WO2023180282A1 - Coprécipités de méthionylméthionine avec des composés organiques - Google Patents

Coprécipités de méthionylméthionine avec des composés organiques Download PDF

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WO2023180282A1
WO2023180282A1 PCT/EP2023/057139 EP2023057139W WO2023180282A1 WO 2023180282 A1 WO2023180282 A1 WO 2023180282A1 EP 2023057139 W EP2023057139 W EP 2023057139W WO 2023180282 A1 WO2023180282 A1 WO 2023180282A1
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precipitate
animals
metmet
ala
organic compound
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PCT/EP2023/057139
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English (en)
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Thomas BERNGRUBER
Robert Gerstmeir
Sascha Braune
Arif MUSIC
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Evonik Operations Gmbh
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Publication of WO2023180282A1 publication Critical patent/WO2023180282A1/fr

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K50/00—Feeding-stuffs specially adapted for particular animals
    • A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/08—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to hydrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/22—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated the carbon skeleton being further substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention concerns a co-precipitate of methionylmethonine with at least one further organic compound, preferably with 5-aminolevulinic acid, PQQ or thiamine, methods for preparing such co-precipitates and the use of such co-precipitates, in particular as feed and food additives and as pharmaceutical.
  • 5-Aminolevulinic acid is a non-proteinogenic amino acid and a common metabolic precursor of tetrapyrrole compounds including, heme, chlorophyll and vitamin B12 and is therefore applied in numerous biotechnological applications.
  • 5-ALA is used in photodynamic treatment (PDT) for selected cutaneous diseases (Peng et al. (1997), Clin. Res. and fut. challenges. Cancer 79, 2282-2308).
  • 5-ALA has been proposed for the application as herbicide and insecticide due to its photosensitizing properties (Sasikala et al. (1994), Biotechnol. Prog. 1994, 10, 451 ; Yang et al. (2011), Agric. Sci. in China 10(7):1056).
  • Such herbicidal and insecticidal activity of 5-ALA depends on a photosensitizing mechanism which is only active in bright (sun-)light.
  • 5-ALA has been shown to prevent bacterial and viral infection particularly in aquaculture animals (EP1153546B1). Yet, the application of 5-ALA for nutrition in aquaculture is limited by the high solubility and instability of 5-ALA in water (Elfsson et al. (1998), Eur. J. of Pharm. Sci., 7:87). High solubility can in particular lead to leakage from aquaculture feed pellets. Furthermore, due to the instability of 5-ALA in water at neutral pH, degradation of 5-ALA is a likely consequence of leakage, in particular as soon as water is soaked into the pellet. Solubility and stability of 5-ALA are a challenge in feed applications, where feed is ingested over a long feeding period like for example in bottom feeding species like shrimp, crayfish or crab. A formulation that reduces solubility and instability of 5-ALA in water would therefore significantly improve its applicability in particular as aquaculture feed.
  • Stability of 5-ALA is also a technical challenge in pharmacological applications (Bunke et al. (2000), J. of Pharm. Sci., 89(10):1335; Gadmara (2002), J. of Photochem. and Photobiol. B: Biology 67:187; Kaliszewski et al. (2007), J Photochem Photobiol B. 87(2):67; De Blois et al. (2002), Lasers Med Sci. 17(3):208).
  • Formulations known to those skilled in the art to stabilize 5-ALA include (a) storage in liquid solution at low pH and removal of oxygen by nitrogen purging (Bunke et al.
  • 5-ALA Due to the protection of 5-ALA by the MetMet matrix, 5-ALA can be dosed more effectively in feeding applications, so that, overall, a significant lower amount of 5-ALA is required to reach the same effect, in particular in aquaculture feed applications.
  • the higher bioavailability is achieved by transporting 5-ALA as insoluble co-precipitate into the digestive system of the animal and targeted release of 5-ALA in the gut of the animal at the onset of the digestion process.
  • 5-ALA is highly soluble at acidic pH but precipitates upon a shift to the isoelectric point.
  • 5-ALA is soluble and highly stable at acidic pH and can thus be homogeneously mixed with MetMet in the soluble state at low pH.
  • the optimal ratio for feeding application is expected to be one part of 5-ALA within 50 to 200 parts of MetMet.
  • This dominance of MetMet in the co-crystal ensures that 5-ALA molecules in the interior of the crystal are protected from contact with water, preventing leakage and degradation of 5-ALA in water.
  • 5-ALA is released at its target location in the digestive tract of the animal where it serves the nutritional demand of the animal.
  • the co-precipitate of 5-ALA and MetMet enables the targeted release of 5-ALA in the animal gut and thus improves efficacy and bioavailability and further significantly reduces the costs of applying an effective dosis of 5-ALA needed to achieve a biological effect.
  • the ratio of about 1 :50 to about 1 :200 of 5-ALA to MetMet seems also to be beneficial out of a nutritional point of view, as the need of the animals for MetMet is much higher than the need of the animals for 5-ALA, so that this mixing ratio represents a suitable premix of 5- ALA and MetMet.
  • the concept of embedding an organic compound into the matrix of MetMet is a method which is principally also applicable to other organic compounds, in particular to such compounds which are either also rather unstable and/or have a high water solubility and/or for which there is a wish or need to achieve a targeted and/or retarded release.
  • the wish to achieve a targeted and/or retarded release is in particular relevant for substances which otherwise have to be used in a higher amounts for reaching the same effect. This is in particular the case for substances with high water solubility like certain vitamins, if applied in feed pellets for aquaculture applications.
  • a first subject of the present invention is a co-precipitate of methionylmethionine and/or a salt thereof and at least one further, preferably exactly one further, organic compound, wherein the at least one further organic compound is preferably not HCN and preferably not methionine and preferably also no other organic compound which may be contained in the co-precipitate or in the methionylmethionine, as used for preparing the co-precipitate, due to the process of producing the methionylmethionine and as disclosed in particular in WO 2010/043558, like derivatives of methionine, in particular 3-(methylthio)propionaldehyde, methionine hydantoin or methionine diketopiperazine.
  • the co-precipitate may contain small amounts of such further compounds like HCN, methionine or derivatives of methionine like 3- (methylthio)propionaldehyde, methionine hydantoin or methionine diketopiperazine, in particular methionine, in addition to methionylmethionine and the at least one further organic compound as contained in the co-precipitate.
  • further compounds like HCN, methionine or derivatives of methionine like 3- (methylthio)propionaldehyde, methionine hydantoin or methionine diketopiperazine, in particular methionine, in addition to methionylmethionine and the at least one further organic compound as contained in the co-precipitate.
  • methionine and/or derivatives of methionine are preferably contained in the co-precipitate in an amount of less than 5 wt.-%, more preferably in an amount of less than 4, 3 or 2 wt.-%, in particular in an amount of less than 1 or 0.5 wt.-%.
  • the methionylmethionine in the salt of methionylmethionine, due to its carboxy group, can be present in anionic form with any kind of positive counter ion, preferably selected from sodium, potassium, ammonium, magnesium and/or calcium.
  • positive counter ion preferably selected from sodium, potassium, ammonium, magnesium and/or calcium.
  • methionylmethionine due to its amino group, methionylmethionine can be present also in cationic form as ammonium salt with negative counter ions, preferably selected from chloride, phosphate, sulfate, acetate, nitrate and/or formiate.
  • methionylmethionine is present in the precipitate completely or mostly in neutral form, i.e., preferably less than 50 wt.-%, more preferably less than 30, 20 or 10 wt.-%, in particular less than 5 %, of the methionylmethionine is present in the coprecipitate in the form of a salt.
  • Neutral form according to the invention also comprises the possibility that the respective molecule is present as zwitterion, i.e., as internal salt.
  • the at least one further organic compound is according to the invention preferably a substance which has a nutritional and/or pharmaceutical effect. It has preferably a molecular weight of 100 to 1000, more preferably 100 to 600, in particular 100 to 400 g/mol. In a preferred embodiment, it has a water solubility of at least 3 g/L, more preferably of at least 20 g/L, in particular of at least 40 g/L.
  • the at least one further, preferably exactly one further, organic compound which is contained in the co-precipitate is an organic acid, preferably an amino acid and/or a keto acid, in particular a non-proteinogenic amino acid, and/or a salt thereof.
  • organic acid is selected from 5-aminolevulinic acid and PQQ ( pyrroloquinoline quinone; 4,5-Dioxo-4,5-dihydro-1 /7-pyrrolo[2,3-/]quinoline-2,7,9-tricarboxylic acid), salts thereof and mixtures thereof.
  • the at least one further, preferably exactly one further, organic compound which is contained in the co-precipitate is an amine and/or a vitamin, preferably thiamine (vitamin B1), and/or a salt thereof.
  • the vitamin may in particular be also another vitamin of the vitamin B complex like vitamin B2 (riboflavin), vitamin B3, vitamin B5 (pantothenic acid), vitamin B6, vitamin B7 (biotin), vitamin B9 (folate) or vitamin B12.
  • the at least one further, preferably exactly one further, organic compound is 5-aminolevulinic acid and/or a salt thereof.
  • the salt of the acid in particular of 5-aminolevulinic acid or PQQ, due to its carboxy group, can be present in anionic form with any kind of positive counter ions, preferably selected from sodium, potassium, ammonium, magnesium and/or calcium.
  • the salt of amino acids and amines, in particular also of 5-aminolevulinic acid and thiamine, due to its amino group, can be present in cationic form as ammonium salt with any kind of negative counter ions, preferably selected from chloride, phosphate, sulfate, acetate, nitrate and/or formiate.
  • the at least one, preferably exactly one, further organic compound which is contained in the co-precipitate, in particular the organic acid, amino acid and/or keto acid is present in the precipitate completely or mostly in neutral form, i.e., preferably less than 50 wt.-%, more preferably less than 30, 20 or 10 wt.-%, in particular less than 5 wt.-%, of the at least one further organic compound which is contained in the co-precipitate is present in the co- precipitate as salt.
  • a special embodiment of the invention is a co-precipitate of methionylmethionine and at least one further, preferably exactly one further, organic acid, wherein the at least one further organic acid is an organic acid, an amino acid and/or a keto acid, wherein the amino acid is preferably a non-proteinogenous amino acid and very preferably 5-aminolevulinic acid, and wherein the compounds are present completely, or at least essentially, in neutral form.
  • co-precipitate according to the invention explicitly comprises any kind of crystalline form and in a preferred embodiment of the invention the co-precipitate of the invention has a crystalline form, i.e., is a co-crystal of MetMet and the at least one further organic compound. It is preferably a particulate composition, i.e. a powder or granulate, wherein the particles of the composition have preferably a particle size of 50 to 500 pm, more preferably of 50 to 300 pm (d50).
  • the co-precipitates of the invention preferably contain at least 90 wt.-%, more preferably at least 95 or 97 wt.-%, in particular 95 to 99.9 wt.-%, 96 to 99.8 wt.-%, 97 to 99.7, above all 97.5 to 99.5 wt.- %, methionylmethionine and/or a salt thereof.
  • the co-precipitates of the invention preferably contain the at least one further organic compound and/or a salt thereof in an amount of from 0.1 to 10 wt.-% or 0.1 to 5 wt.-%, preferably in an amount of from 0.2 to 4 wt.-%, more preferably from 0.3 to 3 wt.-%, above all from 0.5 to 2.5 wt.-%.
  • the co-precipitate of the invention is very preferably a co-precipitate, in particular a co-crystal, of methionylmethionine and/or a salt thereof and 5-aminolevulinic acid and/or a salt thereof, wherein the composition preferably contains from 0.1 to 10 wt.-% or 0.1 to 5 wt.-%, more preferably from 0.2 to 4 wt.-%, in particular from 0.3 to 3 wt.-%, above all 0.5 to 2.5 wt.-%, of aminolevulinic acid and/or a salt thereof.
  • Methionylmethionine or MetMet generally refer to DL-methionyl-DL-methionine, i.e., to all diastereomers of this molecule. It is a compound with the general formula (I)
  • MetMet i.e. DL-methionyl-DL- methionine
  • DD DL-methionyl-DL- methionine
  • the DD and LL compounds, on the one hand, and the DL and LD compounds, on the other hand, are enantiomers, i.e., the DD compound possesses the same physical properties like the LL compound and the DL compound possesses the same physical properties like the LD compound.
  • the DD/LL pair has a solubility in water of 21 .0 g/L
  • the DL/LD pair has a much lower solubility of only 0.4 g/L. Mixtures of all four diastereomers have accordingly a solubility in between these two values.
  • the solubility of the MetMet matrix i.e. precipitate or crystal
  • the MetMet in the ALA-MetMet composition comprises more than 80 wt.-%, preferably more than 90 or 95 wt.-% of the DD/LL pair, in particular consists only of the DD/LL pair.
  • the DL/LD pair and the DD/LL pair are contained in the ALA-MetMet composition in a ratio of 4:1 to 1 :4, preferably in a ratio of 3:1 to 1 :3, in particular in a ratio of 2:1 to 1 :2.
  • the MetMet in the ALA-MetMet composition comprises more than 70 or 80 wt.-%, preferably more than 90 or 95 wt.-% of the DL/LD pair, in particular consists only of the DL/LD pair. Conversion of the DL/LD pair into the DD/LL pair and vice versa can be carried out for example as disclosed in WO 2010/043558.
  • the co-precipitate according to the invention preferably has a residual moisture content of 0.1 to 6 wt.-%, preferably of 0.3 to 5 wt.-%, more preferably of 0.5 to 4 wt.-%. It further preferably exhibits a water activity (a w value) of 0.05 to 0.6, preferably of 0.1 to 0.5.
  • the at least one further organic compound which is embedded into the MetMet matrix is preferably homogeneously distributed with the co-precipitate, in particular the co-crystal, of the invention.
  • the co-precipitate of the invention may directly be used as feed or food additive, but can also be mixed or worked up with agglomeration auxiliaries or carriers, resulting in a composition containing the co-precipitate and such agglomeration auxiliaries or carriers.
  • an agglomeration auxiliary or carrier is added to or mixed with the co-precipitate to provide a feed or food additive, then it is preferably present in an amount of not more than 50 wt.-%.
  • the composition of the invention contains besides MetMet and the at least one further organic compound, in particular 5-ALA, PQQ and/or thiamine, further substances like agglomeration auxiliaries or carriers, if present, in an amount of not more than 25 wt.-%, more preferably in an amount of not more than 10 or 5 wt.-%.
  • feed or food additives are referred to in the context of this application as feed or food compositions.
  • the agglomeration auxiliary or carrier is preferably selected from inert formulation ingredients added to improve recovery, efficacy, or physical properties and/or to aid in packaging and administration.
  • Such carriers may be added individually or in combination and may be selected from anti-caking agents, anti-oxidation agents, bulking agents, binders, structurants, coatings and/or protectants.
  • useful carriers include polysaccharides (in particular starches, maltodextrins, methylcelluloses, gums, chitosan and/or inulins), protein sources (in particular skimmilk powder and/or sweet-whey powder), protein hydrolysates (in particular peptones like soy peptone and/or yeast extract), peptides, sugars (in particular lactose, trehalose, sucrose and/or dextrose), lipids (in particular lecithin, vegetable oils and/or mineral oils), salts (in particular sodium chloride, sodium carbonate, calcium carbonate, chalk, limestone, magnesium carbonate, sodium phosphate, calcium phosphate, magnesium phosphate and/or sodium citrate), and silicates (in particular clays, in particular beolite clay, zeolites, Fuller’s earth, Baylith®, clintpolite, montmorillonite, diatomaceous earth, talc, bentonites, and/or silicate salts like aluminium, magnesium and/or
  • Suitable carriers for animal feed additives are set forth in the American Feed Control Officials, Inc.' s Official Publication, which publishes annually. See, for example Official Publication of American Feed Control Officials, Sharon Krebs, editor, 2006 edition, ISBN 1-878341-18-9.
  • the carriers can be added after concentrating the fermentation broth containing the microorganisms of the invention and/or during and/or after drying of the fermentation broth.
  • the MetMet as well as the at least one further organic compound, in particular 5-ALA can be obtained by chemical synthesis or by biotechnological production, i.e., by applying a classical fermentation process employing microorganisms which produce said substances.
  • the co-precipitate of the invention is preferably obtained by a method comprising the following steps: a) Providing an aqueous medium with acidic pH which contains MetMet and the at least one further organic compound, wherein the at least one further organic compound is preferably not HCN, methionine or a derivative of methionine, preferably 5-ALA, PQQ and/or thiamine, wherein the pH is preferably from 0 to 3, more preferably from 0.5 to 2.5, in particular from 1 to 2; b) Increasing the pH of the aqueous solution to obtain a co-precipitate or co-crystal of MetMet and/or a salt thereof and the at least one further organic compound, preferably 5-ALA, PQQ and/or thiamine and/or a salt thereof,
  • a MetMet mother liquor is provided, which is obtained as a side-stream in a Methionine production process. Ways to obtain such a MetMet mother liquor are described for example in WO 2010/043558.
  • MetMet may be purchased in dried form and subsequently dissolved in water or an aqueous solution.
  • MetMet is sold under the trademark AquaviOMetMet by the applicant (Evonik Operations, Germany).
  • the at least one further organic compound, in particular 5-ALA, PQQ and/or thiamine can be added to the MetMet containing aqueous medium.
  • MetMet and 5-ALA, PQQ and/or thiamine can be employed in crystalline form and simultaneously dissolved in water or an aqueous solution.
  • the co-precipitates of the invention in particular the 5-ALA-MetMet co-precipitates, and the feed or food additives containing such co-precipitates, can be used for the preparation of feed, food and pharmaceutical compositions and can be added to drinking and rearing water.
  • 10g to 50 kg of the co-precipitate or feed additive in particular 50g to 20 kg of the co- precipitate or feed additive, are used per ton of feed, drinking or rearing water to provide compositions which can be used for feeding animals.
  • the feed and food compositions can be prepared by mixing the co-precipitates or feed or food additive, containing such a co-precipitate, with typical feed or food ingredients, respectively.
  • a further subject of the present invention is also a feed, food or pharmaceutical composition, containing a co-precipitate of the invention, wherein the co-precipitate is preferably contained in an amount of 0.001 to 5 wt.-%, more preferably in an amount of 0.005 to 2 wt.-%, in particular in an amount of 0.01 to 1 wt.-%, above all in an amount of 0.05 to 0.25 wt.-%.
  • a further subject of the present invention is therefore also a feed or food composition, containing a co-precipitate according to the invention and preferably at least one further feed or food additive.
  • a further subject of the present invention is also the use of a co-precipitate of the invention for preparing a feed or food composition.
  • a further subject of the present invention is also a method of preparing a feed or food composition according to the invention, wherein a co-precipitate of the invention is mixed with further feed or food additives.
  • a further subject of the present invention is also a pharmaceutical composition containing a co- precipitate of the invention and at least on pharmaceutically acceptable carrier.
  • 5-ALA can be used in photodynamic treatment (PDT) of cutaneous diseases (Peng et al. (1997), Clin. Res. and fut. challenges. Cancer 79, 2282-2308). Further, 5-ALA can be used for preventing bacterial, viral and parasitic infections, particularly in aquaculture animals, in particular infections which are caused by Edwardsiella tarda, Streptococcus sp., Staphylococcus sp., Staphylococcus epidermidis, Pseudomonas sp., Vibrio anguillarum, Iridovirus, Birnavirus, in particular marine birnavirus (MABV), White spot syndrome virus (WSSV), or Scutica (EP1153546B1). Further, the pharmaceutical effects of PQQ and vitamins like thiamine are well known.
  • a further subject of the invention is also the use of a co-precipitate of the invention, in particular of a 5-ALA-MetMet, PQQ-MetMet orthiamine-MetMet co-precipitate of the invention, for preparing a pharmaceutical composition, in particular a pharmaceutical composition for treating, preventing or mitigating the course of a disease selected from a cutaneous disease, bacterial infections, viral infections and parasitic infections wherein the bacterial infection is preferably an infection caused by Edwardsiella tarda, Streptococcus sp., Staphylococcus sp., Staphylococcus epidermidis, Pseudomonas sp.
  • the viral infection is preferably an infection caused by Iridovirus, Birnavirus, in particular marine birnavirus (MABV), or White spot syndrome virus (WSSV), and the parasitic infection is preferably an infection caused by Scutica.
  • Iridovirus Birnavirus
  • MABV marine birnavirus
  • WSSV White spot syndrome virus
  • a further subject of the present invention is also a method of preparing a pharmaceutical composition according to the invention, wherein a co-precipitate of the invention, in particular a 5- ALA-MetMet, PQQ-MetMet orthiamine-MetMet co-precipitate of the invention, is mixed with a pharmaceutically acceptable carrier.
  • the co-precipitates of the invention when administered to animals, can enhance the health of such animals and/or improve the general physical condition of such animals and/or improve the feed conversion rate of such animals and/or decrease the mortality rate of such animals and/or increase the survival rate of such animals and/or improve the weight gain of such animals and/or increase the productivity of such animals and/or increase the disease resistance of such animals and/or modulate the immune response of such animals and/or establish or maintain a healthy gut microflora in such animals and/or improve the meat quality of such animals, in particular the meat elasticity and/or the meat hardness, and/or reduce the shedding of bacterial and/or viral and/or parasitic pathogens through the feces of such animals.
  • the 5-ALA-MetMet coprecipitates of the invention might be used to assist in re-establishing a healthy balance of the gut microflora after administration of antibiotics for therapeutic purposes.
  • a further subject of the invention is therefore a method of enhancing the health of animals and/or of improving the general physical condition of animals and/or of improving the feed conversion rate of animals and/or of decreasing the mortality rate of animals and/or of increasing the survival rates of animals and/or of improving the weight gain of animals and/or of increasing the productivity of animals and/or of increasing the disease resistance of animals and/or of modulating the immune response of animals and/or of establishing or maintaining a healthy gut microflora in animals and/or of improving the meat quality of animals and/or of reducing the shedding of bacterial and/or viral and/or parasitic pathogens through the feces of animals, wherein at least one co-precipitate, feed or pharmaceutical composition of the invention is administered to animals.
  • a further subject of the invention is therefore also a method of enhancing the health of human beings and/or of improving the general physical condition of human beings and/or of increasing the disease resistance of human beings and/or of modulating the immune response of human beings and/or of establishing or maintaining a healthy gut microflora in human beings, wherein at least one co-precipitate, food or pharmaceutical composition of the invention is administered to human beings.
  • composition(s) of the invention refers to coprecipitates as described before, preferably to the 5-ALA-MetMet co-precipitates as described before, as well as to compositions containing such co-precipitates like the feed, food and pharmaceutical compositions as also described before.
  • a further subject of the invention is therefore also the use of at least one composition of the invention for (preparing a composition for) enhancing the health of animals and/or for improving the general physical condition of animals and/or for improving the feed conversion rate of animals and/or for decreasing the mortality rate of animals and/or for increasing the survival rates of animals and/or for improving the weight gain of animals and/or for increasing the productivity of animals and/or for increasing the disease resistance of animals and/or for modulating the immune response of animals and/or for establishing or maintaining a healthy gut microflora in animals and/or for improving the meat quality of animals and/or for reducing the shedding of bacterial and/or viral pathogens through the feces of animals, wherein the at least one microorganism and/or at least one composition of the invention is administered to animals.
  • a further subject of the invention is therefore also the use of at least one composition of the invention for (preparing a composition for) enhancing the health of human beings and/or for improving the general physical condition of human beings and/or for increasing the disease resistance of human beings and/or for modulating the immune response of human beings and/or for establishing or maintaining a healthy gut microflora in human beings, wherein the at least one composition of the invention is administered to human beings.
  • a further subject of the invention is therefore also at least one composition of the invention for use in a method of enhancing the health of animals and/or human beings and/or of improving the general physical condition of animals and/or human beings and/or of improving the feed conversion rate of animals and/or of decreasing the mortality rate of animals and/or of increasing the survival rate of animals and/or of improving the weight gain of animals and/or of increasing the productivity of animals and/or of increasing the disease resistance of animals and/or human beings and/or of modulating the immune response of animals and/or human beings and/or of establishing or maintaining a healthy gut microflora in animals and/or human beings and/or of improving the meat quality of animals and/or of reducing the shedding of bacterial and/or viral and/or parasitic pathogens through the feces of animals.
  • Increasing the productivity of animals refers in particular to any of the following: production of more or higher quality eggs, milk or meat or increased number of offspring or improved survival of offspring.
  • compositions of the invention preferably an improvement of at least one of the features as mentioned before is realized, wherein realization of the feature preferably means an improvement of at least 1 %, more preferably of at least 3 or at least 5 %, in comparison to an adequate negative control.
  • realization of the feature preferably means an improvement of at least 1 %, more preferably of at least 3 or at least 5 %, in comparison to an adequate negative control.
  • negative control averages known in the animal husbandry field may be used, but preferably as negative control animals which are subjected to the same treatment like the animals tested are used, but without administration of the co-precipitates of the invention.
  • compositions of the invention may be administered or fed to an animal in an amount effective to inhibit and/or decrease the growth of pathogenic bacteria, pathogenic viruses or pathogenic parasites.
  • 5-ALA is able to inhibit the growth of pathogenic bacteria selected from Edwardsiella tarda, Streptococcus sp., Staphylococcus sp., Staphylococcus epidermidis, Pseudomonas sp. and Vibrio anguillarum, of viruses selected from Iridovirus, Birnavirus, in particular marine birnavirus (MABV), and White spot syndrome virus (WSSV), and of the parasite Scutica
  • the methods of the present invention may be used to decrease the amount of pathogenic bacteria, pathogenic viruses and parasites shed in animal feces.
  • the compositions of the present invention are able to maintain an overall healthy microflora.
  • a further subject of the invention is also a method of inhibiting and/or decreasing the growth of pathogenic bacteria, viruses and/or parasites, wherein the compositions of the invention are administered to animals or humans, and wherein the pathogenic bacteria are preferably selected from Edwardsiella tarda, Streptococcus sp., Staphylococcus sp., Staphylococcus epidermidis, Pseudomonas sp. and Vibrio anguillarum, the virus is preferably selected from Iridovirus, Birnavirus, in particular marine birnavirus (MABV), and White spot syndrome virus (WSSV), and the parasite is preferably Scutica.
  • the pathogenic bacteria are preferably selected from Edwardsiella tarda, Streptococcus sp., Staphylococcus sp., Staphylococcus epidermidis, Pseudomonas sp. and Vibrio anguillarum
  • the virus is preferably selected from I
  • the amount of at least one pathogenic bacterium is reduced by at least 0.5 log, more preferably by at least 1 log, 2 log, or 3 log.
  • compositions of the invention for use in a method of inhibiting and/or decreasing the growth of pathogenic bacteria and/or pathogenic viruses and/or parasites
  • the pathogenic bacteria are preferably selected from Edwardsiella tarda, Streptococcus sp., Staphylococcus sp., Staphylococcus epidermidis, Pseudomonas sp. and Vibrio anguillarum
  • the virus is preferably selected from Iridovirus, Birnavirus, in particular marine birnavirus (MABV), and White spot syndrome virus (WSSV)
  • the parasite is preferably Scutica.
  • a preferred embodiment of the invention are the compositions of the invention for use in a method of preventing and/or treating a disease caused by at least one of the microorganisms and/or viruses as mentioned before, wherein the disease is very preferably White spot syndrome.
  • compositions of the invention can be pharmaceutical or nonpharmaceutical, in particular therapeutic or non-therapeutic.
  • methods and uses are non-pharmaceutical, in particular non-therapeutical, preferably feed and food applications.
  • Preferred food compositions according to the invention are fermented foods and/or dairy products, in particular yoghurt, cheese, milk, butter, curd and natto.
  • the microorganisms according to the invention may in particular be used in beverages and in milk replacers, for examples in a baby formula.
  • compositions according to the invention preferably contain at least one pharmaceutically acceptable carrier. They may further contain other ingredients like typical feed or food ingredients as listed further below.
  • the pharmaceutical composition according to the invention is preferably a liquid, a paste, an aerosol, a suppository or a dried composition, in particular to be administered to the pharyngeal/respiratory tract, to the gastro-intestinal tract, to the urogenital tract or to the skin. Administration might be carried out by using a medical device, for example a spray, a pump or an inhalator.
  • a further subject of the present invention is also a method of preparing a pharmaceutical composition, wherein a co-precipitate of the invention, in particular a 5-ALA-MetMet co-precipitate of the invention, is mixed with a pharmaceutically acceptable carrier and optionally further compounds and wherein the pharmaceutical composition may be provided in the form of a medical device.
  • a further subject of the present invention is in particular also a nutritional supplement containing compositions of the invention and at least one pharmaceutically acceptable carrier.
  • compositions of the invention are administered orally to animals or human beings.
  • the administration is preferably carried out in form of feed and food compositions, but may also be carried out by applying the co-precipitates of the invention to drinking or rearing water.
  • a further subject of the present invention is water, in particular an aqueous solution or an aqueous suspension, containing at least one co-precipitate of the invention.
  • the co-precipitates of the invention may be applied in the form of compositions, in particular tablets, which after exposure to the drinking or rearing water dissolve easily and set free the co-precipitates into the aqueous environment.
  • Such compositions, in particular tablets, are a further preferred embodiment of the invention.
  • Those compositions preferably comprise carriers like betaine salts, citrates, carbonates and/or bicarbonates like for example disclosed in WO 2020/225020.
  • the feed, food and pharmaceutical compositions of the invention may comprise carriers or further typical feed ingredients or combinations thereof.
  • Suitable carriers for the preparation of feed, food and pharmaceutical compositions are the same as mentioned before as possibly contained in the feed or food additives of the invention, containing a co-precipitate of the invention.
  • Suitable typical animal feed ingredients which may be contained in the feed, food and pharmaceutical compositions according to the invention include one or more of the following: proteins, carbohydrates, fats, probiotics, prebiotics, enzymes, vitamins, immune modulators, milk replacers, minerals, amino acids, carriers, coccid iostats, acid-based products and/or medicines, such as antibiotics.
  • Carbohydrates containing components which may be used according to the invention are for example forage, roughage, wheat meal, corn meal, sunflower meal or soya meal, and mixtures thereof.
  • Proteins containing components which may be used according to the invention are for example soya protein, pea protein, wheat gluten, corn gluten, rice, canola meal, meal of marine animals, in particular fishmeal, meal of terrestrial animals, and mixtures thereof.
  • “Meal of marine animals” includes meat meal, meat and bone meal, blood meal, liver meal, poultry meal, silkworm meal, silkworm pupae meal and combinations thereof.
  • Fats are typically provided as oils of marine animals, vegetable oils or oils of microorganisms, in particular oils of microalgae, or combinations thereof.
  • vegetable oils are soybean oil, rapeseed oil, sunflower seed oil, canola oil, cottonseed oil, flaxseed oil and palm oil.
  • Oils of marine animals include fish oil as well as oil of krill, bivalves, squids or shrimps and further fatty oils from fish of the families Engraulidae, Carangidae, Clupeidae, Osmeridae, Scombridae and/or Ammodytidae.
  • oils of microalgae are in particular oil of Labyrinthulea, preferably oil of Schizochytria or Thraustochytria.
  • the defatted biomass itself may also be used as fat source, i.e. in particular the meal of a marine animals, preferably fishmeal, or a plant meal, in particular soybean meal, rapeseed meal, sunflower meal, canola meal, cottonseed meal and/or flax seed meal.
  • Proteins containing components which additionally contain fats which may be used according to the invention are for example fish meal, krill meal, bivalve meal, squid meal or shrimp shells, as well as combinations thereof.
  • the feedstuff according to the invention has preferably a total protein content of 20 to 50 wt.-% and/or a total fat content of 1 to 15 wt.-% and/or a total carbohydrate content of 20 to 60 wt.-%.
  • the feed, food and pharmaceutical compositions of the invention contain at least one microorganism, in particular at least one probiotic microorganism, wherein the microorganism may be used in the form of a preferably dried fermentation broth.
  • microorganism in particular probiotic microorganism, is preferably contained in the compositions of the invention in an amount of about 1x10 2 to about 1x10 10 CFU/g, more preferably in an amount of about 1x10 4 to about 1x10 9 CFU/g, in particular in an amount of 1x10 6 to 1x10 8 CFU/g.
  • Probiotic microorganisms which may be used according to the invention are preferably bacteria selected from the genus Bacillus, more preferably from the species Bacillus subtilis, Bacillus licheniformis, Bacillus paralicheniformis, Bacillus lentus, Bacillus pumilus, Bacillus laterosporus, Bacillus coagulans, Bacillus alevi, Bacillus cereus, Bacillus badius, Bacillus thurigiensis, Bacillus amyloliquefaciens, Bacillus velezensis, Enterococcus faecium, and Pediococcus acidilactici.
  • Preferred examples are Bacillus pumilus DSM 32539 and Bacillus subtilis DSM 32540 (both deposited with the DSMZ on June 14, 2017 under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure) and derivatives thereof, Bacillus licheniformis DSM 32314 and Bacillus subtilis DSM 32315 (both deposited with the DSMZ on May 12, 2016 under the provisions of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure) and derivatives thereof, Bacillus subtilis PB6 (as described in US Patent No. 7,247,299 and deposited as ATCC Accession No.
  • PTA-6737 which is sold by Kemin under the trademark CLOSTAT®, Bacillus subtilis C-3102 (as described in US Patent No. 4,919,936 and deposited as FERM BP- 1096 with the Fermentation Research Institute, Agency of Industrial Science and Technology, in Japan), sold by Calpis as CALSPORIN®, Bacillus subtilis DSM 17299, as sold by Chr. Hansen under the trademark GalliPro®, Bacillus licheniformis DSM 17236, as sold by Chr. Hansen under the trademark GalliProTect®, a mixture of Bacillus licheniformis DSMZ 5749 and Bacillus subtilis DSMZ 5750 spores, as sold by Chr.
  • non-Bacillus probiotics such as Saccharomyces cerevisiae, Pichia pastoris, Aspergillus niger, Aspergillus oryzae, or Hansenula, may also be used in compositions of the present invention.
  • probiotics which are known to be useful to the human health may be used such as lactic acid producing bacteria of the order Lactobacillales, more preferably of the families Aerococcaceae, Carnobacteriaceae, Enterococcaceae, Lactobacillaceae, Leuconotocaceae or Streptococcaceae, or of the order Bifidobacteriales, preferably of the family Bifidobacteriaceae, in particular of the genus Bifidobacterium. If said further probiotics are not formulated as part of the compositions of the present invention, they may be administered together (either at the same time or at different times) with the compositions of the present invention.
  • microorganisms and fermentation broths to be used according to the present invention can be obtained by culturing the microorganisms according to methods well known in the art, including by using the media and other methods as described for example by Elisashvili et al. (Probiotics and Antimicrobial Proteins 11 , 731-747 (2019)), Ren et al. (AMB Express 8:21 (2016)) or as described in the Report 179 of the Food and Agriculture Organization of the United Nations (FAO) with the title “Probiotics in Animal Nutrition” (Bajagai et al., FAO (2016)).
  • a probiotic microorganism is used according to the invention which is able to inhibit the growth of pathogenic microorganisms which occur in aquaculture like Vibrio parahaemolyticus.
  • a probiotic microorganisms with this capacity is for example B. velezensis CECT 5940.
  • Vibrio parahaemolyticus is in particular responsible for diseases of crustaceans like the Early Mortality Syndrome (EMS), also known as Acute Hepatopancreatic Necrosis Disease (AHPND), which affects both Giant Tiger Prawn (Penaeus monodori) and Whiteleg Shrimp (Penaeus vannamei).
  • EMS Early Mortality Syndrome
  • AHPND Acute Hepatopancreatic Necrosis Disease
  • the combined use of the 5-ALA-MetMet co-precipitate of the invention and probiotic microorganisms which are able to inhibit the growth of pathogenic microorganisms of aquaculture is a very effective means for fighting and/or preventing diseases which occur in aquaculture livestocks.
  • a particularly preferred embodiment of the invention are feed or pharmaceutical compositions which contain a 5-ALA-MetMet co-precipitate of the invention and at least one probiotic microorganism which is able to inhibit the growth of pathogenic microorganisms of aquaculture, in particular the growth of Vibrio parahaemolyticus, and the use of such compositions for treating and/or preventing in addition Early Mortality Syndrome (EMS) or Acute Hepatopancreatic Necrosis Disease (AHPND), in particular with respect to animals which are kept in aquaculture, wherein the animals are preferably crustaceans, in particular shrimps or prawns.
  • EMS Early Mortality Syndrome
  • AHPND Acute Hepatopancreatic Necrosis Disease
  • Prebiotics which may be used according to the invention are preferably oligosaccharides, in particular selected from galactooligosaccharides, sialyloligosaccharides, lactulose, lactosucrose, fructooligosaccharides, palatinose or isomaltose oligosaccharides, glycosyl sucrose, maltooligosaccharides, isomaltooligosaccharides, cyclodextrins, gentiooligosaccharides, soybean oligosaccharides, xylooligosaccharides, dextrans, pectins, polygalacturonan, rhamnogalacturonan, mannan, hemicellulose, arabinogalactan, arabinan, arabinoxylan, resistant starch, mehbiose, chitosan, agarose, inulin, tagatose, polydextrose, and alginate.
  • Enzymes which may be used according to the invention and which may aid in the digestion of feed are preferably selected from phytases (EC 3.1 .3.8 or 3.1 .3.26), xylanases (EC 3.2.1 .8), galactanases (EC 3.2.1 .89), galactosidases, in particular alpha-galactosidases (EC 3.2.1.22), proteases (EC 3.4), phospholipases, in particular phospholipases A1 (EC 3.1 .1 .32), A2 (EC 3.1.1.4), C (EC 3.1.4.3), and D (EC 3.1.4.4), lysophospholipases (EC 3.1 .1.5), amylases, in particular alpha-amylases (EC 3.2.1.1 ); lysozymes (EC 3.2.1 .17), glucanases, in particular beta- glucanases (EC 3.2.1 .4 or EC 3.2.1 .6), glucoamylases, cellul
  • phytases examples include Bio-FeedTM Phytase (Novozymes), Ronozyme® P and HiPhosTM (DSM Nutritional Products), NatuphosTM (BASF), Finase® and Quantum® Blue (AB Enzymes), the Phyzyme® XP (Verenium/DuPont) and Axtra® PHY (DuPont).
  • Other preferred phytases include those described in e.g. WO 98/28408, WO 00/43503, and WO 03/066847.
  • Examples of commercially available xylanases include Ronozyme® WX and G2 (DSM Nutritional Products), Econase® XT and Barley (AB Vista), Xylathin® (Verenium) and Axtra® XB (Xylanase/beta-glucanase, DuPont).
  • Examples of commercially available proteases include Ronozyme® ProAct (DSM Nutritional Products).
  • Vitamins which may be used according to the invention are for example vitamin A, vitamin D3, vitamin E, vitamin K, e.g., vitamin K3, vitamin B12, biotin, choline, vitamin B1 , vitamin B2, vitamin B6, niacin, folic acid and pantothenate, e.g. Ca-D-pantothenate, or combinations thereof.
  • Immune modulators which may be used are for example antibodies, cytokines, spray-dried plasma, interleukins, or interferons, or combinations thereof.
  • Minerals which may be used according to the invention are for example boron, cobalt, chloride, chromium, copper, fluoride, iodine, iron, manganese, molybdenum, selenium, zinc, calcium, phosphorous, magnesium, potassium, or sodium, or combinations thereof.
  • Amino acids which may be used according to the invention are for example lysine, alanine, threonine, methionine or tryptophan, or combinations thereof.
  • compositions of the invention may further comprise betaine and/or choline and/or other physiologically effective methyl group donors.
  • the feedstuffs may further comprise polyunsaturated fatty acids, in particular DHA and/or EPA.
  • a further embodiment of the invention is also a method of preparing an animal feed composition
  • a co-precipitate of the invention in particular in an amount effective to enhance animal health, in particular gut health, with feed ingredients, such as proteins, lipids and/or carbohydrates, and optionally further beneficial substances, preferably as mentioned before, to provide a feeding product.
  • This method may comprise for example also a pelleting step.
  • the feed compositions are feed pellets and/or feed extrudates.
  • Standard pelleting processes known to those of skill in the art may be used, including extrusion processing of dry or semi-moist feeds.
  • Preferred pelleting temperatures are between about 65° C and about 120° C.
  • compositions of the invention can be administered to animals in feed and/or drinking water and/or rearing water over multiple days throughout the animal's life or during particular stages or portions of the animal's life.
  • the compositions may be administered only in a starter diet or only in a finisher diet of farm animals.
  • compositions of the invention can further be employed in a wide dosage range.
  • Daily doses are, for example, in the range of between approximately 1 mg and approximately 500 mg, in particular in the range of approximately 5 mg and approximately 200 mg, in the range of from approximately 10 mg to approximately 100 mg or in the range of from approximately 20 to approximately 60 mg per kilogram live weight.
  • an effective amount of a co-precipitate of the invention is used in the embodiments of the invention.
  • the term “effective amount” refers to an amount which effects at least one beneficial effect to an animal and/or to the environment, in particular with respect to the features as already mentioned before, in comparison to an animal or environment that has not been administered the co-precipitate of the invention, but besides that has been administered the same diet (including feed and other compounds) or the same composition, respectively.
  • a therapeutic amount of the co-precipitate of the invention is used.
  • the term "therapeutic amount” refers to an amount sufficient to ameliorate, reverse or prevent a disease state in an animal.
  • Optimal dosage levels for various animals can easily be determined by those skilled in the art, by evaluating, among other things, the composition's ability to (i) inhibit or reduce pathogenic viruses and/or bacteria and/or parasites at the target location at various doses, (ii) increase or maintain levels of the co-precipitate or coprecipitate containing composition and /or (iii) enhance animal health at various doses.
  • the methods of the present invention may be used for all kinds of animals, in particular all kinds of vertebrates such as mammals, aquatic animals and birds.
  • Animals that may benefit from the invention include but are not limited to farm animals, pets, exotic animals, zoo animals, animals used for sports, recreation or work.
  • the animals are farm animals, which are raised for consumption or as food-producers, such as poultry, swine and ruminants.
  • the poultry may be selected from productive or domestic poultry, but also from fancy poultry or wild fowl.
  • Preferred productive poultry in this context are chickens, turkeys, ducks and geese.
  • the productive livestock in this context is preferably poultry optimized for producing young stock or poultry optimized for bearing meat.
  • Preferred fancy poultry or wild fowl are peacocks, pheasants, partridges, chukkars, guinea fowl, quails, capercaillies, grouse, pigeons and swans, with quails being especially preferred.
  • Further preferred poultry are ratites, in particular ostriches and emus, as well as parrots.
  • Ruminants according to the invention are preferably selected from cattle, goat and sheep.
  • the compositions of this invention may be fed to preruminants to enhance their health and, in particular, to decrease the incidence of diarrhea in these animals.
  • Preruminants are ruminants, including calves, ranging in age from birth to about twelve weeks.
  • Pets are preferably selected from dogs, cats, domestic birds and domestic exotic animals. Animals used for sports may in particular be horses.
  • the animals which may benefit from the invention are aquatic animals.
  • the aquatic animals according to the invention are preferably finfish, in particular of the class Actinopterygii, or crustaceans.
  • Actin opterygii include, in particular, tilapia and other cichlids, carps and other cyprinids, salmons and other salmonids, catfish, in particular African catfish, American catfish and pangasius, tuna, perch, cod, smelt, cobia, flatfish, sturgeon, eels, milkfish, gourami, seabass, in particular barramundi, seabream, grouper and snakehead fish.
  • Preferred types of salmon and salmonids in this context are the Atlantic salmon, red salmon (sockeye salmon), masu salmon (cherry salmon), king salmon (Chinook salmon), keta salmon (chum salmon), coho salmon, Danube salmon, Pacific salmon, pink salmon and trout, in particular rainbow trout.
  • carps and cyprinids include silver carp, grass carp, common carp, bighead carp, catla, rohu, carassius .
  • a preferred type of tilapia is the Nile tilapia.
  • Crustaceans include in particular shrimps, lobster, crabs, krill, prawns and crayfish.
  • Preferred types of shrimps in this context are Litopenaeus, Farfantepenaeus and Penaeus, in particular Penaeus stylirostris, Penaeus vannamei, Penaeus monodon, Penaeus chinensis, Penaeus occidentalis, Penaeus calif omiensis, Penaeus semisulcatus, Penaeus esculentu, Penaeus setiferus, Penaeus japonicus, Penaeus aztecus, Penaeus duorarum, Penaeus indicus, and Penaeus merguiensis.
  • Very preferred according to the invention are the shrimps Penaeus vannamei, also called whiteleg shrimp, and Pennaeus monodon, also called black tiger shrimp.
  • a preferred prawn is the giant river prawn.
  • the aquatic animals, and in particular the shrimp, which are treated or fed with the compositions according to the invention can in particular be larvae, post-larvae or juvenile shrimp.
  • the aquatic animals may in particular also be fish which is subsequently processed into fish meal or fish oil.
  • the fish are preferably herring, pollack, cod or small pelagic fish like anchovy, blue whiting, capelin, driftfish, jack, mackerel, menhaden, sardine or scad fish.
  • the fish meal or fish oil thus obtained, in turn, can be used in aquaculture for farming edible fish or crustaceans.
  • the aquatic animals may further be oysters, clams, cockles, arkshells, bivalves, mussels or scallops.
  • the aquatic animals may also be small organisms which are used as feedstuff in aquaculture. These small organisms may take the form of, for example, nematodes, small crustaceans or rotifers.
  • the farming of aquatic animals may take place in ponds, tanks, basins or else in segregated areas in the sea or in lakes or in rivers, in particular in this case in cages or net pens. Farming may be used for farming the finished edible fish, but also may be used for farming fry which are subsequently released so as to restock the wild fish stocks. Principally, farming can be carried out in freshwater as well as in salt water, depending on the kind of aquatic animals.
  • the fish are preferably first grown into smolts in freshwater tanks or artificial watercourses and then grown on in cages or net pens which float in the sea, ponds or rivers and which are preferably anchored in bays or fjords.
  • the feed composition according to the invention is preferably a feedstuff for use in the farming of the above-mentioned animals.
  • Preferred applications for animal feed according to the invention is in the feed of cattle, swine, poultry, fish, crustaceans or companion animals, with fish and crustaceans being particularly preferred.
  • the 5-ALA solution is added to the MetMet solution under stirring (500 rpm) and the pH is adjusted to pH 1 again with hydrogen chloride.
  • NaOH (30 wt.-%) is added dropwise under constant stirring, until a pH of 4 is reached.
  • 82 g NaOH (30 wt.-%) are added.
  • the solution becomes cloudy.
  • the precipitate is separated by filtration and washed two times with 100 ml water. As last step the precipitate is dried under vacuum at a temperature of 50° overnight.
  • a solution of NaMetMet is prepared by reacting MetMet diketo piperazine with NaOH (see WO 2010/043558) and subsequent dilution with distilled water under stirring, resulting in a solution with a pH of 11 .2, containing 8.85 wt.-% MetMet (2.97 wt.-% DDLL, 5.88 wt.-% DLLD). 2000 g of this stock solution is cooled under stirring in an ice bath, until a temperature of about 4°C is reached. On the other hand, 50 g 5-ALA (chloride salt) is dissolved in 400 g water under stirring and the pH is subsequently adjusted to pH 1 by addition of hydrogen chloride. The 5-ALA solution is also cooled to about 4°C.
  • the alkaline MetMet solution is added dropwise under constant stirring (500 rpm) into the 5-ALA solution, until a pH of 5 is reached.
  • a pH of 5 In the course of 60 minutes 842.2 g NaMetMet solution are added.
  • the 5-ALA solution becomes cloudy.
  • the precipitate is separated by filtration and washed two times with 100 ml water. As last step the precipitate is dried under vacuum at a temperature of 50° over-night.
  • tissue bags (Ankom Technology Part# R510, 5x10 cm) are each filled with 0.5 g of the coprecipitates as obtained in examples 1 (“Prec 1”) and 2 (“Prec 2”).
  • tissue bags are filled with 0.5 g of a premix mixture of 1 .6 wt.-% 5-ALA and 98.4 wt.-% MetMet.
  • tissue bags are prepared. The tissue bags are then fixed in screw lid jars which are filled with 50 ml of sea water (33 g/L SERA Marin salt in water), so that the water covers the lower half of the tissue bags, where the samples are located.
  • tissue bags containing the precipitate of example 1 and 2 (Prec 1 and 2) and a tissue bag containing the mixture of 5-ALA and MetMet (Ref) are removed from the srew lid jars and dried by exposure to a stream of cold air overnight. After that the residual amount of 5-ALA as still contained in the tissue bags is determined by qNMR. The results are depicted in the following table.
  • the co-precipitates of 5-ALA and MetMet show practically no leaching of 5-ALA from the tissue bags, even after 210 minutes of incubation in sea water, which means that the 5-ALA is very effectively protected from leaching due to the encapsulation into the MetMet matrix.
  • the mere mixture of 5-ALA and MetMet shows very strong leaching of the 5-ALA from the tissue bag: Even after two minutes of exposure to the sea water more than 50 % of the 5-ALA is lost and after 120 minutes no 5-ALA can be found anymore in the residual sample as still contained in the tissue bag.
  • tissue bags (Ankom Technology Part# R510, 5x10 cm) are each filled with 0.5 g of the coprecipitates as obtained in examples 4 (“Prec 4”).
  • tissue bags are filled with 0.5 g of a premix mixture of 1 .34 wt.-% thiamine and 98.66 wt.-% MetMet.
  • tissue bags are prepared.
  • the tissue bags are then fixed in screw lid jars which are filled with 50 ml of sea water (33 g/L SERA Marin salt in water), so that the water covers the lower half of the tissue bags, where the samples are located.
  • the screw lid jars are then put on a shaker plate rotating with 100 rpm at room temperature.
  • tissue bags containing the precipitate of example 4 (Prec 4) and a tissue bag containing the mixture of thiamine and MetMet (Ref 2) are removed from the srew lid jars and dried by exposure to a stream of cold air over-night. After that the residual amount of thiamine as still contained in the tissue bags is determined by qNMR. The results are depicted in the following table.
  • the co-precipitates of thiamine and MetMet show practically no leaching of thiamine from the tissue bags, even after 210 minutes of incubation in sea water, which means that the thiamine is very effectively protected from leaching due to the encapsulation into the MetMet matrix.
  • the mere mixture of thiamine and MetMet shows strong leaching of the thiamine from the tissue bag: Even after two minutes of exposure to the sea water more than 50 % of the thiamine is lost and after 120 minutes less than 20 % of the thiamine as originally contained can still be found in the tissue bag.

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Abstract

La présente invention concerne un coprécipité de méthionylméthionine avec au moins un autre composé organique, de préférence avec de l'acide aminolévulinique, de la PQQ ou de la thiamine, des procédés de préparation de tels coprécipités et l'utilisation de tels coprécipités, en particulier en tant qu'additifs pour aliments destinés à l'alimentation humaine et animale et en tant que produits pharmaceutiques.
PCT/EP2023/057139 2022-03-24 2023-03-21 Coprécipités de méthionylméthionine avec des composés organiques WO2023180282A1 (fr)

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