB-RE-1UC transgenic mouse model. This animal model express luciferase under the control of NF-kappaB, enabling real- time in vivo imaging of NF-kappaB activity and thereby inflammation in intact animals.
  • one age-related biomarker comprises an F2-isoprostane.
  • F2-isoprostanes are related a group of bioactive prostaglandin F2-like compounds generated by oxidatively catalyzed reaction of arachidonic acid, are considered as the reliable marker of lipid peroxidation in vivo.
  • the 8-isoprostane (8-isoprostaglandin F2a; the major F2-isoprostane), the well- known compound belonging to the F2-isoprostane class, is usually quantified in urine instead of plasma for practical use because of the short half- life of plasma F2- isoprostane. Elevated levels of plasma and/or urinary 8-isoprostane have been reported in several conditions such as diabetes , alcoholic liver disease, and cardiovascular disease.
  • in vivo models can be used to determine: i) a superior reduction in drusen spots in retina by treatment with Krill Meal 1 or Krill Meal 2, and the additional ingredients of zinc, xeastazantin, lutein and astaxanthin; ii) an improved lipid profile and reduction of inflammatory markers in APOE3 mice with either Krill Meal 1 or Composition 4 supplemented with krill oil and 60% omega-3 fattu acids; iii) a reduction of mflammatory markers in humans with cardiovascular risk factors CRP, Oxidized LDL, isoprotanes, TG, LDL, HDL.
  • Example 25 Example 25
  • HPLC atmospheric pressure chemical ionization (APCI)/MS, GC MS, HPLC diode array detection (DAD), and NMR is used for the identification of astaxanthin and astaxanthin fatty acid esters in krill (Euphausia superb Dana).
  • Matrix solid phase dispersion is applied for the extraction of the carotenoids. This gentle and expeditious extraction technique for solid and viscous samples leads to distinct higher enrichment rates than the conventional liquid-liquid extraction.
  • the chromatographic separation is achieved employing a C30 RP column that allows the separation of shape-constrained geometrical isomers.
  • a methanol/tert-butylmethyl ether/water gradient maybe applied. Astaxanthin and the geometrical isomers are identified by HPLC APCI/MS, by coelution with isomerized authentical standard, by UV spectroscopy (DAD), and three isomers are unambiguously assigned by microcoil NMR spectroscopy.
  • microcoils are transversally aligned to the magnetic field and have an increased sensitivity compared to the conventional double-saddle Helmholtz coils, thus enabling the measurement on small samples.
  • the carotenol fatty acid esters are saponified enzymatically with Lipase type VII from Candida rugosa.
  • the fatty acids are detected by GC MS after transesterification, but also without previous derivatization by HPLC APCI/MS.
  • C14:0, C16:0, C16: l, C18: l, C20:0, C20:5, and C22:6 are found in astaxanthin monoesters and in astaxanthin diesters. Astaxanthin is identified as the main isomer in six fatty acid ester fractions by NMR. Quantitation is carried out by the method of internal standard.
  • the absorption of calcium carbonate is compared between a commercial calcium dietary supplement with Composition 5.
  • the assay is performed using a calcium switch assay with Caco-2 cells.
  • Caco-2 a human colonic epithelial cell line, are obtained from the American Type Culture Collection and maintained routinely in 100- x 15-mm petri dishes at 37°C with 5% C0 2 95% air atmosphere and >95% humidity.
  • the cell monolayers are grown in DMEM (Mediatech) supplemented with 10% fetal bovine serum, 100 kiu/L penicillin, 100 mg/L streptomycin, 1-glutamine (2 mmol/L), and non-essential amino acids. All experiments are performed in the same medium without 10% fetal bovine serum, i.e. in the serum-free medium.
  • S-MEM is removed and cell monolayers are washed 3 times with serum-free DMEM.
  • the cell monolayers are then incubated in the regular serum-free DMEM for pre-specified time periods under standard cell culture conditions. Reassembly of tight junctions and restoration of barrier function are determined at various time points by measuring the TER.
  • the data is expected to show that a PPC composition calcium source show superior calcium availablity (i.e., faster switching) that commercially available calcium supplements.
  • a PPC composition is made according to Example I but is mixed with glucosamine, chondroitin and a natural antioxidant (for example green tea extract or tocopherols) or other natural health promoting ingredients (for example curcumin). Additional ingredients are mixed with the PPC composition to include a ratio of krill oil omega-3 fatty acid to glucosamine and chondroitin matches with what is considered to be beneficial to alleviate the symptoms in dogs with osteoarthritis. For example, PPC composition 30 %, glucosamine and chondroitin 30 % and excipients 30 % (w/w) are mixed together. The stability and homogeneity of the product is studied.
  • the product is further processed into a tablet using known methods in the art.
  • the tablet there is at least 4 % krill oil omega-3 fatty acids.
  • a tablet and a prior art soft gelatin capsule are administered to a dog and compared, whether the dog prefers to consume the tablet over the capsule or vice versa.
  • the ingredients were mixed so that the ratio of krill oil omega-3 fatty acid to glucosamine and chondroitin matched with what is considered to be beneficial to alleviate the symptoms in dogs with osteoarthritis.
  • krill meal 30 %, glucosamine and chondroitin 30 % and excipients 30 % (w/w) were mixed together and processed into a tablet using known methods in the art.
  • the product was found to be homogenous with respect to the oil content, but it was not stable with respect to the oil quality.
  • the level of free fatty acids and lyso-phospholipids increased gradually over time.
  • a tablet and a prior art soft gelatin capsule filled with krill oil were administered individually to a group of ten dogs. It was found that 9 out of 10 dogs ate the tablets, none of the dogs ate the capsule voluntarily.
  • krill oil product is obtained (Neptune Biotech, Laval, Canada) and combined with commercially available glucosamine and chondroitin into a liquid product. The chemical stability of the three products is studied and compared.
  • the levels of lyso-phospholipids, omega-3 fatty acids, peroxide value, p-anisidine value andastaxanthin in the tablets are compared with their levels in the liquid krill oil product.
  • Krill oil and glucosamine + chondroitin are mixed in ratios 4:1, 1 : 1 and 1 :4 and it is studied whether the lipid (krill oil) and non-lipid (glucosamine + chondroitin) phase are separated.
  • krill meal and glucosamine + chondroitin are mixed in ratios 4: 1, 1 :1 and 1 :4 based on the oil content of krill meal and a tablet using methods known in the art is produced.
  • the homogeneity and stability of the krill meal and glucosamine + chondroitin tablets is compared to the homogeneity and stability of the capsulated krill oil glucosamine + chondroitin mixture.
  • liquid krill oil products result on a phase separation and is therefore not homogenous. It is also to be observed that the liquid krill oil product compared to the tablets results in higher levels of lyso-phospholipids, lower omega-3 levels, higher peroxide values, higher p-anisidine values and lower Astaxanthin values. These results clearly show that there is an improved chemical and physical stability of the krill tablets compared to the krill oil product.
  • Tablets made with PPC compositions are prepared in accordance with Example I were tested for palatability with 10 dogs.
  • the control tablet contains only glucosamine and chondroitin as active ingredients.
  • Palatability tests are performed as follows: each dog receives three products: i) Krill Meal 1 tablets; ii) Krill Meal 2 tablets); and iii) control tablets. Tablets are administered daily with food in the morning at 1 tablet/10 kg body weight for 30 days. The order of administration of these tablets is random, but is recorded with observations on palatability.
  • QRILL ® Krill meal is obtained from Aker Biomarine (Oslo, Norway) and added to dry animal food at four different levels of inclusion: 5%, 1%, or 0.1% (w/w) level and one formulation without any krill meal (0% or Control).
  • PPC compositions made in accordance with Example I is added to dry animal food at four different levels of inclusion: 5%, 1%, or 0.1% (w/w) level and one formulation without any PPC (0% or Control).
  • a healthy treat comprising a PPC composition made in accordance with Example I and cartilage protecting substances is prepared.
  • the formula of healthy treat combines 2000 mg of PPC, 500 mg of glucosamine + chondroitin and 2500 mg of base ingredients for a total weight of 5 g/treat.
  • Base ingredients include, but are not limited to, meat meals and extracts, other animal by-products, fish meal and extracts, plant protein meals, cereal meals or fractions of cereals and various binding agents known in the art.
  • Pet treats may also contain additional ingredients that provide desirable consistency and bulk to the product.
  • the 5 g treat can be produced from PPC and cartilage protecting substances alone by mixing 4500 mg of PPC + binding agents with 500 mg of glucosamine + chondroitin. After mixing the ingredients the mixture is pelleted, extruded or otherwise processed into treats of different shapes.
  • Example 1 The mixture of ingredients described in accordance with Example 1 are used to fill hard gelatin capsules (e.g., sprinkle capsules) in accordance with Example 19.
  • the capsule is opened and its contents sprinkled over a bowl of food.
  • the palatability of the capsules is assessed and compared with control capsules in accordance with Example 32.
  • a nutritional supplement is prepared for dogs comprising a PPC composition made in accordance with Example 1 and cartilage protecting substances.
  • the supplement combined 90% of PPC and 10% glucosamine hydrochloride + chondroitin sulfate (in 60:40 ratio). After mixing, the ingredients are pelleted with a matrix type granulation unit and stored in aluminum foil plastic bags under a nitrogen atmosphere. This supplement is then used in a clinical test involving 10 dogs with degenerative joint disease (i.e., for example,
  • OA is often associated with pain and thus it influences the movement of the dog.
  • the dogs are brought to the veterinary clinic for examination which includes, but is not limited to, weighing, body condition scoring, palpation of the joints and observations on the movement of the dogs.
  • a force plate (4LegCheck; ReDog, Vasteras, Sweden) is used to determine the distribution of weight between the four legs while the dog was standing. Deviation from equal distribution of weight ( ⁇ 5%) between the left and right leg suggests pain/lameness. Also, deviation from the typically observed 60:40 distribution of weight ( ⁇ 5%) between front and rear legs is considered to be a sign of lameness.
  • the dogs are then fed their normal diet and nutritional supplement (5 g/lOkg body weight) for six weeks. After six weeks, the clinical examination is repeated as described above. In addition to the clinical re-examination, the dogs' owner fills in a questionnaire regarding the mobility of the dog by using a modified Helsinki Chronic Pain Index (HCPI) questionnaire (Hielm- Bjorkman et al.
  • HCPI modified Helsinki Chronic Pain Index
  • the data show a consistent improvement in the mobility of the dogs during the six week nutritional supplementation period.
  • force plate measurements indicate that 7 out of 10 dogs demonstrated reduced lameness due to supplementation.
  • owner assessment show that the average mobility score improved in 8 out of 10 cases with mobility indexes ranging from 3.5 to 5.
  • This dog demonstrated significant improvement in mood, activity and playing.
  • increased mobility is associated with greatly increased difficulty in moving after rest.
  • clinical examination by the veterinarian documented 6 cases of improved movement, 5 cases of reduced pain and one case of reduced lameness and pain, respectively.
  • 8 out of 10 dogs demonstrated improvement in one or more clinical endpoints.
  • PPC Composition Treatment of Degenerative Joint Disease A nutritional supplement for dogs comprising a PPC composition is prepared having the ingredients described in accordance with Example 1. PPC is then pelleted with a matrix type granulation unit and stored in aluminum foil plastic bags under nitrogen atmosphere. Pelleted PPC is used as a supplement in a clinical test involving 8 dogs with degenerative joint disease (i.e., for example, osteoarthritis; OA). The test was performed by a veterinary clinic.
  • force plate measurements demonstrate significant reduction in lameness in 2 out of 8 dogs. Owner's assess an average mobility score improved in 5 out of 8 cases with mobility indexes ranging from 3.25 to 4.5. In 3 out of 8 cases there was no change. Finally, the clinical examination by a veterinarian documents 2 cases of improved movement, 1 case of reduced pain, 1 case of reduced lameness and 2 cases of reduced stiffness. In total, 4 out of 8 dogs demonstrate improvement in one or more clinical endpoints. In this group the dogs demonstrate, in general, less symptoms at the baseline and their forceplate measurements also indicate less lameness. Thus, the apparent lower efficacy of the PPC supplement compared to the combination supplement may be influenced by the random selection of less symptomatic test subjects into this group.
  • PPC Krill Phospholipid-Peptide Complex Treatment Of Skin Disorders Twenty individuals are orally administered 1 spoon of Krill Meal 1 or Krill Meal 2 (PPC) per day for fourteen (14) days. The data is expected to show that PPC administration result in: i) healthier looking skin (50%); ii) softer skin (50%); and ii) more supple skin (50%).
  • Krill Phospholipid-Peptide Complex Treatment Of Skeletomuscular Disorders Twenty individuals are orally administered 1 spoon of Krill Meal 1 or Krill Meal 2 (PPC) per day for fourteen (14) days. The data is expected to show that PPC administration resulted in: i) decreased joint pain (20%); ii) improved joint flexibility (20%). Additionally, one patient is diagnosed with severe joint pain, and undergoing the same PPC administration protocol, reports significant reduction in pain and improved joint function.
  • Krill Phospholipid-Peptide Complex Treatment Of sexual Disorders One patient is diagnosed with impotence and orally administered 1 spoon of Krill Meal 1 or Krill Meal 2 (PPC) per day for fourteen (14) days. The data is expected to show that PPC administration resulted in improved erection and resultant sexual performance.
  • PPC Krill Meal 1 or Krill Meal 2

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Abstract

Cette invention concerne des traitements de troubles médicaux à l'aide de compositions de phospholipide-peptide-protéine (PPC) de crustacés. Par exemple, la composition selon l'invention peut être une composition à basse teneur en fluorure, une composition à basse teneur en triméthylamine ou une composition à basse teneur à la fois en fluorure et triméthylamine. Les compositions PPC peuvent en outre être complétées par des substances supplémentaires comprenant, entre autres, une huile de crustacés à basse teneur en fluorure (par ex., huile de krill à basse teneur en fluorure), des acides gras oméga 3, des vitamines, des minéraux et/ou des antioxydants.
PCT/IB2014/001068 2013-02-07 2014-02-06 Procédés d'utilisation de complexes phospholipide-peptide-protéine de crustacés WO2014184655A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017031502A1 (fr) * 2015-08-20 2017-02-23 Avoca, Inc. Procédé pour augmenter la croissance musculaire en utilisant un extrait de krill
WO2019150197A1 (fr) * 2018-01-30 2019-08-08 Aker Biomarine Antarctic As Hydrolysat protéique marin à faible teneur en fluorure et triméthylamine
CN110907568A (zh) * 2019-12-17 2020-03-24 大连工业大学 一种利用基质固相分散萃取固体或半固体食品中游离脂肪酸的方法
CN111432654A (zh) * 2017-12-04 2020-07-17 雾凇科技有限公司 从甲壳类捕获物中生产蛋白质磷脂复合物的方法

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017031502A1 (fr) * 2015-08-20 2017-02-23 Avoca, Inc. Procédé pour augmenter la croissance musculaire en utilisant un extrait de krill
CN111432654A (zh) * 2017-12-04 2020-07-17 雾凇科技有限公司 从甲壳类捕获物中生产蛋白质磷脂复合物的方法
WO2019150197A1 (fr) * 2018-01-30 2019-08-08 Aker Biomarine Antarctic As Hydrolysat protéique marin à faible teneur en fluorure et triméthylamine
EP4091620A1 (fr) * 2018-01-30 2022-11-23 Aker Biomarine Antarctic As Hydrolysat de protéines de krill à faible teneur en fluor et en triméthylamine
CN110907568A (zh) * 2019-12-17 2020-03-24 大连工业大学 一种利用基质固相分散萃取固体或半固体食品中游离脂肪酸的方法

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