WO2020011629A1 - Composition of powderous instant drink, its preparation and use - Google Patents

Composition of powderous instant drink, its preparation and use Download PDF

Info

Publication number
WO2020011629A1
WO2020011629A1 PCT/EP2019/067924 EP2019067924W WO2020011629A1 WO 2020011629 A1 WO2020011629 A1 WO 2020011629A1 EP 2019067924 W EP2019067924 W EP 2019067924W WO 2020011629 A1 WO2020011629 A1 WO 2020011629A1
Authority
WO
WIPO (PCT)
Prior art keywords
ingredient
zinc
tyrosine
composition
mixtures
Prior art date
Application number
PCT/EP2019/067924
Other languages
French (fr)
Inventor
Ivica Cepanec
Marko Dragicevic
Zeljko BIHAR
Original Assignee
Ivica Cepanec
Marko Dragicevic
Zeljko BIHAR
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ivica Cepanec, Marko Dragicevic, Zeljko BIHAR filed Critical Ivica Cepanec
Publication of WO2020011629A1 publication Critical patent/WO2020011629A1/en

Links

Classifications

    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • 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
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/30—Zinc; Compounds thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • 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
    • A23V2250/00—Food ingredients
    • A23V2250/15—Inorganic Compounds
    • A23V2250/156—Mineral combination
    • A23V2250/1642—Zinc
    • 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
    • A23V2250/00—Food ingredients
    • A23V2250/70—Vitamins
    • A23V2250/704—Vitamin B

Definitions

  • the present invention relates to a composition which is used as a functional food product, food supplement, or pharmaceutical product.
  • the present invention solves subsidiary technical problems of obtaining an improved product for :
  • mood improvement including seasonal affective disorder (SAD); improvement of well-being;
  • vitamins from B-group selected from the group consisting of: niacin (B3) , pyridoxine (B6) , folic acid (B9) and vitamin B12
  • solubility enhancer of L-tyrosine (1) which facilitates its bioavailability.
  • composition is used in the form of a powderous composition for the preparation of an instant cappuccino-like drink, which completely masks all off-tastes and off-odours of the said active substances while preserving their overall pharmacological profile.
  • MDD major depressive disorder
  • L-Tyrosine (1; TYR) is a conditionally essential natural amino acid, which serves not only as a building block of body proteins, but also as a precursor for biosynthesis of neurotransmitters from the class of catecholamines: dopamine (DA), norepinephrine (NE) or noradrenaline, and epinephrine (EN) or adrenaline, and their simple amines: tyramine and phenylethylamine . Biosynthesis of these compounds starts from L-phenylalanine which is converted by hydroxylation to L- tyrosine (1) .
  • L-Tryptophan (2; TRP) is an essential amino acid which serves for synthesis of body proteins, and also as a precursor for biosynthesis of neurotransmitter serotonin (SE) and neurohormone melatonin (ME) .
  • Trimethylglycine (3; TMG) , also known under trivial name betaine, because it is, besides in its synthetic form, commonly manufactured by isolation from sugar beet (Beta vulgaris L.) .
  • TMG Trimethylglycine
  • SAME s-adenosyl-L- metionine
  • microelement zinc For microelement zinc (Zn) it is also known in the prior art that it shows pharmacological activity similar to an antidepressant, presumably because it acts as a cofactor in the biosynthesis of the above-mentioned neurotransmitters. In depressive patients lower plasma concentration was observed along with certain improvement of the medical condition after zinc supplementation; see literature reference 7 :
  • Pardee and Birk disclosed a new therapy for biosynthesis stimulation of serotonin, glycine, and gamma-aminobutyric acid (GABA) , and for the treatment of acute anxiety, hyperactivity, panic attack, confusions, sleep disorder, mood disorder, depression, obsessive compulsive disorder (OCD) , and some other diseases of the central nervous system (CNS) with the use of a specific composition of: acetyl- L-carnitine, a-lipoic acid, biotin, vitamin Bl, L-glutamine, vitamin B6, taurine, folic acid (B9 ) , vitamin B12, trimethylglycine ( 3 ) and L-tryptophan ( 2 ) ; see literature reference 9:
  • composition can optionally contain other substances as follows: lithium orotate, vitamins C, E, D, B2 , B3, B5, and nystatin, calcium, and magnesium.
  • GSD gastroesophageal reflux disease
  • amino acid selected from the group consisting of; trimethylglycine (3; betaine) , N-acetyl-L-cysteine (NAC) , s- adenosyl-L-methionine (SAME) , L-tryptophan (2) and glutathione (GSH) ; see literature reference 11:
  • the said composition does not recognize the importance of parallel use of L-tyrosine (1) and zinc (Zn) . Also, it does not disclose any details about other key substances and about the way of acting as does the composition from the present invention.
  • composition for memory stimulation which is consisting of:
  • a drug which stimulates brain memory function 5-HTP, phosphatidyl choline, dimethylamino ethanol, phosphatidyl serine, s-adenosyl-L-methionine ( SAME ) , DL-phenylalanine , inositol, fisetin, L-tryptophan (2), L-tyrosine (1), lithium, or their combinations;
  • a drug which delivers food and oxygen to the brain acetyl -L- carnitine, vinpocetine, Ginkgo biloba extract, puerarin, biotin (B7), vitamins Bl, B2, B3, B5, B6, B9, chromium, glutamic acid, glycine, alanine, or their combinations;
  • a drug which maintains a normal level of oxidative stress in the brain lipoic acid, trimethylglycine (3; betaine), vitamin C, glutathione, huperzine A, lycopene, vitamin E, selenium, zinc (Zn); or their combinations.
  • composition is useful for enhancement of learning ability, treatment of cognitive disorders and prevention and treatment of Alzheimer's disease; see literature reference 12:
  • composition contains almost all active substances like the composition from the present invention, it does not recognize :
  • EP 1275399B1 (2001); A. J. Kiliaan, R. J. J. Hageman: Method and preparation for preventing and/or treating vascular disorders and secondary disorders associated therewith; applicant: N. V. Nutricia (NL) .
  • composition is based on the combination of:
  • phosphatidyl esters phosphatidyl serine, phosphatidyl inositol, phosphatidyl choline, phosphatidyl diethanolamine; and,
  • the said composition may contain other substances such as: hypericin, extract of the plant Withania somnifera, citrates, L-tryptophan ( 2 ) or proteins containing L- tryptophan, s-adenosyl-L-methionine ( SAME ) , choline, trimethylglycine ( 3 ; betaine), copper, carnitine, vitamin Bl, vitamin B5, coenzyme Q10, vitamin C, vitamin E, lipoic acid, selenium salts, carotenoids, extract of gingko (Gingko biloba L.) and vitamin D3.
  • other substances such as: hypericin, extract of the plant Withania somnifera, citrates, L-tryptophan ( 2 ) or proteins containing L- tryptophan, s-adenosyl-L-methionine ( SAME ) , choline, trimethylglycine ( 3 ; betaine), copper, carnitine, vitamin Bl, vitamin B5, coenzyme
  • composition is claimed to be effective in prevention and treatment of bipolar and unipolar depression, depression connected with menstruation and menopause, schizophrenia, attention deficit hyperactivity disorder (ADHD) , anxiety, insomnia, seasonal affective disorder (SAD), dementia, and Parkinson's disease.
  • ADHD attention deficit hyperactivity disorder
  • SAD seasonal affective disorder
  • dementia dementia
  • composition based on the combination of food acids (citric and/or tartaric acid) and sodium bicarbonate (NaHCOs) ; see literature reference 15;
  • hydrogel (iii) the form of hydrogel, using sodium hydroxide (NaOH) as the agent for dissolution of L-tyrosine with subsequent release of fine particles of L-tyrosine upon the action of acid and their stabilization within the hydrogel of gelatin.
  • NaOH sodium hydroxide
  • Such hydrogel provides improved solubility and bioavailability of L- tyrosine.
  • such hydrogel is not suitable for liquid products or powderous instant compositions; see literature reference 17 :
  • Figure 1 shows :
  • Figure 2 shows :
  • Figure 3 shows :
  • FIG. 4 shows a known metabolic pathway of s-adenosyl metionine (SAME) biosynthesis as a natural terminal methylation agent and the role of the key ingredients from the present invention: trimethylglycine (3; TMG) , vitamin B12 (B12) , folic acid (vitamin B9; B9) and zinc (through enzyme BHMT) in the biosynthesis of SAME as well as in a decreasing concentration of harmful homocysteine (HC) .
  • TMG trimethylglycine
  • B12 vitamin B12
  • folic acid vitamin B9
  • BHMT zinc
  • HC harmful homocysteine
  • Figure 5 shows a mechanism of action of solubility enhancer of L- tyrosine (1; TYR) in the composition from the present invention when used as a powderous instant cappuccino-like drink.
  • solubility enhancer of TYR L- tyrosine
  • Figure 5 shows a mechanism of action of solubility enhancer of L- tyrosine (1; TYR) in the composition from the present invention when used as a powderous instant cappuccino-like drink.
  • NaHCCt sodium hydrogencarbonate
  • the present invention is related to an improved product which belongs to the group of functional food products, food supplements, or pharmaceutical products for prevention and treatment of central nervous system disorders.
  • the product involves a powderous composition which is added to water or milk for the preparation of a liquid functional drink with taste and appearance similar to cappuccino, which consists of:
  • coffee substitute is selected from the group consisting of: chicory ( Cichorium intybus L) root; barley (Hordeum vulgare L) seeds; barley malt; rye ( Secale cereale L) seeds; rye malt; wheat ( Triticum vulgare L) seeds; wheat malt; chickpea ( Cicer arietinum L) seeds; dandelion ( Taraxacum officinalis L) root; fig ( Ficus carica L) fruit; carob ( Ceratonia siliqua L) fruit; or mixtures of these ingredients; (ii) fat; selected from the group consisting of: coconut fat, palm oil, hydrogenated palm oil, palm kernel oil, hydrogenated palm kernel oil, rapeseed oil, sunflower oil, soybean oil, cottonseed oil, milk fat, or mixtures of these ingredients;
  • full fat or skimmed milk powder milk proteins, whey proteins, plant proteins, or mixtures of these substances;
  • carbohydrate ingredient selected from the group consisting of: sugar, honey, glucose syrup, glucose-fructose syrup, fructose syrup, glucose, fructose, maltose, lactose, maltodextrin, dextrin, starch, inulin, oligofructose , full fat or skimmed milk powder, or mixtures of these substances; and,
  • food additives required for the formation of desired technological properties of the present composition, which are selected from the group consisting of: salt (NaCl), spices, flavours, emulsifier salts, food colours, preservatives, food acids, anti-caking agents, thickeners, sweeteners, taste enhancers, or mixtures of these substances; and
  • niacin B3
  • pyridoxine B6
  • folic acid B9 or its pharmaceutical equivalents
  • vitamin B12 and, optionally, other vitamins of B-complex: thiamine (Bl), riboflavin (B2), pantothenic acid (B5), and biotin (B7);
  • solubility enhancer of L-tyrosine (1) is used as follows:
  • one or more food additives selected from the group consisting of: sodium carbonate (Na 2 CC>3) , sodium bicarbonate (NaHCCt) , sodium sesquicarbonate (Na 2 C0 3 *NaHC0 3 *2H 2 0) , potassium carbonate (K 2 CO 3 ) , potassium bicarbonate (KHCO 3 ) , or mixtures of these substances.
  • Fat the ingredient (ii) in the composition of the present invention, is selected from the group consisting of: cold-pressed, hot-pressed, refined, partially hydrogenated or fully hydrogenated oils or fats from coconut ( Cocos nucifera L.), palm [Elaeis guineensis Jacq., Elaeis oleifera (Kunth) Cortes, Attalea maripa (Aubl . ) Mart.] or palm kernel, rape and canola (Brassica napus L., Brassica rapa ssp. oleifera L., Brassica juncea L.), sunflower ( Helianthus annuus L.), soybean ( Glycine max. (L.) Merr.
  • coconut Cocos nucifera L.
  • palm Elaeis guineensis Jacq., Elaeis oleifera (Kunth) Cortes, Attalea maripa (Aubl . ) Mart.
  • palm kernel rape and can
  • fat is selected from the group consisting of: coconut fat, palm oil, hydrogenated palm oil, palm kernel oil, hydrogenated palm kernel oil, rapeseed oil, sunflower oil, soybean oil, cottonseed oil, milk fat, or mixtures of these substances.
  • Food emulsifier for plant oils and fats in the formulation of the base, the ingredient (iii), is selected from the group consisting of: polyoxyethylene (40) stearate (E431); polysorbates (E432-435) like polysorbate 80 (E433); mono- and diglycerides of fatty acids (E471); acetate esters of mono- and diglycerides of higher fatty acids (E472a) ; lactate esters of mono- and diglycerides of higher fatty acids (E472b) ; citrate esters of mono- and diglycerides of higher fatty acids (E472c) ; tartrate esters of mono- and diglycerides of higher fatty acids (E472d) ; mono- and diacet
  • Protein ingredient, the ingredient (iv) in the formulation of the base is selected from the group consisting of: full fat or skimmed milk powder, milk proteins, whey proteins, plant proteins, or mixtures of these substances.
  • Carbohydrate ingredient the ingredient (v) in the formulation of the base, is selected from the group consisting of: sugar, honey, glucose syrup, glucose-fructose syrup, fructose syrup, glucose, fructose, maltose, lactose, maltodextrin, dextrin, starch, inulin, oligofructose, full fat or skimmed milk powder, or mixtures of these substances .
  • ingredient (v) carbohydrate ingredient
  • full fat or skimmed milk powder can be employed, which usually contains approx. 45-55% lactose, approx. 0.5-4% milk fat and approx. 25-35% milk proteins.
  • ingredient (iii) food emulsifier for fat
  • a suitable plant fat for instance fully hydrogenated or refined coconut fat; which is emulsified with,
  • a suitable food emulsifier such as mono- and diglycerides of higher fatty acids (E471) and mono- and diacetyl tartaric esters of mono- and diglycerides of higher fatty acids (E472e) or suitable emulsifying salts like potassium phosphate (E340) as food additive intended for emulsification of the said plant fats; which are spray-dried onto,
  • a suitable edible carrier such as dehydrated glucose syrup.
  • Such complex ingredients can replace the separate ingredients (ii)- (iv) , and partially the ingredient (v) .
  • Examples of such coffee creamer and coffee foamer are described in the experimental Examples 1-3.
  • the ingredient (v) in liquid dosage forms of the composition from the present invention, natural or artificial fruit or vegetable juices can be used as the base with approx. 7-12% w/w of sugar saccharose or an equivalent concentration of sugar substitute: glucose syrup, glucose-fructose syrup, fructose syrup, or mixtures of these substances.
  • natural apple juice, natural orange juice, and natural carrot juice is outlined. The example of such use is disclosed in the experimental Example 4.
  • the ingredients (vi) are selected from the groups consisting of:
  • spices cinnamon (Cinnamomum verum J.Presl), clove (Syzygium aromaticum L.), nutmeg (Myristica fragrans Houtt . ) , laurel (Laurus nobilis L.), piment [ Pimenta dioica (L.) Merr.
  • flavours powderous or liquid flavours of coffee, vanilla, hazelnut, milk, other flavours, and mixtures of these flavours; emulsifier salts: lactates like sodium lactate (E325), potassium lactate (E326) , calcium lactate (E327); citrates such as sodium citrates (E331), potassium citrates (E332), calcium citrates (E333) ; phosphates like sodium phosphates (E339) , potassium phosphates (E340), diphosphates (E450) , triphosphates (E451) and polyphosphates (E452);
  • curcumin E100
  • riboflavin E101
  • caramel E150
  • carotenes E160a
  • lutein E161b
  • anthocyanins E163
  • betanin E162
  • preservatives benzoic acid (E210) or its salts like sodium benzoate (E211); sorbic acid (E200) or its salts such as potassium sorbate (E202); lactic acid (E270); parabens like methyl 4- hydroxybenzoate (E218), ethyl 4-hydroxybenzoate (E214) or propyl 4-hydroxybenzoate (E216) , sulphites such as potassium metabisulphite (E224); other food or pharmaceutically acceptable preservatives; or mixtures of these substances;
  • anti-caking agents magnesium oxide (MgO; E530), calcium oxide (CaO; E529), silicium dioxide (SiCh; E551), calcium phosphate [Ca 3 (P0 4 ) 2 ; E341iii] , magnesium carbonate (MgC0 3 »nH 2 0; E504i), magnesium hydroxide carbonate (E504ii), talc (E553b) , aluminium silicate (kaolin; E559) , magnesium salts of higher fatty acids (E470b) like magnesium stearate, other food or pharmaceutically acceptable anti-caking agents; or mixtures of these substances; thicken
  • sweeteners acesulfame K (E950), aspartame (E951), cyclamate (E952), saccharin (E954), sucralose (E955), thaumatin (E957), neohesperidin DC (E959 ) , neotame (E961), salts of aspartame and acesulfame (E962), sorbitol (E420) , mannitol (E421), isomalt (E 953 ) , maltitol (E 965 ) , lactitol (E966 ) , xylitol (E967), erythritol (E968), or mixtures of these substances;
  • E620 glutamic acid
  • E621 monosodium glutamate
  • E622 monopotassium glutamate
  • E622 calcium diglutamate
  • E 623 monoammonium glutamate
  • E624 magnesium diglutamate
  • E 625 guanylic acid
  • E626 disodium guanylate
  • E627 dipotassium guanylate
  • E628 calcium guanylate
  • E629 inosinic acid
  • E630 disodium inosinate
  • E631 dicalcium inosinate
  • E633 calcium 5 ' -ribonucleotide
  • E634 disodium 5 ' -ribonucleotide
  • E 635 glycine or sodium glycinate
  • E640 glycine or sodium glycinate
  • L-tyrosine (1) L-tryptophan (2) , and trimethylglycine (3) in the form of free amino acids
  • acids are selected from the group consisting of: citric; malic; tartaric; isocitric; lactic; pyruvic; aconitic; a-keto-glutaric; fumaric; gluconic; acetic; succinic; adipic; hydrochloric; sulphuric; phosphoric; other pharmaceutically acceptable acids; or mixtures of these acids.
  • Examples of such alternative salts which can be used instead of free amino acids are: L-tyrosine hydrochloride, L-tryptophan hydrochloride, trimethylglycine hydrochloride, trimethylglycine citrate and others.
  • extract of sugar beet Beta vulgaris L with the content of >25% w/w compound 3 can be used .
  • compositions of the present invention are selected from the group consisting of: zinc oxide; zinc carbonate; zinc sulphate; zinc chloride; zinc acetate; zinc phosphate; zinc gluconate; zinc lactate; zinc citrate; zinc malate; zinc glycinate; zinc aspartate; zinc a- keto-glutarate ; hydrates of the said compounds; other pharmaceutically acceptable zinc salts or complexes; hydrates of the said compounds; and mixtures of these substances.
  • composition of the present invention are selected from the group consisting of:
  • niacin (B3) nicotinic acid, nicotinamide, or mixtures of these substances ;
  • pyridoxine (B6) pyridoxine hydrochloride, pyridoxine 5'- phosphate, pyridoxine dipalmitate, or mixtures of these substances ;
  • folic acid (B9) folic or pteroyl-L-glutamic acid, dihydrofolic acid, tetrahydrofolic acid, 5-metiltetrahydrofolic acid, and folinic acid; salts of the said acids with pharmaceutically acceptable cations like sodium (Na + ) , potassium (K+) , magnesium (Mg 2+ ) , calcium (Ca 2+ ) ; or mixtures of these substances;
  • vitamin B12 cyanocobalamin, hydroxycobalamin, metilcobalamin, cobalamin or adenosyl-cobalamin; of mixtures of the said forms of vitamin B12;
  • thiamine (Bl) thiamine hydrochloride, thiamine mononitrate, or mixtures of these substances;
  • riboflavin (B2) riboflavin, riboflavin 5 '-phosphate sodium salt; pantothenic acid (B5) : calcium D-pantothenate , sodium D- pantothenate , dexpanthenol ; and,
  • biotin (B7) D-biotin.
  • the following forms of B vitamins are used: nicotinamide (B3) , pyridoxine hydrochloride (B6) , pteroyl-L-glutamic acid (B9) , and cyanocobalamin (B12), and, optionally: thiamine hydrochloride (Bl), riboflavin (B2), calcium pantothenate (B5), and biotin (B7) .
  • L-tyrosine (1) is characterized by very poor water solubility: about 45 mg in 100 g water at 25 °C (see literature reference 14), it is of essential importance for the present invention to use an L-tyrosine solubility enhancer. The latter enables improvement of its bioavailability and thus better pharmacological effects on the human health.
  • L-tyrosine (1) solubility Apart from the enhancement of L-tyrosine (1) solubility, its effect must not compromise the sensory profile of the main composition matrix from the present invention. In the case of the use of a powderous instant drink based on coffee or coffee substitute, the said L-tyrosine (1) solubility enhancer must not develop any chemical incompatibility with other ingredients of the composition.
  • solubility enhancers can be used: sodium carbonate (Na 2 CC>3) , sodium bicarbonate (NaHCCb) , sodium sesquicarbonate (Na2C03*NaHC03*2H 2 0) , potassium carbonate (K2CO3) , potassium bicarbonate (KHCO3) , or mixtures of these substances.
  • sodium bicarbonate NaHCCb
  • NaHCCb sodium bicarbonate
  • the powderous composition from the present invention is characterized by the following weight percentages (%, w/w) of the ingredients:
  • ingredient (vi) 0.5-5% w/w; of which salt (NaCl) 0.1-1% w/w; and,
  • ingredient (viii) 1-25% w/w;
  • ingredient (ix) 0.1-25% w/w;
  • ingredient (x) 0.1-5% w/w;
  • ingredient (xi) 0.001-1% w/w each of the vitamins: niacin
  • B3 pyridoxine (B6) , folic acid (B9) and, optionally, other vitamins of B complex: thiamine (Bl), riboflavin (B2), pantothenic acid (B5) , and biotin (B7); and,
  • the powderous composition from the present invention is characterized by the following weight percentages (%, w/w) of the ingredients :
  • A. formulation of the base from 80-90% w/w; ingredient (i) : 10-15% w/w;
  • ingredient (ii) 5-10% w/w;
  • ingredient (vi) 0.5-5% w/w; of which salt (NaCl) 0.25- 0.75% w/w; and,
  • ingredient (vii) 2-5% w/w;
  • ingredient (viii ) 1-5% w/w;
  • ingredient (ix) 2-5% w/w;
  • ingredient (x) 0.05-1% w/w;
  • niacin B3
  • pyridoxine B6
  • folic acid B9
  • other vitamins of B complex thiamine (Bl), riboflavin (B2), pantothenic acid (B5) , and biotin (B7); and,
  • active substances known to those skilled in the art, which help in disorders of the central nervous system can also be optionally employed in the composition of the present invention.
  • active substances are selected from the group comprising:
  • Mg magnesium
  • Se selenium
  • I iodine
  • pharmaceutical equivalents of the said vitamins or pharmaceutically acceptable salts of these minerals or mixtures of these substances.
  • composition from the present invention can be used in various dosage forms suitable for practical use: (i) functional food product forms: instant powder for preparation of a cappuccino-like drink with water or milk, liquid cappuccino, instant powderous or liquid drinks based on coffee or coffee substitutes, instant powderous or liquid non alcoholic beverages, wine, beer, yogurt, milk drinks, chewing gums, functional energy bars, muesli-like products, functional ice cream, and other suitable forms of functional food products; or,
  • compositions in the case of pharmaceutical products and food supplements powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution.
  • the ingredients (i-vi) various food ingredients can be used: food liquids such as water, milk, yogurt, wine, beer, fruit juices, vegetable juices and others; cereals such as whole, polished, rolled or extruded seeds of wheat, barley, oat, rye, triticale, maize, and other cereals; dried fruits such as raisins, bananas, apples, strawberries, blueberries, figs, pineapple, and other fruits; natural sugars like sucrose, honey, glucose, fructose, glucose syrup, fructose syrup, glucose-fructose syrup; natural sweeteners such as liquorice ( Glycyrrhiza glabra L.) or stevia ( Stevia rebaudiana) ; soluble plant fibres like inulin, oligofructose , pectins; oligo- and polysaccharides such as dextrins, maltodextr
  • the composition from the present invention in the form of functional food can also contain different food additives which, alike the ingredient (vi), help to stabilize, preserve, enable the desired consistency of the products, etc.
  • the use of food additives is common in the food industry and is known to those skilled in the art of food technology.
  • the formulation (B.) of active substances (vii)-(xi) is not employed in the dosage form of the powderous instant form for preparation of a cappuccino-like drink, but it is used in some of the dosage forms typical for food supplements or pharmaceutical products such as: powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution, then, instead of the formulation base (A. ) , the ingredients
  • one or more pharmaceutical excipients are used.
  • Such pharmaceutical excipients are selected from the groups consisting of: fillers, binders, disintegrants, lubricants, diluents (solvents), buffer substances, antioxidants, stabilizers, preservatives, colours, flavours, and other kinds of excipients that are commonly employed in the dosage forms of powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution.
  • fillers sugar like sucrose, honey, glucose, fructose, lactose, other edible sugars or mixtures of these substances; starch, dextrins, maltodextrins , and other starch derivatives; sugar alcohols such as sorbitol, maltitol, xylitol, mannitol, lactitol, isomalt, erythritol, other sugar alcohols or mixtures of these substances;
  • sweeteners aspartame, saccharin, acesulfame, sucralose, cyclamate, glycyrrhizin, ammonium glycyrrhizinate or extract of liquorice ( Glycyrrhiza glabra L.) root, neohesperidin dihydrochalcone (NHDC) , stevia, stevia extracts, rebaudioside A and other steviosides;
  • NHDC neohesperidin dihydrochalcone
  • anti-caking agents like magnesium or calcium salts of higher fatty acids such as magnesium stearate, silicon dioxide;
  • soluble fibres polydextrose, inulin, oligofructose , other soluble dietary fibres; or mixtures of these substances.
  • Other examples of such substances that can be used are given under the definition of the ingredient (vi) .
  • the process of preparation of the composition includes the homogenization of the ingredients (i-xii) .
  • the process can be performed by separately homogenizing the base formulation (the ingredients i-vi) and separately the formulation of active substances (vii-xi) , with or without addition of the solubility enhancer of L- tyrosine, the ingredient (xii) .
  • final homogenization of the base formulation (i-vi) and formulation of active substances (vii-xi, xii) yields the final product according to the present invention.
  • composition from the present invention can be :
  • functional food product forms instant powder for preparation of a cappuccino-like drink with water or milk, liquid cappuccino, instant powderous or liquid drinks based on coffee or coffee substitutes, instant powderous or liquid non alcoholic beverages, wine, beer, yogurt, milk drinks, chewing gums, functional energy bars, muesli-like products, functional ice cream, and other suitable forms of functional food products; or,
  • compositions in the case of pharmaceutical products and food supplements powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution.
  • the forms intended for use as functional food are prepared by homogenization of active substances (vii)-(xi), with or without the solubility enhancer L-tyrosine (1), the ingredient (xii), into the corresponding matrix of the food product.
  • the powderous instant cappuccino-like drink is prepared by homogenization of powderous active substances (i)-(xii) . Typical examples of such procedures for the preparation of a powderous instant cappuccino-like drink are described in Examples 1-3.
  • a functional non-alcoholic beverage is prepared by dissolution and/or suspension of the ingredients (vii)-(xi) in suitable fruit juice, for instance apple juice.
  • suitable fruit juice for instance apple juice.
  • suitable fruit juice for instance apple juice.
  • Typical example of the preparation of a liquid functional food drink is described in Example 4.
  • Functional muesli is manufactured by homogenization of powderous formulation of active substances (vii)-(xi) with an inert edible powder, e.g. maltodextrin .
  • an inert edible powder e.g. maltodextrin .
  • Such a premix is further homogenized with rolled wheat or oat, small parts of dried fruits, sugar, with or without addition of flavour, protein source, other food additives or other nutritional ingredients.
  • Typical example of such preparation of a functional muesli form is described in Example 5.
  • a functional energy bar is prepared by:
  • fat e.g. fully hydrogenated palm fat
  • emulsifier for fats e.g. sunflower or soybean lecithin
  • carbohydrate ingredient e.g. honey, glucose syrup, sugar syrup or similar carbohydrate syrup, or mixtures of these substances; with,
  • a suitable protein ingredient e.g. milk powder, whey proteins, milk protein, plant protein like pea protein or wheat protein, other suitable edible protein-containing ingredients, or mixtures of these substances; and
  • humectants glycerol (E422), sorbitol (E420), maltitol (E965) , other hygroscopic polyols, or mixtures of these substances;
  • food acids citric acid (E330), malic acid (E296), other food acids, or mixtures of these substances;
  • preservatives e.g. potassium sorbate (E202), sodium benzoate (E211), other suitable preservatives, or mixtures of these substances;
  • flavours e.g. vanillin, chocolate, hazelnut or fruit flavours; with,
  • non-chocolate melted coating separately prepared from: suitable fat such as palm fat, sugar, skimmed milk powder, vanilla flavour and lecithin as emulsifier.
  • Example 6 Typical example of such a procedure for the preparation of the composition from the present invention in the form of a functional energy bar is described in Example 6.
  • fat e.g. palm oil
  • emulsifier for fat e.g. sunflower or soybean lecithin
  • carbohydrate ingredient e.g. honey, glucose syrup, sugar, similar carbohydrate syrup, or mixtures of these substances; with, (iv) addition of a suitable protein ingredient; e.g. milk powder, whey proteins, milk proteins, plant proteins like pea or wheat proteins, other suitable edible proteins; or mixtures of these substances; and,
  • humectants glycerol (E422), sorbitol (E420) , maltitol (E965) , other hygroscopic polyols, or mixtures of these substances ;
  • preservatives e.g. potassium sorbate (E202), sodium benzoate (E211), other suitable preservatives, or mixtures of these substances;
  • flavours e.g. vanilla, chocolate, hazelnut or fruit flavours
  • thickeners e.g. xanthan gum (E415) , guar gum (E412), pectins (E440) , other edible thickeners, or mixtures of these substances; with,
  • Example 7 Typical example of the procedure for preparation of the composition from the present invention in the form of functional ice cream is shown in Example 7.
  • the formulation of active substances (vii)- (xi) , with or without the solubility enhancer L-tyrosine, the ingredient (xii) is used in conventional dosage forms typical for food supplements and pharmaceutical products; typical examples are described in Examples 8 11
  • composition from the present invention in the dosage form of the powder is prepared by homogenization of powderous active substances (vii)-(xi) and optionally (xii) with one or more powderous auxiliary ingredients (excipients), often inert fillers such as microcrystalline cellulose, inulin, mannitol or similar; with or without anti-caking agent like magnesium stearate or colloidal silicon dioxide.
  • powderous active substances (vii)-(xi) and optionally (xii) with one or more powderous auxiliary ingredients (excipients), often inert fillers such as microcrystalline cellulose, inulin, mannitol or similar; with or without anti-caking agent like magnesium stearate or colloidal silicon dioxide.
  • Typical example of preparation of the composition from the present invention in the form of powder is described in Example 8.
  • effervescent powder dry excipients are employed which in contact with water generate gaseous carbon dioxide (CO2) .
  • CO2 gaseous carbon dioxide
  • mixtures of sodium hydrogencarbonate (NaHCCb) and citric and/or malic acid are used.
  • NaHCCb sodium hydrogencarbonate
  • citric and/or malic acid are used.
  • a binder and a disintegrant are added into the homogeneous mixture for the preparation of the powder.
  • a binder and a disintegrant are added into the homogeneous mixture for the preparation of the powder.
  • HPMC hydroxypropyl methylcellulose
  • PVP cross-linked polyvinylpyrrolidone
  • obtained homogeneous mixture is processed into tablets by direct compression.
  • the homogeneous powder can be directly filled into gelatine or vegetable capsules yielding the dosage form of capsules.
  • Typical example of preparation of the composition from the present invention in the form of capsules is described in Example 10.
  • Liquid dosage forms of the composition are prepared by dissolving or suspending the active substances (vii)-(xi) with or without the ingredient (xii) in purified water, plant oil or solution of sugar syrup. This gives the following dosage forms: solution, suspension or syrup.
  • obtained compositions are eventually further processed with preservatives, stabilizers, antioxidants, colours, and flavours, in order to obtain the desired stability and flavour of the product.
  • Typical example of preparation of the composition from the present invention in the form of syrup is disclosed in Example 11.
  • L-tyrosine (1; TYR) serves as a metabolic precursor for the biosynthesis of neurotransmitters from the group of catecholamines: dopamine (DA), norepinephrine (NE) and epinephrine (EN) or adrenaline. Supplementation of L-tyrosine (1) results in an increase of its concentration in plasma and its concentration in the brain. Resorption of L-tyrosine (1) into the brain is dependent on its concentration in plasma and the total concentration of large neutral amino acids (phenylalanine, tryptophan, methionine, valine, leucine, isoleucine) in plasma. The latter compete with L-tyrosine for crossing the blood-brain barrier (BBB) .
  • BBB blood-brain barrier
  • L-tyrosine (1) concentration in the brain stimulates natural biosynthesis of the said neurotransmitters. This results in regulation and increasing of all processes in the brain which are regulated by these neurotransmitters, which are: motivation, award, cognition control, emotional stability, short-term memory, motion, and arousal; see literature reference 18:
  • L-tyrosine (1) involves the treatment of depression, stress, hypertension, cognitive function, memory, Parkinson's disease, phenylketonuria, and narcolepsy. It is profoundly effective in stress conditions and cognitively demanding situations where it acts as an efficient stimulator of cognitive performances: strengthening memory, increasing attention and learning process; see literature reference 19:
  • L-DOPA formed by the action of enzyme L- DOPA decarboxylase (AADC ) , in the presence of pyridoxal phosphate ( B6PP) , yields dopamine (DA) . Further hydroxylation of the latter with molecular oxygen (O2) in the presence of ascorbic acid (AA; vitamin C) gives norepinephrine (NE ) with generation of dehydroascorbic acid (DHAA) .
  • methylation of amino group yields epinephrine (EN) or adrenaline in the presence of enzyme phenylethanolamine N- methyltransferase (PNMT ) and s-adenosyl methionine ( SAME ) as a terminal donor of the methyl group.
  • EN epinephrine
  • PNMT phenylethanolamine N- methyltransferase
  • SAME s-adenosyl methionine
  • L-tyrosine 1 ; TYR
  • vitamin B6 pyridoxine
  • AADC L-DOPA decarboxylase
  • L-tryptophan (2; TRP) is a metabolic precursor for the synthesis of neurotransmitter serotonin (SE) and neurohormone melatonin (ME); see literature reference 21:
  • L-Tryptophan (2) is converted by hydroxylation with molecular oxygen (O2) in the presence of tetrahydrobiopterin (THB) , under the action of enzyme tryptophan hydroxylase (TH) , into 5-hydroxytryptophan (5- HTP) . This is accompanied with the elimination of dihydrobiopterin (DHB) .
  • 5-HTP is further converted to serotonin (SE) by decarboxylation which is catalysed by enzyme 5-HTP decarboxylase (5-HTPD) in the presence of pyridoxal phosphate (B6PP) .
  • Melatonin (ME) is directly generated from serotonin (SE) by methylation with s-adenosyl methionine (SAME); see Figure 2. Thanks to the use of trimethylglycine (3; TMG) in the composition of the present invention, and vitamins of B-group, specifically vitamins B6, folic acid (B9) and vitamin B12, the biosynthesis of methylation agent SAME is especially stimulated, what additionally stimulates the biosynthesis of melatonin (ME) from serotonin (SE) .
  • TMG trimethylglycine
  • L-tryptophan (2; TRP) ; a key precursor of their biosynthesis, what is known in the prior art; but also the ingredients:
  • vitamin B6 pyridoxine
  • 5-HTPD L-5-HTP decarboxylase
  • trimetilglicine (3; TMG); as a terminal methyl group donor which, after supplementation, directly increases the concentration of s-adenosyl methionine (SAME) in plasma; see literature reference 20.
  • L-tryptophan (2; TRP) The whole metabolic pathway of the biosynthesis of serotonin (SE) and melatonin (ME) from L-tryptophan (2; TRP), and the synergistic activity of the key metabolic factors vitamin B6 (B6 ) , zinc (Zn 2+ ), and trimethylglycine (3; TMG) , what has not been recognized in the prior art, is shown in Figure 2.
  • L-tryptophan (2; TRP) is degraded by the enzyme tryptophan pyrrolase (TP) into kynurenin (KY) . The latter is further converted to 3-hydroxykynurenin (3HKY) .
  • the organism From 3HKY the organism further synthetizes nicotinic acid (NA) or niacin (vitamin B3) in several steps through 3-hydroxyanthranilic acid (3HA ⁇ ) .
  • NA nicotinic acid
  • vitamin B3 niacin
  • 3-hydroxyanthranilic acid (3HA ⁇ ) 3-hydroxyanthranilic acid
  • the composition from the present invention contains niacin in the form of nicotinamide (B3)
  • its parallel supplementation through the composition has the target to block (inhibit) this alternative metabolic pathway of L-tryptophan (2) degradation into niacin. This would result in a higher concentration of L-tryptophan (2) to be available for conversion into serotonin (SE) through the first metabolic pathway, and thus would stimulate its biosynthesis; see Figure 3.
  • nicotinamide (B3) acts as a competitive inhibitor of biosynthesis of nicotinic acid (NA; vitamin B3) from L-tryptophan (2) , that favours its expenditure to an alternative metabolic pathway - and this is its conversion into serotonin (SE) [and melatonin (ME) before sleep] .
  • SE serotonin
  • ME melatonin
  • composition from the present invention contains:
  • vitamins from B-complex specifically nicotinamide (B3 ) , vitamin B6, folic acid (B9 ) , and vitamin B12.
  • TMG (3) in a combination with vitamins B9 and B12, directly increases the available concentration of s-adenosyl methionine (SAME) as a key terminal methylation agent in the organism. This directly stimulates all methylation processes in the organism, including also: (i) direct decreasing homocysteine ( HC ) concentration which is otherwise harmful for the health of the brain and the nervous system;
  • SAME s-adenosyl methionine
  • Trimethylglycine ( 3 ; TMG ) directly converts harmful homocysteine (HC) into methionine (MET) under the influence of enzyme betaine- homocysteine s-methyltransferase ( BHMT ) in the presence of zinc (Zn 2+ ) as a cofactor. This occurs even without:
  • vitamin B12 cycle (i) vitamin B12 cycle; vitamin B12 ( B12 ) - methyl vitamin B12
  • THB tetrahydrobiopterin
  • HC homocysteine
  • SE serotonin
  • composition from the present invention stimulates the biosynthesis of dopamine ( DA) and serotonin ( SE ) , and indirectly, other neurotransmitters from the class of catecholamines: norepinephrine (NE ) and epinephrine ( EN) , as well as neurohormone melatonin (ME ) .
  • DA dopamine
  • SE serotonin
  • other neurotransmitters from the class of catecholamines norepinephrine
  • EN epinephrine
  • ME neurohormone melatonin
  • zinc (Zn 2+ ) also plays a key synergistic role which: (i) on the one side stimulates the biosynthesis of metabolically active form of vitamin B6, pyridoxal phosphate ( B6PP ) required for decarboxylation of L-DOPA or 5-hydroxytryptophan ( 5-HTP) into the corresponding decarboxylated derivatives, dopamine ( DA) and serotonin ( SE ) ; and,
  • the composition from the present invention exhibits several beneficial pharmacological effects: antidepressant; anxiolytic; antioxidant; improves sleep quality; neuroprotective ; decreases tiredness and fatigue; improves cognitive performances (memory, attention and learning process); improves mood and well being; antihyperhomocysteinemic activity, and thus acts as a hepatoprotective , cardioprotective, and as an anticancer agent; against osteopenia and osteopo
  • the solubility enhancers of L-tyrosine (1) from the present invention act by forming an equilibrium concentration of its sodium or potassium salts which are well-soluble in water, in the preparation phase of the instant cappuccino-like drink with hot water.
  • sodium bicarbonate (NaHCCt) and L-tyrosine (1) in hot water at approx. 70-90 °C react with formation of the corresponding sodium salt of L-tyrosine (la) .
  • the composition from the present invention also contains some acidic components (R-COOH) which, gradually, after dissolution, react both with NaHCCb and with the already formed sodium salt of L-tyrosine (la) , free L-tyrosine (1) is released again from such generated salt la, but it:
  • (i) is partially solubilized by forming hydrogen bonds with numerous compounds in the solution of the instant drink; e.g. with amino-groups (R-NH2) and carboxylic groups (R-COOH) of the protein ingredient from the composition of the present invention as a stabilized solubilized form of lb; or, (ii) is released again in the free form lc, but in the form of fine particles now, presumably of nano- and colloidal dimensions, which are absorbed well in the gastrointestinal tract.
  • R-NH2 amino-groups
  • R-COOH carboxylic groups
  • L-tyrosine (1) significantly improved resorption of L-tyrosine (1) is achieved, together with all beneficial pharmacological effects of the composition from the present invention.
  • Other solubility enhancers of L-tyrosine (1) also act in a similar way according to the present invention.
  • Example 1 the composition in the form of a powderous instant drink from Example 1 (coffee based) and Example 2 (chicory root based) was selected.
  • the sensory study was performed in a specialized company, Technology Management (TM) , Richigen (BE) , Switzerland (CH) , by a reputable expert in the field, Dr. Theo W. Kuypers, whose most important reference in the field is mentioned herein as literature reference 23:
  • Example 12 Detailed description of the analysis of the composition from the present invention, including the sensory study, is described in Example 12.
  • composition from the present invention is used as a functional food product, food supplement or as a pharmaceutical product for:
  • composition from the present invention is used in the prevention and treatment of disorders of the central nervous system selected from the group consisting of: major depressive disorder, mood disorder, manic-depressive disorder, anxiety, anxiety-depressive disorder, post-traumatic stress disorder, sleep disorders, attention deficit disorder, attention deficit hyperactivity disorder, memory function disorder, seasonal affective disorder, autism, schizophrenia, dementia, Parkinson's disease, Huntington's disease, and Alzheimer's disease .
  • the composition from the present invention is used for prevention and treatment of: major depressive disorder or depression like symptoms.
  • the recommended daily dosage of the composition is typically 2-3 x 10-20 g of the powderous composition for the preparation of an instant cappuccino like drink, where the said dosages are equivalent to the content of the active substances as follows:
  • vitamin B6 0.7-100 mg
  • folic acid (B9) or its pharmaceutical equivalent 100-1,500 pg; d. vitamin B12, 1.25-1,000 pg; and, optionally,
  • pantothenic acid (B5) 3-60 mg;
  • room temperature is related to the temperature interval of 20-25 °C. All percentage (%) shares of the ingredients are expressed as weight portions (w/w) .
  • the mixing speed is expressed as the number of revolutions of the mixing bin per minute (o/min) .
  • Example 1 Preparation of the composition from the present invention in the form of an instant powderous cappuccino-like drink
  • composition 1000 g of the powderous composition for instant preparation of a functional cappuccino-like drink
  • plant fat fully hydrogenated coconut fat; 24%;
  • emulsifier salt potassium phosphates (E340); to 100%;
  • Preparation The ingredients (1-5) were added to the ingredient (8), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (6), (7), (9-13), and homogenized for 15 minutes. Then, (14) was added, and the mixture was further homogenized for 5 minutes.
  • Composition of functional powderous cappuccino (15-20 grams per single dose for preparation of 150 mL drink with hot water or milk) : 375-500 mg L-tyrosine; 225-300 mg L-tryptophan; 375-500 mg trimethylglycine; 4,5-6 mg (approx. 50% NRV) zinc, and 37.5-50% NRV each of the vitamins from B group (B3, B6, B9, B12) .
  • the recommended dose is up to 2 x 15-20 g of instant cappuccino daily, what is equivalent to the intake of 750-1,000 mg L-tyrosine, 450-600 mg L-tryptophan, 750-1,000 mg trimethylglycine, and 9-12 mg (approx. 100% NRV) zinc, and 100% NRV per each of the B-vitamins : Bl, B2, B3, B5 , B6, B7 , B9, and B12.
  • roasted chicory Cichorium intybus L.
  • roasted seeds of various cereals such as rye ( Secale cereale M. Bieb.), barley (Hordeum vulgare L.), wheat ( Triticum vulgare L.), other coffee substitutes, or mixtures of these substances.
  • Example 2 Preparation of the composition from the present invention in the form of an instant powderous cappuccino-like caffeine-free drink
  • composition 1000 g powderous composition for instant preparation of a functional cappuccino-like drink
  • plant fat fully hydrogenated coconut fat; 24%;
  • emulsifier salt potassium phosphates (E340); to 100%;
  • Preparation The ingredients (1-5) were added to the ingredient (8), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (6), (7), (9-13), and homogenized for 15 minutes. Then, (14) was added, and the mixture was further homogenized for 5 minutes.
  • Composition of functional powderous cappuccino (15-20 grams per single dose for preparation of 150 mL drink with hot water or milk) : 375-500 mg L-tyrosine; 225-300 mg L-tryptophan; 375 mg trimethylglycine ; 9-12 mg (ca. 100% NRV) zinc, and approx. 50% NRV for each of the vitamins from B group.
  • the recommended dose is up to 2 x 15-20 g of instant cappuccino daily, what is equivalent to the intake of 750-1,000 mg L-tyrosine, 450-600 mg L-tryptophan, 750-1,000 mg trimethylglycine, and 18-24 mg (ca. 200% NRV) zinc, and 100% NRV per each of the B-vitamins : Bl, B2, B3, B5, B6, B7 , B9, and B12.
  • Example 3 Preparation of the composition from the present invention in the form of an instant powderous cappuccino-like drink -so
  • composition 1000 g powderous composition for instant preparation of a functional cappuccino-like drink
  • il 50.00 g L-tyrosine (l); 1
  • B-vitamins complex B1 , B2 , B3 , B5 , B6, B7 , B9, B12 ) 4 of strength lOxNRV 5 / g; on maltodextrin as carrier; content per gram: 11.1 mg thiamine (Bl) as thiamine hydrochloride; 14 mg riboflavin (B2) as riboflavin 5 ' -phosphate sodium salt; 160 mg niacin (B3) as nicotinamide; 60 mg pantothenic acid (B5) in the form of calcium D-pantothenate ; 14 mg pyridoxine (B6) as pyridoxine hydrochloride; 0.5 mg biotin (B7); 2 mg folic acid
  • plant fat fully hydrogenated coconut fat; 24%;
  • emulsifier salt potassium phosphates (E340); to 100%;
  • Preparation The ingredients (1-5) were added to the ingredient (7), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (6), (8-14), and homogenized for 15 minutes. Then, (15) was added, and the mixture was further homogenized for 5 minutes.
  • Composition of functional powderous cappuccino (15-20 grams per single dose for preparation of 150 mL drink with hot water or milk) : 750- 1.000 mg L-tyrosine; 450-600 mg L-tryptophan; 750-1,000 mg trimethylglycine ; 9-12 mg (ca. 100% NRV) zinc, and approx. 100% NRV for each of the vitamins from B group.
  • the recommended dose is up to 2 x 15-20 g of instant cappuccino daily, what is equivalent to the intake of 1,500-2,000 mg L-tyrosine, 900- 1,200 mg L-tryptophan, 1,500-2,000 mg trimethylglycine, and 18-24 mg (approx. 200% NRV) zinc, and 200% NRV per each of the B-vitamins : Bl, B2, B3, B5 , B6, B7, B9, and B12.
  • Example 4 Preparation of the composition from the present invention in the form of a liquid functional non-alcoholic drink
  • composition 1000 g functional non-alcoholic drink
  • composition of functional drink 0.415% L-tyrosine; 0.415% L- tryptophan; 0.5% trimethylglycine; 0.11% zinc; lOx NRV/L vitamins B3, B6, B9, B12.
  • the recommended dose is 100-300 ml of drink daily, what is equivalent to the intake of 415-1,245 mg L-tyrosine, 415-1,245 mg L-tryptophan, 415-1,245 mg trimethylglycine, 10-30 mg (100-300 NRV) zinc, and 100- 300% NRV of vitamins B3, B6, B9 and B12.
  • Example 5 Preparation of the composition from the present invention in the form of muesli based on rolled oat and dehydrated fruits
  • Composition 1000 g oat-fruit muesli: (1) 5.00 g L-tyrosine (l); 1
  • Preparation The ingredients (1-8) were added to the mixture of (12) and (13), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (9-11) and (15), and homogenized by stirring for 15 minutes. Then, the previously molten (at 40-45 °C) ingredient (14) was added, and the mixture was stirred in a planetary mixer at temperatures from 35 °C to room temperature for 15 minutes.
  • composition of functional muesli 0.5% L-tyrosine; 0.5% L-tryptophan; 0.5% trimethylglycine; 0.01% zinc; !OxNRV/kg vitamins B3, B6, B9, B12.
  • the recommended dose is 50-150 g of muesli daily, what is equivalent to the intake of 250-750 mg L-tyrosine, 250-750 mg L-tryptophan, 250- 750 mg trimethylglycine, 5-15 mg zinc, and 50-150% NRV of vitamins B3, B6, B9, and B12.
  • Example 6 Preparation of the composition from the present invention in the form of a functional energy bar
  • Composition 1000 g of the mass for extrusion of functional energy bars :
  • Composition of functional energy bars according to the present invention (per approx. 40 g) : 500 mg L-tyrosine; 500 mg L-tryptophan; 500 mg trimethylglycine ; 10 mg (100% NRV) zinc; 16 mg (100% NRV) niacin (B3); 1.4 mg (100% NRV) vitamin B6; 200 pg (100% NRV) folic acid (B9 ) ; 2.5 pg (100% NRV) vitamin B12.
  • the recommended dose is 1-2 bars daily, what is equivalent to the intake of 500-1,000 mg L-tyrosine, 500-1,000 mg L-tryptophan, 500- 1,000 mg trimethylglycine, 10-20 mg (100-200% NRV) zinc, and 100-200% NRV of vitamins B3, B6, B9, and B12.
  • Example 7 Preparation of the composition from the present invention in the form of functional ice cream
  • Composition 1000 g ice cream
  • Composition 1000 g ice cream
  • Preparation of the aqueous phase To purified water (18), the ingredients (12-17) were added, and the mixture was homogenized at 60-65 °C for 10 minutes. Then, the premix of active substances (1-9) was added.
  • Preparation of the fatty phase Lecithin (11) was separately disperged in palm oil (10) at 60-65 °C for 15 minutes. Then the aqueous and fatty phases were mixed by intensive stirring and homogenization at a high shear conditions, 2-3,000 rpm or more, for 10-20 minutes. The mixture was subjected to pasteurization at TO TS °C for 10 minutes. The mixture was then cooled by stirring at 2-4 °C for 1 h.
  • Composition of functional ice cream according to the present invention (50 g dose) : 500 mg L-tyrosine; 500 mg L-tryptophan; 500 mg trimethylglycine ; 10 mg (100% NRV) zinc; 16 mg (100% NRV) niacin (B3); 1.4 mg (100% NRV) vitamin B6; 200 pg (100% NRV) folic acid (B9 ) ; 2.5 pg (100% NRV) vitamin B12.
  • the recommended dose is 1-2 (50-100 g) ice creams daily, what is equivalent to the intake of 500-1,000 mg L-tyrosine, 500-1,000 mg L- tryptophan, 500-1,000 mg trimethylglycine, 10-20 mg (100-200% NRV) zinc, and 100-200% NRV of vitamins B3, B6, B9, and B12.
  • composition 100 g of powder:
  • Composition 25% L-tyrosine; 25% L-tryptophan; 10% trimethylglycine; 0.5% (lOxNRV) zinc; 50xNRV vitamins B3, B6, B9, and B12.
  • the powder can be used as such, or divided in the form of sachets containing 2.00 g each, of which 1-3 represent the recommended daily dosage containing: 500-1,500 mg L-tyrosine; 500-1,500 mg L-tryptophan; 200-600 mg trimethylglycine; 10-30 mg (100-300% NRV) zinc; and 100- 300% NRV vitamins B3, B6, B9, and B12.
  • Example 9 Preparation of the composition from the present invention in the form of effervescent powder
  • composition 100 g of effervescent powder:
  • Composition 5% L-tyrosine; 10% L-tryptophan; 10% trimethylglycine; 0.1% (lOxNRV) zinc; lOxNRV vitamins B3, B6, B9, and B12.
  • the powder can be used as such or divided in the form of sachets containing 10 g each, of which 1-3 represent the recommended daily dosage: 500-1,500 mg L-tyrosine; 1,000-3,000 mg L-tryptophan; 1,000- 3,000 mg trimethylglycine; 10-30 mg (100-300% NRV) zinc; and 100-300% NRV vitamins B3, B6, B9, and B12.
  • Composition 100 g of mixture for capsules filling:
  • composition of each capsule 100 mg L-tyrosine; 100 mg L-tryptophan; 100 mg trimethylglycine; 5 mg zinc; and 50% NRV vitamins B3, B6, B9, and B12.
  • the recommended daily dose is 3-9 capsules, what is equivalent to the intake of 300-900 mg L-tyrosine, 300-900 mg L-tryptophan, 300-900 mg trimethylglycine, 15-45 mg (150-450% NRV) zinc, and 150-450% NRV of vitamins B3, B6, B9, and B12.
  • Composition 100 g of syrup: (1) 5.00 g L-tyrosine; 1
  • Preparation The ingredients (11-13) and (14) were dissolved in the ingredient (16) by stirring at room temperature for 15 minutes. Such an obtained solution was heated to 40-45 °C, and then the ingredients (1-10), (15) and (17) were added, and the mixture was stirred for 15 minutes. Such an obtained product was additionally homogenized by stirring at room temperature from 40 °C to room temperature for 15-30 minutes. Such an obtained product was in the form of a viscous syrup- suspension of yellow colour, and agreeable flavour resembling lemon. Composition of syrup: 5% L-tyrosine; 5% L-tryptophan; 5% trimethylglycine ; 0.1% zinc.
  • the recommended daily dose is 1-3 x 10 ml of syrup, what is equivalent to the intake of 500-1,500 mg L-tyrosine, 500-1,500 mg L-tryptophan, 500-1,500 mg trimethylglycine, 10-30 mg (100-300% NRV) zinc, and 100- 300% NRV vitamins B3, B6, B9, and B12.
  • Example 12 Sensory study of the composition from the present invention from Examples 1 and 2 in the form of a powderous instant drink
  • composition in the form of a powderous instant drink was selected, with the corresponding preparations described in:
  • Example 1 composition based on coffee; sachets containing 16 g each for the preparation of drink with 150 g milk; and,
  • Example 2 composition based on chicory root; sachets containing 15 g each for the preparation of drink with 150 g milk.
  • Test drinks were prepared with skimmed milk warmed to 80 °C, briefly stirred and evaluated according to the methodology common for this category of cappuccino-like products; see Table 2.
  • compositions from the present invention For both compositions from the present invention, a clean taste without any off-taste was observed. Other taste characteristics are: very sweet, milky, with a good level of mouthfullness . The tendency of foam generation and its stability are good. Full wettability of the powders and dissolution were observed only after stirring.
  • composition from the present invention based on a specific combination of :
  • L-tyrosine (1; TYR) and L-tryptophan (2; TRP) as metabolic precursors of neurotransmitters dopamine (DA) , norepinephrine (NE) and epinephrine (EN) as well as serotonin (SE) and neurohormone melatonin (ME) ;
  • the ingredient (xii) for example sodium bicarbonate (NaHCCb) ;
  • the matrix of the composition from the present invention e.g. a powderous base for an instant cappuccino-like drink, enables full sensory masking of bad tastes of active substances, the ingredients (vii)-(xi) of the composition.
  • composition from the present invention in the form of an instant cappuccino-like drink solves in a novel and inventive way the technical problem of:
  • composition from the present invention is used for manufacturing functional food products, food supplements, or pharmaceutical products, intended for the prevention and treatment of central nervous system disorders, for the improvement of cognitive performances, mood improvement, anti-stress activity, and other useful beneficial nutritional and pharmacological effects. In this way, industrial applicability of the present invention is obvious.

Abstract

The present invention relates to the composition for: prevention and treatment of disorders of the central nervous system; improvement of cognitive performances: memory, attention, and learning process. The powderous composition from the present invention consists of: A. a powderous instant formulation of the base for the preparation of a cappuccino-like drink by addition of hot water or milk; and, B. a formulation of active substances: amino acids L-tyrosine and L-tryptophan, trimethylglycine and zinc salts of pharmaceutically acceptable acids, and vitamins of B-group: niacin (B3), pyridoxine (B6), folic acid (B9), and vitamin B12, any optionally, other B vitamins: thiamine (B1), riboflavin (B2), pantothenic acid (B5), and biotin (B7); with improved solubility of L-tyrosine in the hot instant drink, which improves its bioavailability. The compositionis used as a pharmaceutical product, a food supplement, or as a functional food product.

Description

COMPOSITION OF POWDEROUS INSTANT DRINK, ITS PREPARATION AND USE
DESCRIPTION
Technical Field
The present invention relates to a composition which is used as a functional food product, food supplement, or pharmaceutical product.
Technical Problem and Summary of the Invention
The present invention solves the technical problems of:
(1) obtaining an improved product for:
(a) prevention and treatment of depression and anxiety; and
(b) improvement of cognitive performances: memory, attention, and learning process;
using natural active substances;
(2) very low water solubility of L-tyrosine (1; TYR) and, consequently, its poor bioavailability; and
(3) masking off-odours and off-flavours of certain natural active substances such as, e.g.
(a) bitter taste of amino acids L-tyrosine (1) and L-tryptophan
(2; TRP) ;
(b) astringent or metallic taste of zinc salts; and,
(c) off-odours and tastes of some B-vitamins.
Besides solving the technical problem no. (1), the present invention solves subsidiary technical problems of obtaining an improved product for :
(i) mood improvement including seasonal affective disorder (SAD); improvement of well-being;
(ii) anti-stress activity;
(iii) improvement of sleep quality;
(iv) reduction of tiredness and fatigue, and increase of energy and physical performances: strength and endurance; (v) prevention and treatment of liver diseases due to its hepatoprotective and detoxifying effect;
(vi) prevention and treatment of hyperhomocysteinemia, and thus for prevention and treatment of cardiovascular diseases and diabetes; and,
(vii) prevention and treatment of osteopenia and osteoporosis.
The said technical problem is solved by the use of specific composition of active substances based on a synergistic effect of:
(i) L-tyrosine (1; TYR);
(ii) L-tryptophan (2; TRP) ;
(iii) trimethylglycine (3; TMG) ;
(iv) pharmaceutically acceptable zinc (Zn) salt; and,
(v) vitamins from B-group selected from the group consisting of: niacin (B3) , pyridoxine (B6) , folic acid (B9) and vitamin B12
(B12) ;
together with the use of solubility enhancer of L-tyrosine (1) which facilitates its bioavailability.
The composition is used in the form of a powderous composition for the preparation of an instant cappuccino-like drink, which completely masks all off-tastes and off-odours of the said active substances while preserving their overall pharmacological profile.
State of the Art
The diseases and disorders of the central nervous system represent a significant part of hardships of the modern man. Among them, relatively the most important is major depressive disorder (MDD) and generally there are various symptoms of depression which occur in almost 15% of the general population.
L-Tyrosine (1; TYR) is a conditionally essential natural amino acid, which serves not only as a building block of body proteins, but also as a precursor for biosynthesis of neurotransmitters from the class of catecholamines: dopamine (DA), norepinephrine (NE) or noradrenaline, and epinephrine (EN) or adrenaline, and their simple amines: tyramine and phenylethylamine . Biosynthesis of these compounds starts from L-phenylalanine which is converted by hydroxylation to L- tyrosine (1) .
Figure imgf000004_0001
1
L-Tryptophan (2; TRP) is an essential amino acid which serves for synthesis of body proteins, and also as a precursor for biosynthesis of neurotransmitter serotonin (SE) and neurohormone melatonin (ME) .
Figure imgf000004_0002
2
In the prior art it is known that L-tyrosine (1) and L-tryptophan (2) exhibit mild antidepressant activity; see literature references 1-3:
1) A. J. Gelenberg, C. J. Gibson: Tyrosine for the treatment of depression, Nutr. Health 3 (1984) 163-173.
2) A. A. Badawy: Tryptophan: the key to boosting brain serotonin synthesis in depressive illness, J. Psychopharmacol . 27 (2013)
878-893.
3) S. Meyers: Use of neurotransmitter precursors for treatment of depression, Altern. Med. Rev. 5 (2000) 64-71.
Trimethylglycine (3; TMG) , also known under trivial name betaine, because it is, besides in its synthetic form, commonly manufactured by isolation from sugar beet (Beta vulgaris L.) . Recently, DiPierro and Settembre described that trimethylglycine ( 3 ) in combination with s-adenosyl-L- metionine ( SAME) acts as an effective fixed combination in the treatment of mild depression; see literature references 4 and 5:
Figure imgf000005_0001
3
4) F. DiPierro, R. Settembre: Preliminary results of a randomized controlled trial carried out with a fixed combination of s- adenosyl-L-methionine and betaine versus amitriptyline in patients with mild depression, Int . J. Gen. Med. 8 (2015) 73-78;
5) F. DiPierro, R. Orsi, R. Settembre: Role of betaine in improving the antidepressant effect of s-adenosyl-methionine in patients with mild-to-moderate depression, J. Multidisc . Healthcare 8 (2015) 39-45.
Besides in combination with SAME , trimethylglycine ( 3 ) itself exhibits mild antidepressant activity; see literature reference 6:
6) J. C. Lin, M. Y. Lee, M. H. Chan, Y. C. Chen, H. H. Chen: Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice, Psychopharmacol . (Berl.) 233 (2016) 3223-
3235.
For microelement zinc (Zn) it is also known in the prior art that it shows pharmacological activity similar to an antidepressant, presumably because it acts as a cofactor in the biosynthesis of the above-mentioned neurotransmitters. In depressive patients lower plasma concentration was observed along with certain improvement of the medical condition after zinc supplementation; see literature reference 7 :
7) G. Nowak, B. Szewczyk, A. Pile: Zinc and depression. An update,
Pharmacol Rep. 57 (2005) 713-718. Related to the possibility of therapeutic use of a neurotransmitter precursors combination, Wurtman described a method of depression alleviation by the use of L-tyrosine (1) or a combination of L-tyrosine ( 1 ) and L-tryptophan ( 2 ) ; see literature reference 8:
8) US 4,377,595 (1980); R. J. Wurtman: Process for reducing depression; Massachusetts Institute of Technology (SAD) .
Pardee and Birk disclosed a new therapy for biosynthesis stimulation of serotonin, glycine, and gamma-aminobutyric acid (GABA) , and for the treatment of acute anxiety, hyperactivity, panic attack, confusions, sleep disorder, mood disorder, depression, obsessive compulsive disorder (OCD) , and some other diseases of the central nervous system (CNS) with the use of a specific composition of: acetyl- L-carnitine, a-lipoic acid, biotin, vitamin Bl, L-glutamine, vitamin B6, taurine, folic acid (B9 ) , vitamin B12, trimethylglycine ( 3 ) and L-tryptophan ( 2 ) ; see literature reference 9:
9) WO 2009051609A1 (2009); J. D. Pardee, A. V. Birk: Metabolic enhancement therapy.
Besides the mentioned active ingredients, such composition can optionally contain other substances as follows: lithium orotate, vitamins C, E, D, B2 , B3, B5, and nystatin, calcium, and magnesium.
Despite the fact that the said composition contains L-tryptophan ( 2 ) and trimethylglycine ( 3 ) , it is clear to a person skilled in the art that this is a very specific composition with many different ingredients. Therefore, it is impossible to presume possible, either positive or negative, synergistic pharmacological effects. This composition is considered as irrelevant for the present invention.
De Souza Pereira described the food supplement composition for the treatment of gastritis, stomach ulcer, and gastroesophageal reflux disease (GERD) , containing: vitamin B6, L-tryptophan ( 2 ) , trimethylglycine (3; betaine), folic acid (B9) , vitamin B12, melatonin and methionine; see literature reference 10:
10) WO 2007112524A1 (2007); R. de Souza Pereira: Dietary supplement for healing or regressing symptoms of gastroesophageal reflux disease, gastritis and ulcers.
Despite the fact that this composition contains L-tryptophan (2) and trimethylglycine (3), it:
(a) does not contain other specific substances of the composition from the present invention;
(b) is not intended for depression treatment nor treatment of other diseases of the central nervous system; and,
(c) in no way suggests synergy in pharmacological activity as is the case in the composition from the present invention.
Bredesen and Tzannis described a complex composition for the treatment of various diseases of the central nervous system and improvement of nervous function, which consists of:
(i) the complex of vitamins B, C, D, E, coenzyme Q10, vitamin K and folic acid (B9) ;
(ii) selenium, lithium, magnesium and molybdenum;
(iii) omega-3 higher fatty acids; and,
(iv) amino acid selected from the group consisting of; trimethylglycine (3; betaine) , N-acetyl-L-cysteine (NAC) , s- adenosyl-L-methionine (SAME) , L-tryptophan (2) and glutathione (GSH) ; see literature reference 11:
11) WO 2014025905A1 (2014); D. E. Bredesen, S. Tzannis: Multi- component composition for improving neurological function, Buck Institute for Research on Aging (US) .
Regardless of the content of L-tryptophan (2) and trimethylglycine (3) , the said composition does not recognize the importance of parallel use of L-tyrosine (1) and zinc (Zn) . Also, it does not disclose any details about other key substances and about the way of acting as does the composition from the present invention.
Yie and co-workers described the pharmaceutical composition for memory stimulation which is consisting of:
(i) a drug which stimulates brain memory function: 5-HTP, phosphatidyl choline, dimethylamino ethanol, phosphatidyl serine, s-adenosyl-L-methionine ( SAME ) , DL-phenylalanine , inositol, fisetin, L-tryptophan (2), L-tyrosine (1), lithium, or their combinations;
(ii) a drug which delivers food and oxygen to the brain: acetyl -L- carnitine, vinpocetine, Ginkgo biloba extract, puerarin, biotin (B7), vitamins Bl, B2, B3, B5, B6, B9, chromium, glutamic acid, glycine, alanine, or their combinations;
(iii) a drug which maintains a normal level of oxidative stress in the brain: lipoic acid, trimethylglycine (3; betaine), vitamin C, glutathione, huperzine A, lycopene, vitamin E, selenium, zinc (Zn); or their combinations.
The composition is useful for enhancement of learning ability, treatment of cognitive disorders and prevention and treatment of Alzheimer's disease; see literature reference 12:
12) WO 2008080333A1 (2006); H. Yie, M. M. Sun, Z. Zhu: Compound preparation for enhancing memory; applicant: Pficker
Pharmaceuticals Ltd (US) .
Although the said composition contains almost all active substances like the composition from the present invention, it does not recognize :
(a) the key importance of vitamin B12 in the metabolism of methylation cycle in which trimethylglycine (3) enters; and,
(b) its synergy with zinc (Zn) in transformation of amino acids L- tyrosine (1) and L-tryptophan (2) into the corresponding neurotransmitters from the classes of catecholamines and serotonin . According to our best knowledge, the closest document of the prior art was published by Kiliaan and Hageman, who disclosed a pharmaceutical, dietetic, and nutritional composition for prevention and treatment of depression connected with vascular disorder; see literature reference 13:
13) EP 1275399B1 (2001); A. J. Kiliaan, R. J. J. Hageman: Method and preparation for preventing and/or treating vascular disorders and secondary disorders associated therewith; applicant: N. V. Nutricia (NL) .
The composition is based on the combination of:
(i) long chain polyunsaturated fatty acids, including DHA and EPA;
(ii) phosphatidyl esters: phosphatidyl serine, phosphatidyl inositol, phosphatidyl choline, phosphatidyl diethanolamine; and,
(iii) one or more compounds which are factors in metabolism of methionine: folic acid, vitamin B12, vitamin B6, magnesium and zinc .
Besides the ingredients (i)-(iii), the said composition may contain other substances such as: hypericin, extract of the plant Withania somnifera, citrates, L-tryptophan ( 2 ) or proteins containing L- tryptophan, s-adenosyl-L-methionine ( SAME ) , choline, trimethylglycine ( 3 ; betaine), copper, carnitine, vitamin Bl, vitamin B5, coenzyme Q10, vitamin C, vitamin E, lipoic acid, selenium salts, carotenoids, extract of gingko (Gingko biloba L.) and vitamin D3.
Besides depression, the composition is claimed to be effective in prevention and treatment of bipolar and unipolar depression, depression connected with menstruation and menopause, schizophrenia, attention deficit hyperactivity disorder (ADHD) , anxiety, insomnia, seasonal affective disorder (SAD), dementia, and Parkinson's disease.
Although the said document, among several active substances whose rationale for use is not specially argumented, explicitly mentions the use of L-tryptophan ( 2 ) , trimethylglycine ( 3 ; betaine) , zinc, folic acid (vitamin B9) , vitamin B12 and vitamin B6, as well as a large number of other active substances, in prevention and treatment of depression and many disorders of the central nervous system, it does not:
(a) contain or recognize the key role of L-tyrosine (1) as a precursor of catecholamines biosynthesis;
(b) recognize the key role of nicotinamide (vitamin B3) for the metabolism of neurotransmitters; and,
(c) recognize the synergistic connection between the pharmacological activity of a fixed combination of:
(1) L-tyrosine (1) and L-tryptophan (1); and,
(2) trimethylglycine ( 3 ) and zinc; as is the case in the present invention .
A separate technical problem with the compositions based on L-tyrosine is its very low water solubility. This results in its relatively poor bioavailability. For instance, the solubility of L-tyrosine (1) at 25 °C is only 45 mg in 100 g water; see literature reference 14:
14) S. Budvari (Ed.) : The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals; Twelfth Edition; Rahway, NJ; Merch & Co., Inc. (1996) p. 1677.
The said technical problem of poor water solubility of L-tyrosine (1) has been solved in different manners, e.g. by:
(i) the composition based on the combination of food acids (citric and/or tartaric acid) and sodium bicarbonate (NaHCOs) ; see literature reference 15;
(ii) the use of lithium bromide (LiBr) as a solubility enhancer of
L-tyrosine (1) ; see literature reference 16; or,
(iii) the form of hydrogel, using sodium hydroxide (NaOH) as the agent for dissolution of L-tyrosine with subsequent release of fine particles of L-tyrosine upon the action of acid and their stabilization within the hydrogel of gelatin. Such hydrogel provides improved solubility and bioavailability of L- tyrosine. However, such hydrogel is not suitable for liquid products or powderous instant compositions; see literature reference 17 :
15) US 6294579B1 (1999); J. W. Carnazzo: Method for improving delivery of tyrosine supplementation; applicant: J. W. Carnazzo (US) .
16) CN 106083625D (2016); Z. Wang, H. Zhang, Z. Li: Chemical modification method of tyrosine; applicant: University Anhui Polytechnic (CN) ;
17) CN 107033369A (2017); Y. Yao, F. Liu, M. Zhang, L. Zhang:
Preparation method for tyrosine-based hybridization hydrogel with enteric solubility; applicant: Central South Univ. of Forestry and Technology (CN) .
The defined technical problems of:
(1) obtaining improved product for:
(a) prevention and treatment of depression and anxiety; and
(b) improvement of cognitive performances: memory, attention, and learning process;
using natural active substances;
(2) very low water solubility of L-tyrosine (1; TYR) and, consequently, its poor bioavailability; and
(3) masking off-odours and off-flavours of certain natural active substances such as, e.g.
(a) bitter taste of amino acids L-tyrosine (1) and L-tryptophan
(2; TRP) ;
(b) astingent or metallic taste of zinc salts; and,
(c) off-odours and tastes of some B-vitamins;
are solved by the present invention in a new and inventive manner as described in the section Detailed Description of the Invention.
Brief Description of Figures
Figure 1 shows :
(a) a known metabolic pathway of catecholamine biosynthesis: dopamine (DA) , norepinephrine (NE) and epinephrine (EN) or adrenaline from L-tyrosine (1; TYR) ; and, (b) unknown key synergistic effect of the ingredients from the present invention (additionally marked with circular) : trimethylglycine (3; TMG) , zinc (Zn2+), and vitamin B6 (B6) on the stimulation of their biosynthesis.
Detailed description of the synergistic action of the fixed combination of L-tyrosine (1; TYR) , trimethylglycine (3; TMG) , zinc (Zn2+) , and vitamin B6 (B6) on the stimulation of catecholamine biosynthesis: DA, NE and EN is described in the section Detailed Description of the Invention.
Figure 2 shows :
(a) a known metabolic pathway of serotonin (SE) and melatonin (ME) biosynthesis from L-tryptophan (1; TRP) ; and,
(b) an unknown key synergistic effect of the ingredients from the present invention (additionally marked with circular) : trimethylglycine (3; TMG) , zinc (Zn2+), and vitamin B6 (B6) on the stimulation of their biosynthesis.
Detailed description of the synergistic action of the fixed combination of L-tryptophan (2; TRP) , trimethylglycine (3; TMG) , zinc (Zn2+), and vitamin B6 (B6) on the stimulation of biosynthesis of serotonin (SE) and melatonin (ME) is described in the section Detailed Description of the Invention.
Figure 3 shows :
(a) a known metabolic pathway of degradation of L-tryptophan (2; TRP) to nicotinic acid (NA; vitamin B3) through kynurenine (KY) ; and,
(b) an assumed key effect of nicotinamide (vitamin B3; B3) on the inhibition of its course and thus the stimulation of an alternative metabolic pathway to serotonin (SE) .
Detailed description of the influence of nicotinamide (B3) on the inhibition of degradation of TRP to nicotinic acid (NA) is described in the section Detailed Description of the Invention.
Figure 4 shows a known metabolic pathway of s-adenosyl metionine (SAME) biosynthesis as a natural terminal methylation agent and the role of the key ingredients from the present invention: trimethylglycine (3; TMG) , vitamin B12 (B12) , folic acid (vitamin B9; B9) and zinc (through enzyme BHMT) in the biosynthesis of SAME as well as in a decreasing concentration of harmful homocysteine (HC) . Detailed description of these processes is described in the section Detailed Description of the Invention.
Figure 5 shows a mechanism of action of solubility enhancer of L- tyrosine (1; TYR) in the composition from the present invention when used as a powderous instant cappuccino-like drink. For illustration, the action of sodium hydrogencarbonate (NaHCCt) as solubility enhancer of TYR is shown. Detailed description of the action of solubility enhancer of TYR according to the present invention is described in the section Detailed Description of the Invention.
Detailed Description of the Invention
The present invention is related to an improved product which belongs to the group of functional food products, food supplements, or pharmaceutical products for prevention and treatment of central nervous system disorders. The product involves a powderous composition which is added to water or milk for the preparation of a liquid functional drink with taste and appearance similar to cappuccino, which consists of:
A. formulation of the base formed from the ingredients (i)-(vi) selected to be:
(i) roasted and milled coffee seeds ( Coffea species), powderous;
powderous or granulated instant roasted coffee; roasted and milled coffee substitute; wherein coffee substitute is selected from the group consisting of: chicory ( Cichorium intybus L) root; barley (Hordeum vulgare L) seeds; barley malt; rye ( Secale cereale L) seeds; rye malt; wheat ( Triticum vulgare L) seeds; wheat malt; chickpea ( Cicer arietinum L) seeds; dandelion ( Taraxacum officinalis L) root; fig ( Ficus carica L) fruit; carob ( Ceratonia siliqua L) fruit; or mixtures of these ingredients; (ii) fat; selected from the group consisting of: coconut fat, palm oil, hydrogenated palm oil, palm kernel oil, hydrogenated palm kernel oil, rapeseed oil, sunflower oil, soybean oil, cottonseed oil, milk fat, or mixtures of these ingredients;
(iii) food emulsifier for fat;
(iv) protein ingredient; selected from the group consisting of:
full fat or skimmed milk powder, milk proteins, whey proteins, plant proteins, or mixtures of these substances;
(v) carbohydrate ingredient; selected from the group consisting of: sugar, honey, glucose syrup, glucose-fructose syrup, fructose syrup, glucose, fructose, maltose, lactose, maltodextrin, dextrin, starch, inulin, oligofructose , full fat or skimmed milk powder, or mixtures of these substances; and,
(vi) food additives; required for the formation of desired technological properties of the present composition, which are selected from the group consisting of: salt (NaCl), spices, flavours, emulsifier salts, food colours, preservatives, food acids, anti-caking agents, thickeners, sweeteners, taste enhancers, or mixtures of these substances; and
B. formulation of active substances consisting of the ingredients
(vii)-(xi), wherein the ingredients (vii)-(xi) are selected to be :
(vii) L-tyrosine (1) or its salts with pharmaceutically acceptable acids ;
Figure imgf000014_0001
(viii) L-tryptophan ( 2 ) or its salts with pharmaceutically acceptable acids ;
Figure imgf000014_0002
(ix) trimethylglycine ( 3 ) , its salts with pharmaceutically acceptable acids, or plant extracts with >25% w/w trimethylglycine ;
Figure imgf000015_0001
(x) zinc in its pharmaceutically acceptable chemical form;
(xi) vitamins of B-complex selected from the group consisting of:
niacin (B3), pyridoxine (B6) , folic acid (B9) or its pharmaceutical equivalents, and vitamin B12; and, optionally, other vitamins of B-complex: thiamine (Bl), riboflavin (B2), pantothenic acid (B5), and biotin (B7);
where the solubility enhancer of L-tyrosine (1) is used as follows:
(xii) one or more food additives selected from the group consisting of: sodium carbonate (Na2CC>3) , sodium bicarbonate (NaHCCt) , sodium sesquicarbonate (Na2C03*NaHC03*2H20) , potassium carbonate (K2CO3) , potassium bicarbonate (KHCO3) , or mixtures of these substances.
Fat, the ingredient (ii) in the composition of the present invention, is selected from the group consisting of: cold-pressed, hot-pressed, refined, partially hydrogenated or fully hydrogenated oils or fats from coconut ( Cocos nucifera L.), palm [Elaeis guineensis Jacq., Elaeis oleifera (Kunth) Cortes, Attalea maripa (Aubl . ) Mart.] or palm kernel, rape and canola (Brassica napus L., Brassica rapa ssp. oleifera L., Brassica juncea L.), sunflower ( Helianthus annuus L.), soybean ( Glycine max. (L.) Merr. ) , cotton ( Gossypium hirsutum L., Gossypium herbaceum L.), sesame (Sesamum indicum L.), safflower (Carthamus tinctorium L.), olive ( Olea europea L.), maize ( Zea mays L.), pumpkin (Cucurbita pepo L.), peanut (Arachis hypogaea L.), other edible fats, milk fat from edible milk from various animals, or mixtures of these ingredients.
Preferably, fat is selected from the group consisting of: coconut fat, palm oil, hydrogenated palm oil, palm kernel oil, hydrogenated palm kernel oil, rapeseed oil, sunflower oil, soybean oil, cottonseed oil, milk fat, or mixtures of these substances. Food emulsifier for plant oils and fats in the formulation of the base, the ingredient (iii), is selected from the group consisting of: polyoxyethylene (40) stearate (E431); polysorbates (E432-435) like polysorbate 80 (E433); mono- and diglycerides of fatty acids (E471); acetate esters of mono- and diglycerides of higher fatty acids (E472a) ; lactate esters of mono- and diglycerides of higher fatty acids (E472b) ; citrate esters of mono- and diglycerides of higher fatty acids (E472c) ; tartrate esters of mono- and diglycerides of higher fatty acids (E472d) ; mono- and diacetyl tartrate esters of mono- and diglycerides of higher fatty acids (E472e) ; mixed acetate and tartrate esters of mono- and diglycerides of higher fatty acids (E472f ) ; sucrose esters of higher fatty acids (E473) ; sucroglycerides (E474); polyglycerol esters of higher fatty acids (E475); polyglycerol polyricinoleate (E476); thermally oxidized soybean oil treated with mono- and diglycerides of higher fatty acids (E479b) ; sodium stearoyl- 2-lactate (E481); calcium stearoyl-2-lactate (E482); sorbitan esters of higher fatty acids (E491-495) ; or mixtures of the said emulsifiers.
Protein ingredient, the ingredient (iv) in the formulation of the base, is selected from the group consisting of: full fat or skimmed milk powder, milk proteins, whey proteins, plant proteins, or mixtures of these substances.
Carbohydrate ingredient, the ingredient (v) in the formulation of the base, is selected from the group consisting of: sugar, honey, glucose syrup, glucose-fructose syrup, fructose syrup, glucose, fructose, maltose, lactose, maltodextrin, dextrin, starch, inulin, oligofructose, full fat or skimmed milk powder, or mixtures of these substances .
In another embodiment of this invention, instead of:
ingredient (ii), fat;
ingredient (iv) , protein ingredient; and,
ingredient (v) , carbohydrate ingredient; full fat or skimmed milk powder can be employed, which usually contains approx. 45-55% lactose, approx. 0.5-4% milk fat and approx. 25-35% milk proteins.
Alternatively, instead of:
ingredient (ii), fat
ingredient (iii) , food emulsifier for fat; and,
ingredient (iv) , protein ingredient; and, partially,
ingredient (v) , carbohydrate ingredient;
already prepared industrial products known under the trivial names of coffee creamer and coffee foamer can be used. These are usually whitish powderous raw materials based on:
(a) a suitable plant fat, for instance fully hydrogenated or refined coconut fat; which is emulsified with,
(b) a suitable food emulsifier such as mono- and diglycerides of higher fatty acids (E471) and mono- and diacetyl tartaric esters of mono- and diglycerides of higher fatty acids (E472e) or suitable emulsifying salts like potassium phosphate (E340) as food additive intended for emulsification of the said plant fats; which are spray-dried onto,
(c) a suitable edible carrier such as dehydrated glucose syrup.
Such complex ingredients can replace the separate ingredients (ii)- (iv) , and partially the ingredient (v) . Examples of such coffee creamer and coffee foamer are described in the experimental Examples 1-3.
Alternatively, instead of the carbohydrate ingredient, the ingredient (v) , in liquid dosage forms of the composition from the present invention, natural or artificial fruit or vegetable juices can be used as the base with approx. 7-12% w/w of sugar saccharose or an equivalent concentration of sugar substitute: glucose syrup, glucose-fructose syrup, fructose syrup, or mixtures of these substances. As an example of such an alternative carbohydrate ingredient, natural apple juice, natural orange juice, and natural carrot juice is outlined. The example of such use is disclosed in the experimental Example 4. As food additives which are required for the achievement of desired technological properties of the present composition, the ingredients (vi) are selected from the groups consisting of:
salt (sodium chloride; NaCl) ;
spices: cinnamon (Cinnamomum verum J.Presl), clove (Syzygium aromaticum L.), nutmeg (Myristica fragrans Houtt . ) , laurel (Laurus nobilis L.), piment [ Pimenta dioica (L.) Merr. ] , black pepper ( Piper nigrum L.), vanilla ( Vanilla planifolia Plumier ex Mill.), anise (Pimpinella anisum L.), star anise ( Illicium verum L.), dill (Anethum graveolens L.), caraway ( Carum carvi L.), coriander (Coriandrum sativum L.), ginger ( Zingiber officinale Roscoe) , thyme (Thymus vulgaris L.), wild thyme (Thymus serpyllum L.), peppermint (Mentha x piperita L.), spearmint (Mentha spicata L.), or mixtures of these spices;
flavours: powderous or liquid flavours of coffee, vanilla, hazelnut, milk, other flavours, and mixtures of these flavours; emulsifier salts: lactates like sodium lactate (E325), potassium lactate (E326) , calcium lactate (E327); citrates such as sodium citrates (E331), potassium citrates (E332), calcium citrates (E333) ; phosphates like sodium phosphates (E339) , potassium phosphates (E340), diphosphates (E450) , triphosphates (E451) and polyphosphates (E452);
food colours: curcumin (E100), riboflavin (E101), caramel (E150), carotenes (E160a), lutein (E161b), anthocyanins (E163), betanin (E162); other food colourings; or mixtures of these substances; preservatives: benzoic acid (E210) or its salts like sodium benzoate (E211); sorbic acid (E200) or its salts such as potassium sorbate (E202); lactic acid (E270); parabens like methyl 4- hydroxybenzoate (E218), ethyl 4-hydroxybenzoate (E214) or propyl 4-hydroxybenzoate (E216) , sulphites such as potassium metabisulphite (E224); other food or pharmaceutically acceptable preservatives; or mixtures of these substances;
food acids: citric acid (E330) , malic acid (E296) , fumaric acid (E297), ascorbic acid (E300) , L- (+) -tartaric acid (E334), adipic acid (E355) , succinic acid (E363), other food or pharmaceutically acceptable acids; or mixtures of these substances; anti-caking agents: magnesium oxide (MgO; E530), calcium oxide (CaO; E529), silicium dioxide (SiCh; E551), calcium phosphate [Ca3(P04)2; E341iii] , magnesium carbonate (MgC03»nH20; E504i), magnesium hydroxide carbonate (E504ii), talc (E553b) , aluminium silicate (kaolin; E559) , magnesium salts of higher fatty acids (E470b) like magnesium stearate, other food or pharmaceutically acceptable anti-caking agents; or mixtures of these substances; thickeners: pectins (E440) , agar (E406) , carrageenan (E407), carob gum (Locust bean gum; E410) , guar gum (E412), tragacanth (E413) , gum arabic (E414), xanthan gum (E415) , other food or pharmaceutically acceptable thickeners; or mixtures of these substances ;
sweeteners: acesulfame K (E950), aspartame (E951), cyclamate (E952), saccharin (E954), sucralose (E955), thaumatin (E957), neohesperidin DC (E959 ) , neotame (E961), salts of aspartame and acesulfame (E962), sorbitol (E420) , mannitol (E421), isomalt (E 953 ) , maltitol (E 965 ) , lactitol (E966 ) , xylitol (E967), erythritol (E968), or mixtures of these substances;
taste enhancers: glutamic acid (E620 ) , monosodium glutamate (E621), monopotassium glutamate (E622), calcium diglutamate (E 623 ) , monoammonium glutamate (E624), magnesium diglutamate (E 625 ) , guanylic acid (E626), disodium guanylate (E627), dipotassium guanylate (E628), calcium guanylate (E629), inosinic acid (E630), disodium inosinate (E631), dicalcium inosinate (E632), calcium inosinate (E633), calcium 5 ' -ribonucleotide (E634), disodium 5 ' -ribonucleotide (E 635 ) , glycine or sodium glycinate (E640) , or mixtures of these taste enhancers;
or mixtures of these substances.
Instead of L-tyrosine (1) , L-tryptophan (2) , and trimethylglycine (3) in the form of free amino acids, alternatively their salts with pharmaceutically and nutritionally acceptable acids can be used; such acids are selected from the group consisting of: citric; malic; tartaric; isocitric; lactic; pyruvic; aconitic; a-keto-glutaric; fumaric; gluconic; acetic; succinic; adipic; hydrochloric; sulphuric; phosphoric; other pharmaceutically acceptable acids; or mixtures of these acids.
Examples of such alternative salts which can be used instead of free amino acids are: L-tyrosine hydrochloride, L-tryptophan hydrochloride, trimethylglycine hydrochloride, trimethylglycine citrate and others.
As an alternative source of trimethylglycine (3) , extract of sugar beet Beta vulgaris L) with the content of >25% w/w compound 3 can be used .
Pharmaceutically acceptable forms of zinc which can be used in the composition of the present invention are selected from the group consisting of: zinc oxide; zinc carbonate; zinc sulphate; zinc chloride; zinc acetate; zinc phosphate; zinc gluconate; zinc lactate; zinc citrate; zinc malate; zinc glycinate; zinc aspartate; zinc a- keto-glutarate ; hydrates of the said compounds; other pharmaceutically acceptable zinc salts or complexes; hydrates of the said compounds; and mixtures of these substances.
The chemical forms of vitamins from B-group that can be used in the composition of the present invention are selected from the group consisting of:
niacin (B3) : nicotinic acid, nicotinamide, or mixtures of these substances ;
pyridoxine (B6) : pyridoxine hydrochloride, pyridoxine 5'- phosphate, pyridoxine dipalmitate, or mixtures of these substances ;
folic acid (B9) : folic or pteroyl-L-glutamic acid, dihydrofolic acid, tetrahydrofolic acid, 5-metiltetrahydrofolic acid, and folinic acid; salts of the said acids with pharmaceutically acceptable cations like sodium (Na+) , potassium (K+) , magnesium (Mg2+) , calcium (Ca2+) ; or mixtures of these substances;
vitamin B12: cyanocobalamin, hydroxycobalamin, metilcobalamin, cobalamin or adenosyl-cobalamin; of mixtures of the said forms of vitamin B12;
and optionally: thiamine (Bl) : thiamine hydrochloride, thiamine mononitrate, or mixtures of these substances;
riboflavin (B2) : riboflavin, riboflavin 5 '-phosphate sodium salt; pantothenic acid (B5) : calcium D-pantothenate , sodium D- pantothenate , dexpanthenol ; and,
biotin (B7) : D-biotin.
Preferably, in the composition of the present invention the following forms of B vitamins are used: nicotinamide (B3) , pyridoxine hydrochloride (B6) , pteroyl-L-glutamic acid (B9) , and cyanocobalamin (B12), and, optionally: thiamine hydrochloride (Bl), riboflavin (B2), calcium pantothenate (B5), and biotin (B7) .
Since it is known that L-tyrosine (1) is characterized by very poor water solubility: about 45 mg in 100 g water at 25 °C (see literature reference 14), it is of essential importance for the present invention to use an L-tyrosine solubility enhancer. The latter enables improvement of its bioavailability and thus better pharmacological effects on the human health.
Apart from the enhancement of L-tyrosine (1) solubility, its effect must not compromise the sensory profile of the main composition matrix from the present invention. In the case of the use of a powderous instant drink based on coffee or coffee substitute, the said L-tyrosine (1) solubility enhancer must not develop any chemical incompatibility with other ingredients of the composition.
Due to a relatively complex composition of the present invention, it is clear to those skilled in the art that this can be any solubility enhancer of L-tyrosine (1), but only those which:
(i) besides the ability to enhance L-tyrosine solubility by forming its sodium salt la;
(ii) do not affect negatively the sensory properties of the basic matrix (type of the composition) of the product; and which are chemically compatible with other ingredients of the product. It was found that in the composition of the present invention the following suitable L-tyrosine (1) solubility enhancers can be used: sodium carbonate (Na2CC>3) , sodium bicarbonate (NaHCCb) , sodium sesquicarbonate (Na2C03*NaHC03*2H20) , potassium carbonate (K2CO3) , potassium bicarbonate (KHCO3) , or mixtures of these substances.
Preferably, as a solubility enhancer, sodium bicarbonate (NaHCCb) is used .
The powderous composition from the present invention is characterized by the following weight percentages (%, w/w) of the ingredients:
A. formulation of the base; 50-99% w/w; of the composition:
ingredient (i) : 5-25% w/w;
ingredient (ii) : 2-10% w/w;
ingredient (iii) 0.1-3% w/w;
ingredient (iv) : 2-30% w/w;
ingredient (v) : 10-90% w/w;
ingredient (vi) : 0.5-5% w/w; of which salt (NaCl) 0.1-1% w/w; and,
formulation of active substances; 1-50% w/w; of the composition: ingredient (vii) : 1-25% w/w;
ingredient (viii) : 1-25% w/w;
ingredient (ix) : 0.1-25% w/w;
ingredient (x) : 0.1-5% w/w;
ingredient (xi) : 0.001-1% w/w each of the vitamins: niacin
(B3), pyridoxine (B6) , folic acid (B9) and, optionally, other vitamins of B complex: thiamine (Bl), riboflavin (B2), pantothenic acid (B5) , and biotin (B7); and,
solubility enhancer of L-tyrosine (1) :
ingredient (xii) : 0.25-3% w/w.
Preferably, the powderous composition from the present invention is characterized by the following weight percentages (%, w/w) of the ingredients :
A. formulation of the base; from 80-90% w/w; ingredient (i) : 10-15% w/w;
ingredient (ii) : 5-10% w/w;
ingredient (iii) : 0.2-2% w/w;
ingredient (iv) : 10-25% w/w;
ingredient (v) : 25-50% w/w;
ingredient (vi) : 0.5-5% w/w; of which salt (NaCl) 0.25- 0.75% w/w; and,
B. formulation of active substances; 10-20% w/w;
ingredient (vii) : 2-5% w/w;
ingredient (viii ) : 1-5% w/w;
ingredient (ix) : 2-5% w/w;
ingredient (x) : 0.05-1% w/w;
ingredient (xi) : 0.001-0.1% w/w each of the vitamins:
niacin (B3), pyridoxine (B6) , folic acid (B9) and, optionally, other vitamins of B complex: thiamine (Bl), riboflavin (B2), pantothenic acid (B5) , and biotin (B7); and,
solubility enhancer of L-tyrosine (1) :
ingredient (xii) : 0.5-2.0% w/w .
Besides the above-mentioned, other active substances, known to those skilled in the art, which help in disorders of the central nervous system can also be optionally employed in the composition of the present invention. Such optional active substances are selected from the group comprising:
(a) vitamins: ascorbic acid (vitamin C) ; a-tocopherol (vitamin E) ; and,
(b) minerals: magnesium (Mg), e.g. in the form of magnesium citrate, gluconate or lactate; selenium (Se) , e.g. in the form of sodium selenate; and iodine (I), e.g. in the form of potassium iodide; pharmaceutical equivalents of the said vitamins or pharmaceutically acceptable salts of these minerals; or mixtures of these substances.
The composition from the present invention can be used in various dosage forms suitable for practical use: (i) functional food product forms: instant powder for preparation of a cappuccino-like drink with water or milk, liquid cappuccino, instant powderous or liquid drinks based on coffee or coffee substitutes, instant powderous or liquid non alcoholic beverages, wine, beer, yogurt, milk drinks, chewing gums, functional energy bars, muesli-like products, functional ice cream, and other suitable forms of functional food products; or,
(ii) pharmaceutical dosage forms in the case of pharmaceutical products and food supplements: powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution.
In different forms of the composition from the present invention suitable for functional food, as excipients or alternative base composition, the ingredients (i-vi) , various food ingredients can be used: food liquids such as water, milk, yogurt, wine, beer, fruit juices, vegetable juices and others; cereals such as whole, polished, rolled or extruded seeds of wheat, barley, oat, rye, triticale, maize, and other cereals; dried fruits such as raisins, bananas, apples, strawberries, blueberries, figs, pineapple, and other fruits; natural sugars like sucrose, honey, glucose, fructose, glucose syrup, fructose syrup, glucose-fructose syrup; natural sweeteners such as liquorice ( Glycyrrhiza glabra L.) or stevia ( Stevia rebaudiana) ; soluble plant fibres like inulin, oligofructose , pectins; oligo- and polysaccharides such as dextrins, maltodextrins , starch; sugar alcohols like sorbitol, maltitol, xylitol, lactitol, mannitol; edible fats such as sunflower oil, rapeseed oil, soybean oil, sesame oil, coconut oil, palm oil, and other plant oils, milk fat; sources of proteins like soybean, maize or wheat protein; various protein hydrolysates; and other food ingredients as sources of carbohydrates, fats, and proteins.
Besides the nutritional ingredients, the composition from the present invention in the form of functional food can also contain different food additives which, alike the ingredient (vi), help to stabilize, preserve, enable the desired consistency of the products, etc. The use of food additives is common in the food industry and is known to those skilled in the art of food technology.
Optionally, if the formulation (B.) of active substances (vii)-(xi) is not employed in the dosage form of the powderous instant form for preparation of a cappuccino-like drink, but it is used in some of the dosage forms typical for food supplements or pharmaceutical products such as: powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution, then, instead of the formulation base (A. ) , the ingredients
(i)-(vi), one or more pharmaceutical excipients are used. Such pharmaceutical excipients are selected from the groups consisting of: fillers, binders, disintegrants, lubricants, diluents (solvents), buffer substances, antioxidants, stabilizers, preservatives, colours, flavours, and other kinds of excipients that are commonly employed in the dosage forms of powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution.
Examples of such pharmaceutical excipients, food ingredients or food additives are:
(i) fillers: sugar like sucrose, honey, glucose, fructose, lactose, other edible sugars or mixtures of these substances; starch, dextrins, maltodextrins , and other starch derivatives; sugar alcohols such as sorbitol, maltitol, xylitol, mannitol, lactitol, isomalt, erythritol, other sugar alcohols or mixtures of these substances;
(ii) sweeteners: aspartame, saccharin, acesulfame, sucralose, cyclamate, glycyrrhizin, ammonium glycyrrhizinate or extract of liquorice ( Glycyrrhiza glabra L.) root, neohesperidin dihydrochalcone (NHDC) , stevia, stevia extracts, rebaudioside A and other steviosides;
(iii) anti-caking agents like magnesium or calcium salts of higher fatty acids such as magnesium stearate, silicon dioxide;
(iv) soluble fibres: polydextrose, inulin, oligofructose , other soluble dietary fibres; or mixtures of these substances. Other examples of such substances that can be used are given under the definition of the ingredient (vi) .
Preparation of the composition from the present invention
The process of preparation of the composition includes the homogenization of the ingredients (i-xii) . Optionally, the process can be performed by separately homogenizing the base formulation (the ingredients i-vi) and separately the formulation of active substances (vii-xi) , with or without addition of the solubility enhancer of L- tyrosine, the ingredient (xii) . Then, final homogenization of the base formulation (i-vi) and formulation of active substances (vii-xi, xii) yields the final product according to the present invention.
The dosage forms of the composition from the present invention can be :
(i) functional food product forms: instant powder for preparation of a cappuccino-like drink with water or milk, liquid cappuccino, instant powderous or liquid drinks based on coffee or coffee substitutes, instant powderous or liquid non alcoholic beverages, wine, beer, yogurt, milk drinks, chewing gums, functional energy bars, muesli-like products, functional ice cream, and other suitable forms of functional food products; or,
(ii) pharmaceutical dosage forms in the case of pharmaceutical products and food supplements: powder, effervescent powder, granules, tablets, effervescent tablets, capsules, solution, suspension, syrup, and injection solution.
The forms intended for use as functional food are prepared by homogenization of active substances (vii)-(xi), with or without the solubility enhancer L-tyrosine (1), the ingredient (xii), into the corresponding matrix of the food product.
The powderous instant cappuccino-like drink is prepared by homogenization of powderous active substances (i)-(xii) . Typical examples of such procedures for the preparation of a powderous instant cappuccino-like drink are described in Examples 1-3.
A functional non-alcoholic beverage is prepared by dissolution and/or suspension of the ingredients (vii)-(xi) in suitable fruit juice, for instance apple juice. Typical example of the preparation of a liquid functional food drink is described in Example 4.
Functional muesli is manufactured by homogenization of powderous formulation of active substances (vii)-(xi) with an inert edible powder, e.g. maltodextrin . Such a premix is further homogenized with rolled wheat or oat, small parts of dried fruits, sugar, with or without addition of flavour, protein source, other food additives or other nutritional ingredients. Typical example of such preparation of a functional muesli form is described in Example 5.
A functional energy bar is prepared by:
A. mixing:
(i) different rolled cereals such as oat or wheat, or mixtures of these ingredients;
(ii) fat; e.g. fully hydrogenated palm fat;
(iii) emulsifier for fats; e.g. sunflower or soybean lecithin;
(iv) carbohydrate ingredient; e.g. honey, glucose syrup, sugar syrup or similar carbohydrate syrup, or mixtures of these substances; with,
(v) addition of a suitable protein ingredient; e.g. milk powder, whey proteins, milk protein, plant protein like pea protein or wheat protein, other suitable edible protein-containing ingredients, or mixtures of these substances; and
(vi) optionally, food additive required for achieving the required technological properties such as:
(a) humectants; glycerol (E422), sorbitol (E420), maltitol (E965) , other hygroscopic polyols, or mixtures of these substances; (b) food acids; citric acid (E330), malic acid (E296), other food acids, or mixtures of these substances;
(c) preservatives; e.g. potassium sorbate (E202), sodium benzoate (E211), other suitable preservatives, or mixtures of these substances;
(d) food colours; e.g. beta-carotene (E160a); and,
(e) suitable flavours; e.g. vanillin, chocolate, hazelnut or fruit flavours; with,
(vii) formulation of active substances (vii-xi) in concentration which corresponds to the amount of 2-4 g (50-100% of daily dose of active substances in a single energy bar, most preferably of the weight 25-50 g; followed by,
B. extrusion of such obtained thick mass with the formation of endless tape which is cut into suitable bars of optimal dimensions, e.g. 1-2 cm of height, 2-5 cm in width, and 5-10 cm of length, and about 25-50 g of total mass; the latter are, if needed,
C. dried up to the desired level of residual moisture; and, optionally,
D. coated with suitable coat; e.g.
(a) with melted chocolate coating; or,
(b) non-chocolate melted coating separately prepared from: suitable fat such as palm fat, sugar, skimmed milk powder, vanilla flavour and lecithin as emulsifier.
Typical example of such a procedure for the preparation of the composition from the present invention in the form of a functional energy bar is described in Example 6.
Functional ice cream is prepared in the following technological phases :
A. mixing the following ingredients:
(i) fat; e.g. palm oil;
(ii) emulsifier for fat; e.g. sunflower or soybean lecithin;
(iii) carbohydrate ingredient; e.g. honey, glucose syrup, sugar, similar carbohydrate syrup, or mixtures of these substances; with, (iv) addition of a suitable protein ingredient; e.g. milk powder, whey proteins, milk proteins, plant proteins like pea or wheat proteins, other suitable edible proteins; or mixtures of these substances; and,
(v) optionally, food additives required for achieving the desired technological properties such as:
(a) humectants; glycerol (E422), sorbitol (E420) , maltitol (E965) , other hygroscopic polyols, or mixtures of these substances ;
(b) food acids; citric acid (E330) , malic acid (E296), other edible acids, or mixtures of these substances;
(c) preservatives; e.g. potassium sorbate (E202), sodium benzoate (E211), other suitable preservatives, or mixtures of these substances;
(d) food colours; e.g. beta-carotene (E160a);
(e) suitable flavours; e.g. vanilla, chocolate, hazelnut or fruit flavours;
(f) thickeners; e.g. xanthan gum (E415) , guar gum (E412), pectins (E440) , other edible thickeners, or mixtures of these substances; with,
(vi) formulation of active substances (vii-xi) in the concentration which corresponds to the amount of 2-4 g (50-100% daily dosage of active substances in a single ice cream of approx, weight of 50 g) ;
at 60-65 °C yielding a homogeneous mixture, which is subsequently subjected to,
B. pasteurization; at 70-75 °C during 5-10 minutes; after which the mixture is exposed to,
C. cooling to 2-4 °C;
D. conditioning; with stirring at +2 to +4 °C for 2-10 h;
E. stirring with aeration;
F. filling into ice cream cornets or jars; and,
G. freezing to -18 °C to -25 °C during 1-5 h.
Typical example of the procedure for preparation of the composition from the present invention in the form of functional ice cream is shown in Example 7. In all other cases, when the formulation of active substances (vii)- (xi) , with or without the solubility enhancer L-tyrosine, the ingredient (xii) , the composition from the present invention is used in conventional dosage forms typical for food supplements and pharmaceutical products; typical examples are described in Examples 8 11
The composition from the present invention in the dosage form of the powder is prepared by homogenization of powderous active substances (vii)-(xi) and optionally (xii) with one or more powderous auxiliary ingredients (excipients), often inert fillers such as microcrystalline cellulose, inulin, mannitol or similar; with or without anti-caking agent like magnesium stearate or colloidal silicon dioxide. Typical example of preparation of the composition from the present invention in the form of powder is described in Example 8.
In the case of manufacturing effervescent powder, dry excipients are employed which in contact with water generate gaseous carbon dioxide (CO2) . Typically, the mixtures of sodium hydrogencarbonate (NaHCCb) and citric and/or malic acid are used. Typical example of preparation of the composition from the present invention in the form of effervescent powder is described in Example 9.
In the case of tablets production, a binder and a disintegrant are added into the homogeneous mixture for the preparation of the powder. For instance, hydroxypropyl methylcellulose (HPMC) as the binder, and cross-linked polyvinylpyrrolidone (PVP) as the disintegrant can be employed. Thus, obtained homogeneous mixture is processed into tablets by direct compression.
Alternatively, the homogeneous powder can be directly filled into gelatine or vegetable capsules yielding the dosage form of capsules. Typical example of preparation of the composition from the present invention in the form of capsules is described in Example 10. Liquid dosage forms of the composition are prepared by dissolving or suspending the active substances (vii)-(xi) with or without the ingredient (xii) in purified water, plant oil or solution of sugar syrup. This gives the following dosage forms: solution, suspension or syrup. Thus, obtained compositions are eventually further processed with preservatives, stabilizers, antioxidants, colours, and flavours, in order to obtain the desired stability and flavour of the product. Typical example of preparation of the composition from the present invention in the form of syrup is disclosed in Example 11.
Mechanism of synergic action of L-tyrosine (1), L-tryptophan (2), trimethylglycine (3), zinc (Zn) and vitamins of B-group: B3, B6, B9 and B12
As it is known in the prior art, L-tyrosine (1; TYR) serves as a metabolic precursor for the biosynthesis of neurotransmitters from the group of catecholamines: dopamine (DA), norepinephrine (NE) and epinephrine (EN) or adrenaline. Supplementation of L-tyrosine (1) results in an increase of its concentration in plasma and its concentration in the brain. Resorption of L-tyrosine (1) into the brain is dependent on its concentration in plasma and the total concentration of large neutral amino acids (phenylalanine, tryptophan, methionine, valine, leucine, isoleucine) in plasma. The latter compete with L-tyrosine for crossing the blood-brain barrier (BBB) . The enhancement of L-tyrosine (1) concentration in the brain stimulates natural biosynthesis of the said neurotransmitters. This results in regulation and increasing of all processes in the brain which are regulated by these neurotransmitters, which are: motivation, award, cognition control, emotional stability, short-term memory, motion, and arousal; see literature reference 18:
18) Monograph: L-Tyrosine, Altern. Med. Rev. 12 (2007) 364-368.
The therapeutic profile of L-tyrosine (1) involves the treatment of depression, stress, hypertension, cognitive function, memory, Parkinson's disease, phenylketonuria, and narcolepsy. It is profoundly effective in stress conditions and cognitively demanding situations where it acts as an efficient stimulator of cognitive performances: strengthening memory, increasing attention and learning process; see literature reference 19:
19) B. J. Jongkees, B. Hommel, S. Kiihn, L. S. Colzato: Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands - A review, J. Psych. Res. 70 (2015) 50-57.
The key process of biosynthesis of catecholamines: dopamine ( DA) , norepinephrine (NE ) , and epinephrine ( EN) from L-tyrosine ( 1 ; TYR) involves enzymatic hydroxylation yielding 3 , 4 -dihydroxy-derivative known as L-DOPA . The reaction is catalysed by the enzyme hydroxylase of aromatic amino acids (AAAH ) with the influence of tetrahydrobiopterin ( THB) and molecular oxygen (O2) , releasing dihydrobiopterin ( DHB) . The L-DOPA formed by the action of enzyme L- DOPA decarboxylase (AADC ) , in the presence of pyridoxal phosphate ( B6PP) , yields dopamine (DA) . Further hydroxylation of the latter with molecular oxygen (O2) in the presence of ascorbic acid (AA; vitamin C) gives norepinephrine (NE ) with generation of dehydroascorbic acid ( DHAA) . From NE, methylation of amino group yields epinephrine (EN) or adrenaline in the presence of enzyme phenylethanolamine N- methyltransferase ( PNMT ) and s-adenosyl methionine ( SAME ) as a terminal donor of the methyl group.
Herein, a key synergistic effect of the ingredients from the present invention on the biosynthesis of catecholamines DA, NE and EN must be outlined :
(1) L-tyrosine ( 1 ; TYR) ; essential as a precursor for their biosynthesis, what is known in the prior art; but also the ingredients :
(2) vitamin B6 (pyridoxine) ; essential as a cofactor for the enzyme L-DOPA decarboxylase (AADC ) ;
(3) zinc (Zn2+) ; essential for the activation of vitamin B6 ( B6 ) in the phase of conversion of pyridoxal ( B6PA) into a metabolically active form of vitamin B6, pyridoxal phosphate (B6PP) under the action of enzyme pyridoxal kinase (PK) ; and,
(4) trimethylglycine (3; TMG) ; as a terminal methyl group donor which, after supplementation, directly increases the concentration of s-adenosyl methionine (SAME) in plasma; see literature reference 20.
20) Monograph: Betaine, Altern. Med. Rev. 8 (2003) 193-196.
The whole metabolic pathway of biosynthesis of catecholamines dopamine (DA) , norepinephrine (NE) , and epinephrine (EN) from L-tyrosine (1; TYR) , and synergistic action of key metabolic factors, vitamin B6 (B6) , zinc (Zn2+) , and trimethylglycine (3; TMG) , what has not been recognized in the prior art, is demonstrated in Figure 1.
On the other hand, L-tryptophan (2; TRP) is a metabolic precursor for the synthesis of neurotransmitter serotonin (SE) and neurohormone melatonin (ME); see literature reference 21:
21) Monograph: L-Tryptophan, Altern. Med. Rev. 11 (2006) 52-56.
L-Tryptophan (2) is converted by hydroxylation with molecular oxygen (O2) in the presence of tetrahydrobiopterin (THB) , under the action of enzyme tryptophan hydroxylase (TH) , into 5-hydroxytryptophan (5- HTP) . This is accompanied with the elimination of dihydrobiopterin (DHB) . 5-HTP is further converted to serotonin (SE) by decarboxylation which is catalysed by enzyme 5-HTP decarboxylase (5-HTPD) in the presence of pyridoxal phosphate (B6PP) . As in the case of biosynthesis of catecholamines, the role of zinc (Zn2+) is also crucial here, as it is essential for the functional conversion of the nutritive form of vitamin B6 (B6) into the metabolically active form of pyridoxal phosphate (B6PP) . The latter is important for the activity of enzyme 5-HTP decarboxylase (5-HTPD); see Figure 2.
Melatonin (ME) , as the second important metabolic product formed from L-tryptophan (2), is directly generated from serotonin (SE) by methylation with s-adenosyl methionine (SAME); see Figure 2. Thanks to the use of trimethylglycine (3; TMG) in the composition of the present invention, and vitamins of B-group, specifically vitamins B6, folic acid (B9) and vitamin B12, the biosynthesis of methylation agent SAME is especially stimulated, what additionally stimulates the biosynthesis of melatonin (ME) from serotonin (SE) .
Melatonin exhibits several positive pharmacological effects on human health wherein, except sleep regulation, it acts as an effective neuroprotectant and antioxidant, which significantly protects the brain and the whole nervous system; see literature reference 22 :
22) Monograph: Melatonin, Altern. Med. Rev. 10 (2005) 326-336.
The synergistic activity of the fixed combination of the composition from the present invention in the prior art has not been recognized, which includes :
(1) L-tryptophan (2; TRP) ; a key precursor of their biosynthesis, what is known in the prior art; but also the ingredients:
(2) vitamin B6 (pyridoxine) ; essential as a cofactor for the enzyme L-5-HTP decarboxylase (5-HTPD) ;
(3) zinc (Zn2+) ; essential for the activation of vitamin B6 (B6) in the phase of conversion of pyridoxal (B6PA) into a metabolically active form of vitamin B6, pyridoxal phosphate (B6PP) under the action of the enzyme pyridoxal kinase (PK) ; and,
(4) trimetilglicine (3; TMG); as a terminal methyl group donor which, after supplementation, directly increases the concentration of s-adenosyl methionine (SAME) in plasma; see literature reference 20.
The whole metabolic pathway of the biosynthesis of serotonin (SE) and melatonin (ME) from L-tryptophan (2; TRP), and the synergistic activity of the key metabolic factors vitamin B6 (B6 ) , zinc (Zn2+), and trimethylglycine (3; TMG) , what has not been recognized in the prior art, is shown in Figure 2. Alternatively, L-tryptophan (2; TRP) is degraded by the enzyme tryptophan pyrrolase (TP) into kynurenin (KY) . The latter is further converted to 3-hydroxykynurenin (3HKY) . From 3HKY the organism further synthetizes nicotinic acid (NA) or niacin (vitamin B3) in several steps through 3-hydroxyanthranilic acid (3HAΆ) . Due to the fact that the composition from the present invention contains niacin in the form of nicotinamide (B3) , its parallel supplementation through the composition has the target to block (inhibit) this alternative metabolic pathway of L-tryptophan (2) degradation into niacin. This would result in a higher concentration of L-tryptophan (2) to be available for conversion into serotonin (SE) through the first metabolic pathway, and thus would stimulate its biosynthesis; see Figure 3.
In this case nicotinamide (B3) acts as a competitive inhibitor of biosynthesis of nicotinic acid (NA; vitamin B3) from L-tryptophan (2) , that favours its expenditure to an alternative metabolic pathway - and this is its conversion into serotonin (SE) [and melatonin (ME) before sleep] . This results partially in the described pharmacological activity of the composition from the present invention; see Figure 3.
As mentioned earlier, besides L-tyrosine (1) and L-tryptophan (2) as precursors for the biosynthesis of neurotransmitters from the catecholamine class: DA, NE, EN, as well as serotonin (SE) and neurohormone melatonin (ME) , the composition from the present invention at the same time contains:
(i) trimethylglycine (3; TMG) ; and,
(ii) vitamins from B-complex, specifically nicotinamide (B3 ) , vitamin B6, folic acid (B9 ) , and vitamin B12.
TMG (3) , in a combination with vitamins B9 and B12, directly increases the available concentration of s-adenosyl methionine (SAME) as a key terminal methylation agent in the organism. This directly stimulates all methylation processes in the organism, including also: (i) direct decreasing homocysteine ( HC ) concentration which is otherwise harmful for the health of the brain and the nervous system;
(ii) stimulation of biosynthesis of epinephrine ( EN) or adrenaline by methylation of norepinephrine ( NE ) ; and,
(iii) stimulation of melatonin (ME ) biosynthesis from serotonin ( SE ) .
Trimethylglycine ( 3 ; TMG ) directly converts harmful homocysteine (HC) into methionine (MET) under the influence of enzyme betaine- homocysteine s-methyltransferase ( BHMT ) in the presence of zinc (Zn2+) as a cofactor. This occurs even without:
(i) vitamin B12 cycle; vitamin B12 ( B12 ) - methyl vitamin B12
(MB12 ) ; and, indirectly,
(ii) folate cycle; tetrahydrofdate ( THF ) - 5-methyl- tetrahydrof ate ( 5MTHF) ; and the related,
(iii) biopterin cycle; dihydrobiopterin ( DHB ) - tetrahydrobiopterin ( THB ) ; see Figure 4.
This enables the increase of the equilibrium concentration of tetrahydrobiopterin ( THB) , and thus the capacity of the biopterin cycle is not spent on methylation of homocysteine (HC) , but it is released for other requirements, especially for the biosynthesis of dopamine ( DA) and serotonin ( SE ) ; see Figure 4.
In this manner, the composition from the present invention stimulates the biosynthesis of dopamine ( DA) and serotonin ( SE ) , and indirectly, other neurotransmitters from the class of catecholamines: norepinephrine (NE ) and epinephrine ( EN) , as well as neurohormone melatonin (ME ) . This results in the sum of the mentioned beneficial pharmacological effects of the composition from the present invention.
For this result, zinc (Zn2+) also plays a key synergistic role which: (i) on the one side stimulates the biosynthesis of metabolically active form of vitamin B6, pyridoxal phosphate ( B6PP ) required for decarboxylation of L-DOPA or 5-hydroxytryptophan ( 5-HTP) into the corresponding decarboxylated derivatives, dopamine ( DA) and serotonin ( SE ) ; and,
(ii) on the other side, and at the same time stimulates the biosynthesis of SAME , because zinc is an essential cofactor for the enzyme betaine-homocysteine methyltransferase ( BHMT ) which directly methylates harmful homocysteine ( HC ) into methionine, which subsequently serves as a precursor for SAME .
In short, the key synergistic role of the ingredients of the composition from the present invention has not been recognized in the prior art:
(1) trimethylglycine ( 3 ; TMG) ; as a potential alternative methylation agent;
(2) vitamin B12;
(3) vitamin B9; and,
(4) zinc (Zn2+); as a cofactor of the key enzyme BHMT ;
- on the function of the methylation system and the increase in the concentration of s-adenosyl methionine ( SAME ) , and, simultaneously, the decrease in the concentration of harmful homocysteine ( HC ) in blood.
Additionally, the synergistic activity of the combination of these ingredients (1-4) and the combination of L-tyrosine ( 1 ; TYR) , L- tryptophan ( 2 ; TRP) and vitamin B3 ( B3 ) on several functions of the nervous system, and thus, subsequently on the prevention and treatment of disorders and diseases of the nervous system has not been recognized .
The whole metabolic pathway for the biosynthesis of SAME and the influence of trimethylglycine ( 3 ; TMG ) in it is shown in Figure 4.
The conclusion upon the synergistic activity of L-tyrosine (1) , L- tryptophan ( 2 ) , trimethylglycine ( 3 ) , zinc (Zn) and vitamins of B- group: B3, B6, B9, and B12 :
Due to a complex activity of trimethylglycine ( 3 ) and zinc (Zn2+) in combination with the required vitamins B3, B6, B9, and B12 on the stimulation of biosynthesis of neurotransmitters dopamine (DA) and serotonin (SE) , and, indirectly, other neurotransmitters from the class of catecholamines: norepinephrine (NE) and epinephrine (EN) , as well as neurohormone melatonin (ME), from L-tyrosine (1) or from L- tryptophan (2) , the composition from the present invention exhibits several beneficial pharmacological effects: antidepressant; anxiolytic; antioxidant; improves sleep quality; neuroprotective ; decreases tiredness and fatigue; improves cognitive performances (memory, attention and learning process); improves mood and well being; antihyperhomocysteinemic activity, and thus acts as a hepatoprotective , cardioprotective, and as an anticancer agent; against osteopenia and osteoporosis.
Schematic representation of the spectrum of beneficial physiological and pharmacological activities of the formulation of active substances (vii)-(xi) and consequently the whole composition from the present invention is shown in Table 1.
Table 1. Beneficial physiological and pharmacological effects of active substances (vii)-(xi) and consequently the whole composition from the present invention.
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Mechanism of action of L-tyrosine (1) solubility enhancer according to the present invention
The solubility enhancers of L-tyrosine (1) from the present invention act by forming an equilibrium concentration of its sodium or potassium salts which are well-soluble in water, in the preparation phase of the instant cappuccino-like drink with hot water. For instance, sodium bicarbonate (NaHCCt) and L-tyrosine (1) in hot water at approx. 70-90 °C react with formation of the corresponding sodium salt of L-tyrosine (la) . However, since the composition from the present invention also contains some acidic components (R-COOH) which, gradually, after dissolution, react both with NaHCCb and with the already formed sodium salt of L-tyrosine (la) , free L-tyrosine (1) is released again from such generated salt la, but it:
(i) is partially solubilized by forming hydrogen bonds with numerous compounds in the solution of the instant drink; e.g. with amino-groups (R-NH2) and carboxylic groups (R-COOH) of the protein ingredient from the composition of the present invention as a stabilized solubilized form of lb; or, (ii) is released again in the free form lc, but in the form of fine particles now, presumably of nano- and colloidal dimensions, which are absorbed well in the gastrointestinal tract.
As a result of these processes, significantly improved resorption of L-tyrosine (1) is achieved, together with all beneficial pharmacological effects of the composition from the present invention. Other solubility enhancers of L-tyrosine (1) also act in a similar way according to the present invention.
The action of the solubility enhancers of L-tyrosine (1) is schematically shown in Figure 5.
Sensory study of the composition from the present invention in the form of a powderous instant drink
As a model example for the sensory testing of the composition from the present invention, in order to demonstrate the efficacy to solve the already described technical problems of:
(1) obtaining an improved product for:
(a) prevention and treatment of depression and anxiety; and
(b) improvement of cognitive performances: memory, attention, and learning process;
using natural active substances;
(2) very low water solubility of L-tyrosine (1; TYR) and, consequently, its poor bioavailability; and
(3) masking off-odours and off-flavours of certain natural active substances such as, e.g.
(a) bitter taste of amino acids L-tyrosine (1) and L-tryptophan
(2; TRP) ;
(b) astingent or metallic taste of zinc salts; and,
(c) off-odours and tastes of some B-vitamins.
- the composition in the form of a powderous instant drink from Example 1 (coffee based) and Example 2 (chicory root based) was selected. The sensory study was performed in a specialized company, Technology Management (TM) , Richigen (BE) , Switzerland (CH) , by a reputable expert in the field, Dr. Theo W. Kuypers, whose most important reference in the field is mentioned herein as literature reference 23:
23) US 4,746,527; T. W. Kuypers: Drink Composition; applicant: Nestec S.A. (CH) .
The results of the physical and chemical properties of a drink prepared from the composition of the present invention from Examples 1 and 2 with skimmed milk, and the results of the sensory study are concisely shown in Table 2.
Table 2. The results of physical and chemical analysis of the prepared instant drink from the composition of the present invention, from Examples 1 and 2, and its sensory study.
Figure imgf000043_0001
Figure imgf000044_0001
Results of the sensory study performed on the composition from the present invention with model compositions from Examples 1 and 2 exhibit that the described technical problems are successfully solved.
Detailed description of the analysis of the composition from the present invention, including the sensory study, is described in Example 12.
Use of the composition from the present invention
The composition from the present invention is used as a functional food product, food supplement or as a pharmaceutical product for:
(i) prevention and treatment of central nervous system disorders;
(ii) improvement of cognitive performances: memory, attention, and learning process;
(iii) mood improvement; including seasonal affective disorder;
increasing the feeling of well-being;
(iv) anti-stress activity;
(v) improvement of sleep quality;
(vi) decreasing tiredness and fatigue, and increasing energy and physical performances: strength and endurance;
(vii) prevention and treatment of liver diseases due to its hepatoprotective and detoxifying effects; (viii) prevention and treatment of hyperhomocysteinemia, and thus for prevention and treatment of cardiovascular diseases and diabetes; and,
(ix) prevention and treatment of osteopenia and osteoporosis.
The composition from the present invention is used in the prevention and treatment of disorders of the central nervous system selected from the group consisting of: major depressive disorder, mood disorder, manic-depressive disorder, anxiety, anxiety-depressive disorder, post-traumatic stress disorder, sleep disorders, attention deficit disorder, attention deficit hyperactivity disorder, memory function disorder, seasonal affective disorder, autism, schizophrenia, dementia, Parkinson's disease, Huntington's disease, and Alzheimer's disease .
Preferably, the composition from the present invention is used for prevention and treatment of: major depressive disorder or depression like symptoms.
Regarding the final dosage form of the composition, wherein the active substances (vii)-(xi) can be more or less diluted with auxiliary substances (excipients) in the given dosage form, the recommended daily dosage of the composition is typically 2-3 x 10-20 g of the powderous composition for the preparation of an instant cappuccino like drink, where the said dosages are equivalent to the content of the active substances as follows:
(i) L-tyrosine, 250-3,000 mg;
(ii) L-tryptophan, 250-3,000 mg;
(iii) trimethylglycine , 250-3,000 mg;
(iv) pharmaceutically acceptable zinc salt equivalent to zinc content 5-50 mg; and,
(v) vitamins from B-complex:
a. niacin (B3), 8-80 mg;
b. vitamin B6, 0.7-100 mg;
c. folic acid (B9) or its pharmaceutical equivalent, 100-1,500 pg; d. vitamin B12, 1.25-1,000 pg; and, optionally,
e. thiamine (Bl), 0.65-50 mg;
f. riboflavin (B2), 0.7-50 mg;
g. pantothenic acid (B5), 3-60 mg; and,
h. biotin (B7), 25-250 pg.
Examples
General remarks
The term "room temperature" is related to the temperature interval of 20-25 °C. All percentage (%) shares of the ingredients are expressed as weight portions (w/w) . The mixing speed is expressed as the number of revolutions of the mixing bin per minute (o/min) .
The supplier and the country of origin assigned by the corresponding ISO 3166 abbreviation are indicated at each of the used raw materials. In all other cases local origin raw material was employed.
NRV = Nutrient Reference Value = recommended daily intake; relates to the recommended daily intake of vitamins and minerals (zinc) according to the Regulation (EU) No 1169/2011.
Example 1. Preparation of the composition from the present invention in the form of an instant powderous cappuccino-like drink
Composition (1000 g of the powderous composition for instant preparation of a functional cappuccino-like drink) :
(1) 25.00 g L-tyrosine (l);1
(2) 15.00 g L-tryptophan (2);1
(3) 25.00 g trimethylglycine (3), type BetaPower;2
(4) 1.30 g zinc lactate dihydrate;3
(5) 2.50 g premix of B-vitamins complex (B3 , B6 , B9, B12 ) 4 of strength lOxNRV5 / g, on maltodextrin as carrier; content per gram: 160 mg niacin (B3) as nicotinamide; 14 mg pyridoxine (B6) as pyridoxine hydrochloride; 2 mg folic acid (B9) in the form of pteroylmonoglutamic acid; 25 pg vitamin B12 as cyanocobalamin; (6) 100.00 g powderous coffee foamer, 24% fat, type Maspex 88/06/11; complex ingredient : 6
(a) plant fat: fully hydrogenated coconut fat; 24%;
(b) protein ingredient: skimmed milk powder; equivalent content of 9.1% protein in the foamer;
(c) glucose syrup; 62%;
(d) food additive for achieving desired technological properties, emulsifier salt: potassium phosphates (E340); to 100%;
(7) 200.00 g powderous coffee creamer, 33% fat, type Maspex SM26/N; complex ingredient : 6
(a) fat: fully hydrogenated coconut fat; 33%;
(b) protein ingredient: milk protein; 1.8%;
(c) glucose syrup; 62%;
(d) food emulsifier for plant fat: mono- and diglycerides of higher fatty acids (E471), mono- and diacetyl tartaric esters of mono- and diglycerides of higher fatty acids (E472e) , anti-caking agent: calcium phosphate (E341), colour: carotenes (E160a) ; up to 100%;
(8) 158.20 g protein ingredient: skimmed milk powder, 1.5% milk fat;7
(9) 100.00 g roasted and powdered instant coffee;8
(10) 350.00 g carbohydrate ingredient: sucrose, powderous;8
(11) 5.00 g vanilla flavour, type Govanil;9-10
(12) 10.00 g sodium bicarbonate, powderous;11-12
(13) 3.00 g milled cooking salt;13-14
(14) 5.00 g colloidal silicon dioxide Aerosil 200F.15-16
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 NRV = Nutrient Reference Value for vitamins and minerals according to Regulation (EU) No 1169/2011, Annex XIII; 6 Maspex (PL) ; 7 Dukat (HR) ; 8 Franck (HR) ; 9 Solvay (BE) ; 10 Food additive required for achieving desired technological properties - flavour; 11 AGZ (HR) ; 12 Solubility enhancer of L-tyrosine; 13 Sodaso (BA) ; 14 Food additive required for formation of desired technological properties - cooking salt; 15 Evonik (DE) ; 16 Food additive required for formation of desired technological properties - anti-caking agent. Preparation: The ingredients (1-5) were added to the ingredient (8), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (6), (7), (9-13), and homogenized for 15 minutes. Then, (14) was added, and the mixture was further homogenized for 5 minutes.
Composition of functional powderous cappuccino (15-20 grams per single dose for preparation of 150 mL drink with hot water or milk) : 375-500 mg L-tyrosine; 225-300 mg L-tryptophan; 375-500 mg trimethylglycine; 4,5-6 mg (approx. 50% NRV) zinc, and 37.5-50% NRV each of the vitamins from B group (B3, B6, B9, B12) .
The recommended dose is up to 2 x 15-20 g of instant cappuccino daily, what is equivalent to the intake of 750-1,000 mg L-tyrosine, 450-600 mg L-tryptophan, 750-1,000 mg trimethylglycine, and 9-12 mg (approx. 100% NRV) zinc, and 100% NRV per each of the B-vitamins : Bl, B2, B3, B5 , B6, B7 , B9, and B12.
In the same way, other similar drinks without coffee and caffeine can be prepared. In these cases, instead of coffee, various coffee substitutes with equal or similar weight percentages (% w/w) are employed, e.g. roasted chicory ( Cichorium intybus L.) root, roasted seeds of various cereals such as rye ( Secale cereale M. Bieb.), barley (Hordeum vulgare L.), wheat ( Triticum vulgare L.), other coffee substitutes, or mixtures of these substances.
Example 2. Preparation of the composition from the present invention in the form of an instant powderous cappuccino-like caffeine-free drink
Composition (1000 g powderous composition for instant preparation of a functional cappuccino-like drink) :
(1) 25.00 g L-tyrosine (l);1
(2) 15.00 g L-tryptophan (2 ) ; 1 (3) 25.00 g trimethylglycine ( 3 ) , type BetaPower;2
(4) 2.60 g zinc lactate dihydrate;3
(5) 2.50 g premix of B-vitamins complex (B1 , B2 , B3 , B5 , B6, B7 , B9, B12 ) 4 of strength lOxNRV5 / g; on maltodextrin as carrier; content per gram: 11.1 mg thiamine (Bl) as thiamine hydrochloride; 14 mg riboflavin (B2) as riboflavin 5 ' -phosphate sodium salt; 160 mg niacin (B3) as nicotinamide; 60 mg pantothenic acid (B5) in the form of calcium D-pantothenate ; 14 mg pyridoxine (B6) as pyridoxine hydrochloride; 0.5 mg biotin (B7); 2 mg folic acid
(B9) as pteroylmonoglutamic acid; 25 pg vitamin B12 as cyanocobalamin;
(6) 100.00 g powderous coffee foamer, 24% fat, type Maspex 88/06/11; complex ingredient : 6
(a) plant fat: fully hydrogenated coconut fat; 24%;
(b) protein ingredient: skimmed milk powder; equivalent content of 9.1% protein in the foamer;
(c) glucose syrup; 62%;
(d) food additive for achieving desired technological properties, emulsifier salt: potassium phosphates (E340); to 100%;
(7) 150.00 g powderous coffee creamer, 33% fat, type Maspex SM26/N; complex ingredient : 6
(a) fat: fully hydrogenated coconut fat; 33%;
(b) protein ingredient: milk protein; 1.8%;
(c) glucose syrup; 62%;
(d) food emulsifier for plant fat: mono- and diglycerides of higher fatty acids (E471), mono- and diacetyl tartaric esters of mono- and diglycerides of higher fatty acids (E472e) , anti-caking agent: calcium phosphate (E341), colour: carotenes (E160a) ; up to 100%;
(8) 156.90 g protein ingredient: skimmed milk powder, 1.5% milk fat;7
(9) 100.00 g instant extract of roasted chicory ( Cichorium intybus L . ) root ; 8
(10) 400.00 g carbohydrate ingredient: sucrose, powderous;8
(11) 5.00 g vanilla flavour, type Govanil;9-10
(12) 10.00 g sodium bicarbonate, powderous;11-12 (13) 3.00 g milled cooking salt;13-14
(14) 5.00 g colloidal silicon dioxide, type Aerosil 200F.15 ' 46
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 NRV = Nutrient Reference Value - referent daily intake of vitamins and minerals according to Regulation (EU) No 1169/2011, Annex XIII; 6 Maspex (PL); 7 Dukat (HR); 8 Franck (HR); 9 Solvay (BE) ; 10 Food additive required for achieving desired technological properties - flavour; 11 AGZ (HR) ; 12 Solubility enhancer of L-tyrosine; 13 Sodaso (BH) ; 14 Food additive required for achieving desired technological properties - cooking salt; 15 Evonik (DE) ; 16 Food additive required for achieving desired technological properties - anti-caking agent.
Preparation: The ingredients (1-5) were added to the ingredient (8), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (6), (7), (9-13), and homogenized for 15 minutes. Then, (14) was added, and the mixture was further homogenized for 5 minutes.
Composition of functional powderous cappuccino (15-20 grams per single dose for preparation of 150 mL drink with hot water or milk) : 375-500 mg L-tyrosine; 225-300 mg L-tryptophan; 375 mg trimethylglycine ; 9-12 mg (ca. 100% NRV) zinc, and approx. 50% NRV for each of the vitamins from B group.
The recommended dose is up to 2 x 15-20 g of instant cappuccino daily, what is equivalent to the intake of 750-1,000 mg L-tyrosine, 450-600 mg L-tryptophan, 750-1,000 mg trimethylglycine, and 18-24 mg (ca. 200% NRV) zinc, and 100% NRV per each of the B-vitamins : Bl, B2, B3, B5, B6, B7 , B9, and B12.
Example 3. Preparation of the composition from the present invention in the form of an instant powderous cappuccino-like drink -so
Composition (1000 g powderous composition for instant preparation of a functional cappuccino-like drink) : il) 50.00 g L-tyrosine (l);1
(2) 30.00 g L-tryptophan ( 2 ) ; 1
(3) 50.00 g trimethylglycine ( 3 ) , type BetaPower;2
(4) 4.20 g zinc gluconate;3
(5) 5.00 g premix of B-vitamins complex (B1 , B2 , B3 , B5 , B6, B7 , B9, B12 ) 4 of strength lOxNRV5 / g; on maltodextrin as carrier; content per gram: 11.1 mg thiamine (Bl) as thiamine hydrochloride; 14 mg riboflavin (B2) as riboflavin 5 ' -phosphate sodium salt; 160 mg niacin (B3) as nicotinamide; 60 mg pantothenic acid (B5) in the form of calcium D-pantothenate ; 14 mg pyridoxine (B6) as pyridoxine hydrochloride; 0.5 mg biotin (B7); 2 mg folic acid
(B9) as pteroylmonoglutamic acid; 25 pg vitamin B12 as cyanocobalamin;
(6) 100.00 g powderous coffee foamer, 24% fat, type Maspex 88/06/11; complex ingredient : 6
(a) plant fat: fully hydrogenated coconut fat; 24%;
(b) protein ingredient: skimmed milk powder; equivalent content of 9.1% protein in the foamer;
(c) glucose syrup; 62%;
(d) food additive for achieving desired technological properties, emulsifier salt: potassium phosphates (E340); to 100%;
(7) 188.80 g protein ingredient: skimmed milk powder, 1.5% milk fat;7
(8) 50.00 g instant roasted and powderous coffee;8
(9) 80.00 g instant extract of roasted chicory ( Cichorium intybus L . ) root ; 8
(10) 300.00 g carbohydrate ingredient: sucrose, powderous;8
(11) 100.00 g carbohydrate ingredient: fructose, crystalline, type Fruit ' n Sweet, milled;9
(12) 5.00 g vanilla flavour, type Govanil ; 10-11
(13) 25.00 g sodium bicarbonate, powderous;12-13
(14) 5.00 g milled cooking salt;14-15
(15) 7.00 g colloidal silicon dioxide Aerosil 200F.16-17 1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 NRV = Nutrient Reference Value = referent daily intake of vitamins and minerals according to Regulation (EU) No 1169/2011, Annex XIII; 6 Maspex (PL); 7 Dukat (HR); 8 Franck (HR); 9 Gadot Biochemical Industries Ltd ( IL) ; 10 Solvay (BE); 11 Food additive required for achieving desired technological properties - flavour; 12 AGZ (HR) ; 13 Solubility enhancer of L-tyrosine; 14 Sodaso (BH) ; 15 Food additive required for achieving desired technological properties - cooking salt; 16 Evonik (DE) ; 17 Food additive required for achieving desired technological properties - anti-caking agent.
Preparation: The ingredients (1-5) were added to the ingredient (7), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (6), (8-14), and homogenized for 15 minutes. Then, (15) was added, and the mixture was further homogenized for 5 minutes.
Composition of functional powderous cappuccino (15-20 grams per single dose for preparation of 150 mL drink with hot water or milk) : 750- 1.000 mg L-tyrosine; 450-600 mg L-tryptophan; 750-1,000 mg trimethylglycine ; 9-12 mg (ca. 100% NRV) zinc, and approx. 100% NRV for each of the vitamins from B group.
The recommended dose is up to 2 x 15-20 g of instant cappuccino daily, what is equivalent to the intake of 1,500-2,000 mg L-tyrosine, 900- 1,200 mg L-tryptophan, 1,500-2,000 mg trimethylglycine, and 18-24 mg (approx. 200% NRV) zinc, and 200% NRV per each of the B-vitamins : Bl, B2, B3, B5 , B6, B7, B9, and B12.
Example 4. Preparation of the composition from the present invention in the form of a liquid functional non-alcoholic drink
Composition (1000 g functional non-alcoholic drink) :
(1) 5.00 g L-tyrosine hydrochloride; (2) 5.00 g L-tryptophan hydrochloride;
(3) 5.00 g trimethylglycine ( 3 ) , type BetaPower;1
(4) 0.70 g zinc gluconate (corresponds to 100 mg zinc; lOxNRV);2
(5) 0.16 g (160 mg) nicotinamide (vitamin B3; lOxNRV);3
(6) 0.017 g (17.00 mg) pyridoxine hydrochloride (corresponds to 14 mg of vitamin B6; lOxNRV);3
(7) 0.002 g (2.00 mg) folic acid (vitamin B9; lOxNRV);3
(8) 0.025 g (25.00 mg) premix (0.1%) cyanocobalamin (corresponds to 25 pg vitamin B12; lOxNRV) on mannitol;3
(9) 2.00 g ascorbic acid;3
(10) 2.00 g potassium sorbate;4
(11) 2.00 g sodium benzoate;5
(12) 978.096 g natural apple juice.
1 DuPont Nutrition and Health (US) ; 2 Jost Chemicals (US) ; 3 DSM (NL) ; 4 Celanese (US) ; 5 FoodChem (CN) .
Preparation : The ingredients (10) and (11) were dissolved in the (12) by stirring at room temperature for 10 minutes. To such an obtained solution, the ingredients (1-9) were added, and dissolved by stirring at room temperature for 10 minutes. The product was in the form of a yellowish-brown drink of agreeable taste resembling apple.
Composition of functional drink: 0.415% L-tyrosine; 0.415% L- tryptophan; 0.5% trimethylglycine; 0.11% zinc; lOx NRV/L vitamins B3, B6, B9, B12.
The recommended dose is 100-300 ml of drink daily, what is equivalent to the intake of 415-1,245 mg L-tyrosine, 415-1,245 mg L-tryptophan, 415-1,245 mg trimethylglycine, 10-30 mg (100-300 NRV) zinc, and 100- 300% NRV of vitamins B3, B6, B9 and B12.
Example 5. Preparation of the composition from the present invention in the form of muesli based on rolled oat and dehydrated fruits
Composition (1000 g oat-fruit muesli) : (1) 5.00 g L-tyrosine (l);1
(2) 5.00 g L-tryptophan (2);1
(3) 5.00 g trimethylglycine (3), type BetaPower;2
(4) 0.70 g zinc gluconate;3
(5) 0.16 g (160 mg) nicotinamide (vitamin B3; lOxNRV);4
(6) 0.017 g (17.00 mg) pyridoxine hydrochloride (corresponds to 14 mg vitamin B6; lOxNRV);4
(7) 0.002 g (2.00 mg) folic acid (vitamin B9; lOxNRV);4
(8) 0.025 g (25.00 mg) premix (0.1%) of cyanocobalamin (corresponds to 25 pg vitamin B12; lOxNRV) on mannitol;4
(9) 30.00 g lyophilized strawberry in the form of small particles;
(10) 30.00 g dried raisins in the form of small particles;
(11) 10.00 g modified maize starch, type Cleargum TD-90;5
(12) 50.00 g carbohydrate ingredient: fructose, crystalline, type Fruit ' n Sweet, milled;6
(13) 50.00 g carbohydrate ingredient: sucrose, powderous; 7
(14) 100.00 g fat: coconut oil;8
(15) 714.096 g rolled oat, classic.
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 Roquette (FR) ; 6 Gadot Biochemical Industries Ltd (IL) ; 7 Franck (HR) , 8 Zvijezda (HR) .
Preparation : The ingredients (1-8) were added to the mixture of (12) and (13), and homogenized in the V-blender for 15 minutes. Such an obtained premix was added into the V-blender together with the ingredients (9-11) and (15), and homogenized by stirring for 15 minutes. Then, the previously molten (at 40-45 °C) ingredient (14) was added, and the mixture was stirred in a planetary mixer at temperatures from 35 °C to room temperature for 15 minutes.
Composition of functional muesli: 0.5% L-tyrosine; 0.5% L-tryptophan; 0.5% trimethylglycine; 0.01% zinc; !OxNRV/kg vitamins B3, B6, B9, B12. The recommended dose is 50-150 g of muesli daily, what is equivalent to the intake of 250-750 mg L-tyrosine, 250-750 mg L-tryptophan, 250- 750 mg trimethylglycine, 5-15 mg zinc, and 50-150% NRV of vitamins B3, B6, B9, and B12.
Example 6. Preparation of the composition from the present invention in the form of a functional energy bar
Composition (1000 g of the mass for extrusion of functional energy bars ) :
(1) 12.50 g L-tyrosine (l);1
(2) 12.50 g L-tryptophan ( 2 ) ; 1
(3) 12.50 g trimethylglycine ( 3 ) , type BetaPower;2
(4) 1.75 g zinc gluconate;3
(5) 0.40 g (400 mg) nicotinamide (vitamin B3; 25xNRV);4
(6) 0.043 g (43.00 mg) pyridoxine hydrochloride (corresponds to 35 mg of vitamin B6; 25xNRV);4
(7) 0.005 g (5.00 mg) folic acid (vitamin B9; 25xNRV);4
(8) 0.063 g (63.00 mg) premix (0.1%) of cyanocobalamin (corresponds to 63 pg vitamin B12; 25xNRV) on mannitol;4
(9) 10.239 g maltodextrin Glucidex l;5
(10) 150.00 g fat; fully hydrogenated palm fat;
(11) 2.00 g emulsifier for fat; sunflower lecithin, type Unilec SF- DP; 6
(12) 264.00 g carbohydrate ingredient: glucose syrup;
(13) 50.00 g carbohydrate ingredient: sucrose, powderous;
(14) 350.00 g rolled oat;
(15) 60.00 g dried raisins; in the form of small particles;
(16) 30.00 g sorbitol, 70%;
(17) 10.00 g protein ingredient: skimmed milk powder;7
(18) 30.00 g hazelnuts, milled;
(19) 2.00 g vanilla flavour, powderous;8
(20) 2.00 g citric acid, anhydrous. 1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 Roquette (FR) ; 6 Unilecithin, Barentz Group (NL) ; 7 Dukat (HR) , 8 Sluys (BE) .
Preparation of the premix of active substances (vii-xi) : The ingredients (1-9) were added into the V-blender and homogenized by stirring at 12 rpm for 15 minutes.
Preparation of functional energy bars: To a mixture of the ingredients (10-13), heated and melted at 50-55 °C, the ingredients (14-20), and the premix (1-9) were added. The mixture was homogenized by stirring (kneading) at 50-55 °C for 10 minutes. Such an obtained warm mixture was extruded through a hole of approx. 1.5x3 cm. Such an obtained endless cake was cut into bars of 10 cm length and cooled. The mass of such obtained functional energy bars was about 40 g.
Composition of functional energy bars according to the present invention (per approx. 40 g) : 500 mg L-tyrosine; 500 mg L-tryptophan; 500 mg trimethylglycine ; 10 mg (100% NRV) zinc; 16 mg (100% NRV) niacin (B3); 1.4 mg (100% NRV) vitamin B6; 200 pg (100% NRV) folic acid (B9 ) ; 2.5 pg (100% NRV) vitamin B12.
The recommended dose is 1-2 bars daily, what is equivalent to the intake of 500-1,000 mg L-tyrosine, 500-1,000 mg L-tryptophan, 500- 1,000 mg trimethylglycine, 10-20 mg (100-200% NRV) zinc, and 100-200% NRV of vitamins B3, B6, B9, and B12.
Example 7. Preparation of the composition from the present invention in the form of functional ice cream
Composition (1000 g ice cream) :
(1) 10.00 g L-tyrosine ( 1) ; 1
(2) 10.00 g L-tryptophan (2 ) ; 1
(3) 10.00 g trimethylglycine ( 3 ) , type BetaPower;2
(4) 1.40 g zinc gluconate;3
(5) 0.32 g (320 mg) nicotinamide (vitamin B3; 20xNRV);4 (6) 0.034 g (34,00 mg) pyridoxine hydrochloride (corresponds to 28 mg vitamin B6; 20xNRV);4
(7) 0.004 g (4.00 mg) folic acid (vitamin B9; 20xNRV);4
(8) 0.050 g (50.00 mg) premix (0.1%) of cyanocobalamin (corresponds to 50 pg vitamin B12; 20xNRV) on mannitol;4
(9) 18.192 g maltodextrin Glucidex l;5
(10) 100.00 g fat; palm oil;
(11) 1.00 g emulsifier for fat; sunflower lecithin, tip Unilec SF- DP; 6
(12) 150.00 g carbohydrate ingredient: sucrose;
(13) 100.00 g protein ingredient: skimmed milk powder;7
(14) 3.00 g vanilla flavour, powderous;8
(15) 0.20 g food additive, colour beta-carotene (E160a), 3% premix, type Beta-Carotene F3 WDP; 9
(16) 1.00 g citric acid, anhydrous;
(17) 3.00 g xanthan gum, type Jungbunzlauer Xanthan Gum FN; 10
(18) 591.80 purified water
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 Roquette (FR) ; 6 Unilecithin, Barentz Group (NL) ; 7 Dukat (HR) ; 8 Sluys (BE) ; 9 San Ei-Gen ( JP) ; 10 Jungbunzlauer (CH) .
Preparation of the premix of active substances (vii-xi) : The ingredients (1-9) were added into the V-blender and homogenized by stirring at 12 rpm for 15 minutes.
Preparation of the aqueous phase: To purified water (18), the ingredients (12-17) were added, and the mixture was homogenized at 60-65 °C for 10 minutes. Then, the premix of active substances (1-9) was added. Preparation of the fatty phase : Lecithin (11) was separately disperged in palm oil (10) at 60-65 °C for 15 minutes. Then the aqueous and fatty phases were mixed by intensive stirring and homogenization at a high shear conditions, 2-3,000 rpm or more, for 10-20 minutes. The mixture was subjected to pasteurization at TO TS °C for 10 minutes. The mixture was then cooled by stirring at 2-4 °C for 1 h. Subsequently the mixture was subjected to conditioning with stirring at +2 to +4 °C during 3 h. After that, to the stirred mixture, air was introduced in order to aerate the product under slow stirring for 30 minutes. Such prepared mixture was filled into commercially available plastic jars per approx. 50 g. Such filled jars were left cooling in a deep freezer at -20 °C for 3 h.
Composition of functional ice cream according to the present invention (50 g dose) : 500 mg L-tyrosine; 500 mg L-tryptophan; 500 mg trimethylglycine ; 10 mg (100% NRV) zinc; 16 mg (100% NRV) niacin (B3); 1.4 mg (100% NRV) vitamin B6; 200 pg (100% NRV) folic acid (B9 ) ; 2.5 pg (100% NRV) vitamin B12.
The recommended dose is 1-2 (50-100 g) ice creams daily, what is equivalent to the intake of 500-1,000 mg L-tyrosine, 500-1,000 mg L- tryptophan, 500-1,000 mg trimethylglycine, 10-20 mg (100-200% NRV) zinc, and 100-200% NRV of vitamins B3, B6, B9, and B12.
Example 8. Preparation of the composition from the present invention in the form of powder
Composition (100 g of powder) :
(1) 25.00 g L-tyrosine ( 1) ; 1
(2) 25.00 g L-tryptophan (2 ) ; 1
(3) 10.00 g trimethylglycine ( 3 ) , type BetaPower;2
(4) 2.18 g zinc lactate dihydrate;3
(5) 0.80 g (800 mg) nicotinamide (vitamin B3; 50xNRV);4
(6) 0.085 g (85.00 mg) pyridoxine hydrochloride (corresponds to 14 mg vitamin B6; 50xNRV);4
(7) 0.01 g (10.00 mg) folic acid (vitamin B9; 50xNRV);4
(8) 0.125 g (125.00 mg) premix (0.1%) cyanocobalamin (corresponds to 125 pg vitamin B12; 50xNRV) on mannitol;4
(9) 35.80 g sorbitol, powderous;5
(10) 1.00 g colloidal silicon dioxide, type Aerosil 200F.6
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 Roquette (FR) ; 6 Evonik (DE) . Preparation: The previously weighed ingredients (1-10) were homogenized in the V-blender for 5 minutes, and then de-agglomerated with pestle in the mortar. Then, the mixture was additionally homogenized in the V-blender for 15 minutes. The product was obtained in the form of fine white, almost odourless powder.
Composition: 25% L-tyrosine; 25% L-tryptophan; 10% trimethylglycine; 0.5% (lOxNRV) zinc; 50xNRV vitamins B3, B6, B9, and B12.
The powder can be used as such, or divided in the form of sachets containing 2.00 g each, of which 1-3 represent the recommended daily dosage containing: 500-1,500 mg L-tyrosine; 500-1,500 mg L-tryptophan; 200-600 mg trimethylglycine; 10-30 mg (100-300% NRV) zinc; and 100- 300% NRV vitamins B3, B6, B9, and B12.
It is used upon dissolution in water, juice, yoghurt or other food liquids and thus obtained liquid is drunk.
Example 9. Preparation of the composition from the present invention in the form of effervescent powder
Composition (100 g of effervescent powder) :
(1) 5.00 g L-tyrosine (l);1
(2) 10.00 g L-tryptophan ( 2 ) ; 1
(3) 10.00 g trimethylglycine ( 3 ) , type BetaPower;2
(4) 0.44 g zinc lactate dihydrate;3
(5) 0.16 g (160 mg) nicotinamide (vitamin B3; lOxNRV);4
(6) 0.017 g (17.00 mg) pyridoxine hydrochloride (corresponds to 14 mg vitamin B6; lOxNRV);4
(7) 0.002 g (2.00 mg) folic acid (vitamin B9; lOxNRV);4
(8) 0.025 g (25.00 mg) premix (0.1%) of cyanocobalamin (corresponds to 25 pg of vitamin B12; lOxNRV) on mannitol;4
(9) 43.146 g carbohydrate ingredient: sucrose, powderous; 5
(10) 20.00 g carbohydrate ingredient: fructose, crystalline, type Fruit 'n Sweet, milled;6 (11) 5.34 g citric acid, anhydrous, milled;7
(12) 4.67 g sodium hydrogencarbonate, powderous; 8
(13) 0.20 g lemon flavouring 7200PV;9
(14) 1.00 g colloidal silicon dioxide, type Aerosil 200F.10
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US) ; 4 DSM (NL) ; 5 Franck (HR) ; 6 Gadot Biochemical Industries Ltd (IL) ; 7 Laiwu Taihe Biochemistry Co. Ltd (CN) ; 8 AGZ (HR) ; 9 P.A. Aromatics (IT) ; 10 Evonik (DE) .
Preparation: To the ingredient (9), the ingredients (5-8) were added, and the mixture was homogenized in the V-blender for 15 minutes. To such an obtained premix, the ingredients (1-4) and (10-14) were added. The mixture was briefly (5 minutes) homogenized in the V-blender, and then de-agglomerated in mortar with a pestle. Then, the powderous mixture was additionally homogenized in the V-blender for 15 minutes. Such an obtained product was in the form of white powder, of fine odour resembling lemon.
Composition : 5% L-tyrosine; 10% L-tryptophan; 10% trimethylglycine; 0.1% (lOxNRV) zinc; lOxNRV vitamins B3, B6, B9, and B12.
The powder can be used as such or divided in the form of sachets containing 10 g each, of which 1-3 represent the recommended daily dosage: 500-1,500 mg L-tyrosine; 1,000-3,000 mg L-tryptophan; 1,000- 3,000 mg trimethylglycine; 10-30 mg (100-300% NRV) zinc; and 100-300% NRV vitamins B3, B6, B9, and B12.
It is used upon dissolution in water; a single 10 g sachet is added into a glass with 100 mL water, stirred and drunk.
Example 10. Preparation of the composition from the present invention in the form of capsules
Composition (100 g of mixture for capsules filling) :
(1) 280.00 g L-tyrosine;1 (2) 280.00 g L-tryptophan; 1
(3) 280.00 g trimethylglycine, type BetaPower; 2
(4) 45.50 g zinc citrate, trihydrate;3
(5) 22.55 g nicotinamide (vitamin B3);4
(6) 2.40 g pyridoxine hydrochloride (vitamin B6);4
(7) 0.30 g folic acid (vitamin B9);4
(8) 3.50 g premix (0.1%) of cyanocobalamin (corresponds to 3.5 mg vitamin B12) on mannitol;4
(9) 75.75 g maltodextrin, type Glucidex l5
(10) 10.00 g magnesium stearate, type LigaFood MF-2-V6
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jungbunzlauer (CH) ; 4 DSM (NL) ; 5 Roquette (FR) ; 6 Peter Greven (NL) .
Preparation: The previously weighed ingredients (1-9) were homogenized in the V-blender for 15 minutes. Then, the ingredient (10) was added, and the mixture was additionally homogenized for 3 minutes. Such an obtained product was in the form of fine white, almost odourless powder. The mixture was filled into white vegetable (HPMC) capsules size "0" (empty capsule weight is 95 mg; Capsugel; CH) using laboratory capsulation machine. This results in approx. 2.800 capsules of gross weight of 450 mg, and net mass of 355 mg.
Composition of each capsule: 100 mg L-tyrosine; 100 mg L-tryptophan; 100 mg trimethylglycine; 5 mg zinc; and 50% NRV vitamins B3, B6, B9, and B12.
The recommended daily dose is 3-9 capsules, what is equivalent to the intake of 300-900 mg L-tyrosine, 300-900 mg L-tryptophan, 300-900 mg trimethylglycine, 15-45 mg (150-450% NRV) zinc, and 150-450% NRV of vitamins B3, B6, B9, and B12.
Example 11. Preparation of the composition from the present invention in the form of syrup
Composition (100 g of syrup) : (1) 5.00 g L-tyrosine;1
(2) 5.00 g L-tryptophan; 1
(3) 5.00 g trimethylglycine, type BetaPower; 2
(4) 0.70 g zinc gluconate;3
(5) 0.16 g (160 mg) nicotinamide (vitamin B3; lOxNRV);4
(6) 0.017 g (17.00 mg) pyridoxine hydrochloride (corresponds to 14 mg vitamin B6; lOxNRV);4
(7) 0.002 g (2.00 mg) folic acid (vitamin B9; lOxNRV);4
(8) 0.025 g (25.00 mg) premix (0.1%) of cyanocobalamin (corresponds to 25 pg vitamin B12; lOxNRV) on mannitol;4
(9) 5.00 g glycerin;5
(10) 25.00 g carbohydrate ingredient: sucrose, crystalline;6
(11) 1.00 g citric acid, anhydrous;7
(12) 0.50 g potassium sorbate;8
(13) 0.30 g sodium benzoate;9
(14) 0.75 g xanthan gum, type Jungbunzlauer Xanthan Gum FN;10
(15) 0.25 g lemon flavour 7200PV;11
(16) 50.796 g purified water;
(17) 0.50 g aqueous solution (0.1%) of food colour tartrazine.
1 Gonmisol (ES) ; 2 DuPont Nutrition and Health (US) ; 3 Jost Chemicals (US); 4 DSM (NL) ; 5 Kemig (HR); 6 Secerana Zupanja (HR); 7 Laiwu Taihe Biochemistry Co. Ltd (CN) ; 8 Celanese (US); 9 Foodchem (CN) ; 10 Jungbunzlauer (CH) ; 11 R.D. Aromatics (IT) .
Preparation : The ingredients (11-13) and (14) were dissolved in the ingredient (16) by stirring at room temperature for 15 minutes. Such an obtained solution was heated to 40-45 °C, and then the ingredients (1-10), (15) and (17) were added, and the mixture was stirred for 15 minutes. Such an obtained product was additionally homogenized by stirring at room temperature from 40 °C to room temperature for 15-30 minutes. Such an obtained product was in the form of a viscous syrup- suspension of yellow colour, and agreeable flavour resembling lemon. Composition of syrup: 5% L-tyrosine; 5% L-tryptophan; 5% trimethylglycine ; 0.1% zinc.
The recommended daily dose is 1-3 x 10 ml of syrup, what is equivalent to the intake of 500-1,500 mg L-tyrosine, 500-1,500 mg L-tryptophan, 500-1,500 mg trimethylglycine, 10-30 mg (100-300% NRV) zinc, and 100- 300% NRV vitamins B3, B6, B9, and B12.
Example 12. Sensory study of the composition from the present invention from Examples 1 and 2 in the form of a powderous instant drink
As the model example for sensory testing of the composition from the present invention, for the demonstration of its efficacy in solving the technical problems mentioned earlier, the composition in the form of a powderous instant drink was selected, with the corresponding preparations described in:
Example 1: composition based on coffee; sachets containing 16 g each for the preparation of drink with 150 g milk; and,
Example 2: composition based on chicory root; sachets containing 15 g each for the preparation of drink with 150 g milk.
Test drinks were prepared with skimmed milk warmed to 80 °C, briefly stirred and evaluated according to the methodology common for this category of cappuccino-like products; see Table 2.
For both compositions from the present invention, a clean taste without any off-taste was observed. Other taste characteristics are: very sweet, milky, with a good level of mouthfullness . The tendency of foam generation and its stability are good. Full wettability of the powders and dissolution were observed only after stirring.
Tastes are:
Product from Example 1: clean rounded, coffee, nutty;
Product from Example 2: clean rounded, caramel, vanilla;
in both cases without a strong coffee note.
The results of physical and chemical properties of the drink prepared from the composition of the present invention (Examples 1 and 2) with skimmed milk, together with the results of the accompanying sensory study are concisely shown in Table 2. Conclusion
The composition from the present invention based on a specific combination of :
(1) amino acids L-tyrosine (1; TYR) and L-tryptophan (2; TRP) as metabolic precursors of neurotransmitters dopamine (DA) , norepinephrine (NE) and epinephrine (EN) as well as serotonin (SE) and neurohormone melatonin (ME) ;
(2) natural methylating agent trimethylglycine (3; TMG) ; in the presence of,
(3) zinc (in the form of pharmaceutically acceptable salt); and,
(4) complex of B vitamins: B3, B6, B9 and B12, and, optionally, vitamins Bl, B2, B5, and B7;
- acts unexpectedly efficiently as an agent for
(i) prevention and treatment of central nervous system disorders;
(ii) improvement of cognitive performances: memory, attention, and learning process;
(iii) mood improvement; including seasonal affective disorder;
increasing the feeling of well-being;
(iv) anti-stress activity;
(v) improvement of sleep quality;
(vi) decreasing tiredness and fatigue, and increasing energy and physical performances: strength and endurance;
(vii) prevention and treatment of liver diseases due to its hepatoprotective and detoxifying effects;
(viii) prevention and treatment of hyperhomocysteinemia, and thus for prevention and treatment of cardiovascular diseases and diabetes; and,
(ix) prevention and treatment of osteopenia and osteoporosis,
- thanks to:
A. synergic activity of active substances (1-4); and,
B. significant improvement of bioavailability of L-tyrosine (1) due to the use of its water solubility enhancer, the ingredient (xii), for example sodium bicarbonate (NaHCCb) ; - wherein the matrix of the composition from the present invention, e.g. a powderous base for an instant cappuccino-like drink, enables full sensory masking of bad tastes of active substances, the ingredients (vii)-(xi) of the composition.
For instance, the composition from the present invention in the form of an instant cappuccino-like drink, solves in a novel and inventive way the technical problem of:
(1) obtaining an improved product for:
(a) prevention and treatment of depression and anxiety; and
(b) improvement of cognitive performances: memory, attention, and learning process;
using natural active substances;
(2) very low water solubility of L-tyrosine (1; TYR) and, consequently, its poor bioavailability; and
(3) masking off-odours and off-flavours of certain natural active substances such as, e.g.
(a) bitter taste of amino acids L-tyrosine (1) and L-tryptophan
(2; TRP) ;
(b) astingent or metallic taste of zinc salts; and,
(c) off-odours and tastes of some B-vitamins;
- while retaining the full beneficial pharmacological profile of the composition from the present invention.
Industrial Applicability
The composition from the present invention is used for manufacturing functional food products, food supplements, or pharmaceutical products, intended for the prevention and treatment of central nervous system disorders, for the improvement of cognitive performances, mood improvement, anti-stress activity, and other useful beneficial nutritional and pharmacological effects. In this way, industrial applicability of the present invention is obvious.

Claims

1. A powderous composition which is added to water or milk for the preparation of a liquid functional drink with a taste and appearance similar to cappuccino, which consists of:
A. formulation of the base formed from the ingredients (i)-(vi) selected to be:
(i) roasted and milled seeds of coffee <Coffea species>, powderous; powderous or granulated instant roasted coffee; roasted and milled coffee substitute; wherein coffee substitute is selected from the group consisting of: chicory <Cichorium intybus L> root; barley <Hordeum vulgare L> seeds; barley malt; rye <Secale cereale L> seeds; rye malt; wheat <Triticum vulgare L> seeds; wheat malt; chickpea <Cicer arietinum L> seeds; dandelion <Taraxacum officinalis L> root; fig <Ficus carica L> fruit; carob <Ceratonia siliqua L> fruit; or mixtures of these ingredients;
(ii) fat; selected from the group consisting of: coconut fat, palm oil, hydrogenated palm oil, palm kernel oil, hydrogenated palm kernel oil, rapeseed oil, sunflower oil, soybean oil, cottonseed oil, milk fat, or mixtures of these ingredients;
(iii) food emulsifier for fat;
(iv) protein ingredient; selected from the group consisting of:
full fat or skimmed milk powder, milk proteins, whey proteins, plant proteins, or mixtures of these substances;
(v) carbohydrate ingredient; selected from the group consisting of: sugar, honey, glucose syrup, glucose- fructose syrup, fructose syrup, glucose, fructose, maltose, lactose, maltodextrin, dextrin, starch, inulin, oligofructose, full fat or skimmed milk powder, or mixtures of these substances; and,
(vi) food additives; which are required for the formation of desired technological properties of the present composition, selected from the group consisting of: salt <NaCl>, spices, flavours, emulsifier salts, food colours, preservatives, food acids, anti-caking agents, thickeners, sweeteners, taste enhancers, or mixtures of these substances; and
B. formulation of active substances consisting of the ingredients (vii)-(xi),
characterised by that the ingredients (vii)-(xi) are selected to be :
(vii) L-tyrosine <1> or its salts with pharmaceutically acceptable acids ;
Figure imgf000067_0001
(viii) L-tryptophan <2> or its salts with pharmaceutically acceptable acids;
Figure imgf000067_0002
2
(ix) trimethylglycine <3> , its salts with pharmaceutically acceptable acids, or plant extracts with >25% w/w trimethylglycine ;
Figure imgf000067_0003
3
(x) zinc in its pharmaceutically acceptable chemical form;
(xi) vitamins of B-complex selected from the group consisting of: niacin <B3>, pyridoxine <B6>, folic acid <B9> or its pharmaceutical equivalents, and vitamin B12; and, optionally, other vitamins of B-complex: thiamine <B1>, riboflavin <B2>, pantothenic acid <B5>, and biotin <B7>; where the solubility enhancer of L-tyrosine <1> is used as follows :
(xii) one or more food additives selected from the group consisting of: sodium carbonate <Na2CC>3>, sodium bicarbonate <NaHCC>3>, sodium sesquicarbonate <Na2C03*NaHCC>3*2H2C», potassium carbonate <K2CC>3>, potassium bicarbonate <KHCC>3>, or mixtures of these substances .
2. A powderous composition according to claim 1, wherein the food emulsifier for plant oils and fats, the ingredient (iii) , is selected from the group consisting of: polyoxyethylene <40> stearate <E431>; polysorbates <E432-435> like polysorbate 80 <E433>; mono- and diglycerides of fatty acids <E471>; acetate esters of mono- and diglycerides higher fatty acids <E472a>; lactate esters of mono- and diglycerides of higher fatty acids <E472b>; citrate esters of mono- and diglycerides of higher fatty acids <E472c>; tartrate esters of mono- and diglycerides of higher fatty acids <E472d>; mono- and diacetyl tartrate esters of mono- and diglycerides of higher fatty acids <E472e>; mixed acetate and tartrate esters of mono- and diglycerides of higher fatty acids <E472f>; sucrose esters of higher fatty acids <E473>; sucroglycerides <E474>; polyglycerol esters of higher fatty acids <E475>; polyglycerol polyricinoleate <E476>; thermally oxidized soybean oil treated with mono- and diglycerides of higher fatty acids <E479b>; sodium stearoyl-2-lactate <E481>; calcium stearoyl-2-lactate <E482>; sorbitan esters of higher fatty acids <E491-495>; or mixtures of the said emulsifiers.
3. A powderous composition according to claims 1 and 2, wherein, L- tyrosine, L-tryptophan, and trimethylglycine is used in the form of salts with pharmaceutically acceptable acids: citric; malic; tartaric; isocitric; lactic; pyruvic; aconitic; a-keto-glutaric; fumaric; gluconic; acetic; succinic; adipic; hydrochloric; sulphuric; phosphoric; or mixtures of these acids.
4. A powderous composition according to any of the claims 1-3, wherein the extract of sugar beet <Beta vulgaris L> is used as a source of trimethylglycine.
5 . A powderous composition according to any of the claims 1-4, wherein pharmaceutically acceptable zinc salt is selected from the group consisting of: zinc oxide; zinc carbonate; zinc sulphate; zinc chloride; zinc acetate; zinc phosphate; zinc gluconate; zinc lactate; zinc citrate; zinc malate; zinc glycinate; zinc aspartate; zinc a-keto-glutarate; hydrates of the said compounds; or mixtures of these zinc compounds.
6. A powderous composition according to any of claims 1-5, wherein chemical forms of B vitamins are selected from the group consisting of:
niacin <B3>: nicotinic acid, nicotinamide, or mixtures of these substances;
pyridoxine <B6>: pyridoxine hydrochloride, pyridoxine 5'- phosphate, pyridoxine dipalmitate, or mixtures of these substances ;
folic acid <B9>: folic or pteroyl-L-glutamic acid, dihydrofolic acid, tetrahydrofolic acid, 5- metiltetrahydrofolic acid, and folinic acid; salts of the said acids with pharmaceutically acceptable cations like sodium <Na+>, potassium <K+>, magnesium <Mg2+>, calcium <Ca2+>; or mixtures of these substances;
vitamin B12: cyanocobalamin, hydroxycobalamin, metilcobalamin, cobalamine or adenosyl-cobalamin; of mixtures of the said forms of vitamin B12;
and optionally:
thiamine <B1>: thiamine hydrochloride, thiamine mononitrate, or mixtures of these substances;
riboflavin <B2>: riboflavin, riboflavin 5 '-phosphate sodium salt ;
pantothenic acid <B5>: calcium D-pantothenate, sodium D- pantothenate , dexpanthenol ; and,
biotin <B7>: D-biotin.
7 A powderous composition according to any of the claims 1-6, wherein as a solubility enhancer of L-tyrosine <1>, the ingredient (xii), sodium bicarbonate <NaHCC>3> is used.
8. A powderous composition according to any of the claims 1-7, wherein the weight percentages <%, w/w> of the ingredients are as follows :
A. formulation of the base; 50-99% w/w; of the composition:
ingredient (i) : 5-25% w/w;
ingredient (ii) : 2-10% w/w;
ingredient (iii) 0.1-3% w/w;
ingredient (iv) : 2-30% w/w;
ingredient (v) : 10-90% w/w;
ingredient (vi) : 0.5-5% w/w; of which salt <NaCl> 0.1-
1% w/w; and,
formulation of active substances , 1-50% w/w; of the composition :
ingredient (vii) : 1-25% w/w;
ingredient (viii) 1-25% w/w;
ingredient (ix) : 0.1-25% w/w;
ingredient (x) : 0.1-5% w/w;
ingredient (xi) : 0.001-1% w/w each of the vitamins:
niacin <B3>, pyridoxine <B6>, folic acid <B9> and, optionally, other vitamins of B complex: thiamine <B1>, riboflavin <B2>, pantothenic acid <B5>, and biotin <B7>; and,
solubility enhancer of L-tyrosine <1>:
ingredient (xii) : 0.25-3% w/w.
9 A powderous composition according to claim 8, wherein the weight percentages <%, w/w> of the ingredients are as follows:
A. formulation of the base; 80-90% w/w;
ingredient (i) : 10-15% w/w;
ingredient (ii) : 5-10% w/w;
ingredient (iii) : 0.2-2% w/w; ingredient (iv) : 10-25% w/w;
ingredient (v) : 25-50% w/w;
ingredient (vi) : 0.5-5% w/w; of which salt <NaCl>
0.25-0.75% w/w; and,
B. formulation of active substances; 10-20% w/w;
ingredient (vii) : 2-5% w/w;
ingredient (viii ) : 1-5% w/w;
ingredient (ix) : 2-5% w/w;
ingredient (x) : 0.05-1% w/w;
ingredient (xi) : 0.001-0.1% w/w each of the vitamins:
niacin <B3>, pyridoxine <B6>, folic acid <B9> and, optionally, other vitamins of B complex: thiamine <B1>, riboflavin <B2>, pantothenic acid <B5>, and biotin <B7>; and,
solubility enhancer of L-tyrosine <1>:
ingredient (xii) : 0.5-2.0% w/w .
10. Use of the composition according to any of the claims 1-9 for:
(i) prevention and treatment of disorders of the central nervous system;
(ii) improvement of cognitive performances: memory, attention, and learning process;
(ill) mood improvement; including seasonal affective disorder;
increasing the feeling of well-being;
(iv) anti-stress activity;
(v) improvement of sleep quality;
(vi) decreasing tiredness and fatigue, and increasing energy and physical performances: strength and endurance;
(vii) prevention and treatment of liver diseases due to its hepatoprotective and detoxifying effects;
(viii) prevention and treatment of hyperhomocysteinemia, and thus for prevention and treatment of cardiovascular diseases and diabetes; and,
(ix) prevention and treatment of osteopenia and osteoporosis.
11. Use of the composition according to any of the claims 1-9 for prevention and treatment of disorders selected from the group consisting of: major depressive disorder, mood disorder, manic- depressive disorder, anxiety, anxiety-depressive disorder, post- traumatic stress disorder, sleep disorders, attention deficit disorder, attention deficit hyperactivity disorder, memory function disorder, seasonal affective disorder, autism, schizophrenia, dementia, Parkinson's disease, Huntington's disease, and Alzheimer's disease.
12. Use of the composition according to any of the claims 1-9, for prevention and treatment of major depressive disorder or depression-like symptoms.
13. Use of the composition according to any of the claims 10-12, in daily dosages of 2-3 x 10-20 g of powderous composition for the preparation of an instant cappuccino-like drink, where the said dosages are equivalent to the content of active substances as follows :
(i) L-tyrosine, 250-3,000 mg;
(ii) L-tryptophan, 250-3,000 mg;
(iii) trimethylglycine , 250-3, 000 mg;
(iv) pharmaceutically acceptable zinc salt equivalent to the zinc content 5-50 mg; and,
(v) vitamins from B-complex:
a. niacin <B3>, 8-80 mg;
b. vitamin B6, 0.7-100 mg;
c. folic acid <B9> or its pharmaceutical equivalent, 100- 1,500 pg;
d. vitamin B12, 1.25-1,000 pg; and, optionally, e. thiamine <B1>, 0.65-50 mg;
f. riboflavin <B2>, 0.7-50 mg;
g. pantothenic acid <B5>, 3-60 mg; and,
h. biotin <B7>, 25-250 pg.
PCT/EP2019/067924 2018-07-07 2019-07-03 Composition of powderous instant drink, its preparation and use WO2020011629A1 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
HRP20181063A 2018-07-07
HRP20181063 2018-07-07
HRP20191089 2019-06-17
HRP20191089A 2019-06-17

Publications (1)

Publication Number Publication Date
WO2020011629A1 true WO2020011629A1 (en) 2020-01-16

Family

ID=67262280

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/067924 WO2020011629A1 (en) 2018-07-07 2019-07-03 Composition of powderous instant drink, its preparation and use

Country Status (1)

Country Link
WO (1) WO2020011629A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114732132A (en) * 2020-12-21 2022-07-12 北京朗迪制药有限公司 Calcium-magnesium niacin liquid nutrient supplement for improving sleep and preparation method thereof
WO2022204561A1 (en) * 2021-03-25 2022-09-29 Brain Luxury Inc. A stable, emulsion-forming liquid composition comprising amino acids
WO2023209730A1 (en) * 2022-04-25 2023-11-02 Bhookhahaathi Hospitality Private Limited A nutraceutical composition of caffeine-free coffee and process to prepare the same

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4377595A (en) 1979-08-13 1983-03-22 Massachusetts Institute Of Technology Process for reducing depression
US4746527A (en) 1984-02-20 1988-05-24 Nestec S.A. Drink composition
US6294579B1 (en) 1999-10-11 2001-09-25 Joseph W. Carnazzo Method for improving delivery of tyrosine supplementation
EP1275399A2 (en) 2001-07-09 2003-01-15 N.V. Nutricia Method and preparation for preventing and/or treating vascular disorders and secondary disorders associated therewith
US20050256031A1 (en) * 1999-01-20 2005-11-17 Hageman Robert Johan J Composition for relieving discomfort
WO2007112524A1 (en) 2006-03-30 2007-10-11 De Souza Pereira Ricardo Dietary supplement for healing or regressing symptoms of gastroesophageal reflux disease, gastritis and ulcers
WO2008080333A1 (en) 2006-12-29 2008-07-10 Pficker Pharmaceuticals Ltd. Compound preparation for enhancing memory
WO2009051609A1 (en) 2007-10-19 2009-04-23 Pardee Joel D Metabolic enhancement therapy
US20130064803A1 (en) * 2011-09-14 2013-03-14 Naidu Lp BIO-REPLENISHMENT (BioRep) FOR COGNITIVE HEALTH
WO2014025905A1 (en) 2012-08-07 2014-02-13 Buck Institute For Research On Aging Multi-component formulation for improving neurological function
CN106083625A (en) 2016-05-31 2016-11-09 安徽工程大学 A kind of chemical modification method of tyrosine
CN107033369A (en) 2017-04-10 2017-08-11 中南林业科技大学 A kind of preparation method of the enteric solubility hybridized hydrogel based on tyrosine

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4377595A (en) 1979-08-13 1983-03-22 Massachusetts Institute Of Technology Process for reducing depression
US4746527A (en) 1984-02-20 1988-05-24 Nestec S.A. Drink composition
US20050256031A1 (en) * 1999-01-20 2005-11-17 Hageman Robert Johan J Composition for relieving discomfort
US6294579B1 (en) 1999-10-11 2001-09-25 Joseph W. Carnazzo Method for improving delivery of tyrosine supplementation
EP1275399A2 (en) 2001-07-09 2003-01-15 N.V. Nutricia Method and preparation for preventing and/or treating vascular disorders and secondary disorders associated therewith
WO2007112524A1 (en) 2006-03-30 2007-10-11 De Souza Pereira Ricardo Dietary supplement for healing or regressing symptoms of gastroesophageal reflux disease, gastritis and ulcers
WO2008080333A1 (en) 2006-12-29 2008-07-10 Pficker Pharmaceuticals Ltd. Compound preparation for enhancing memory
WO2009051609A1 (en) 2007-10-19 2009-04-23 Pardee Joel D Metabolic enhancement therapy
US20090104171A1 (en) * 2007-10-19 2009-04-23 Pardee Joel D Metabolic Enhancement Therapy
US20130064803A1 (en) * 2011-09-14 2013-03-14 Naidu Lp BIO-REPLENISHMENT (BioRep) FOR COGNITIVE HEALTH
WO2014025905A1 (en) 2012-08-07 2014-02-13 Buck Institute For Research On Aging Multi-component formulation for improving neurological function
CN106083625A (en) 2016-05-31 2016-11-09 安徽工程大学 A kind of chemical modification method of tyrosine
CN107033369A (en) 2017-04-10 2017-08-11 中南林业科技大学 A kind of preparation method of the enteric solubility hybridized hydrogel based on tyrosine

Non-Patent Citations (13)

* Cited by examiner, † Cited by third party
Title
"Monograph: Betaine", ALTERN. MED. REV., vol. 8, 2003, pages 193 - 196
"Monograph: L-Tryptophan", ALTERN. MED. REV., vol. 11, 2006, pages 52 - 56
"Monograph: L-Tyrosine", ALTERN. MED. REV., vol. 12, 2007, pages 364 - 368
"Monograph: Melatonin", ALTERN. MED. REV., vol. 10, 2005, pages 326 - 336
"The Merck Index - Encyclopedia of Chemicals, Drugs and Biologicals", 1996, MERCH & CO., INC., pages: 1677
A. A. BADAWY: "Tryptophan: the key to boosting brain serotonin synthesis in depressive illness", J. PSYCHOPHARMACOL., vol. 27, 2013, pages 878 - 893
A. J. GELENBERGC. J. GIBSON: "Tyrosine for the treatment of depression", NUTR. HEALTH, vol. 3, 1984, pages 163 - 173
B. J. JONGKEESB. HOMMELS. KUHNL. S. COLZATO: "Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands - A review", J. PSYCH. RES., vol. 70, 2015, pages 50 - 57
F. DIPIERROR. ORSIR. SETTEMBRE: "Role of betaine in improving the antidepressant effect of s-adenosyl-methionine in patients with mild-to-moderate depression", J. MULTIDISC. HEALTHCARE, vol. 8, 2015, pages 39 - 45
F. DIPIERROR. SETTEMBRE: "Preliminary results of a randomized controlled trial carried out with a fixed combination of s-adenosyl-L-methionine and betaine versus amitriptyline in patients with mild depression", INT. J. GEN. MED., vol. 8, 2015, pages 73 - 78
G. NOWAKB. SZEWCZYKA. PILC: "Zinc and depression. An update", PHARMACOL REP., vol. 57, 2005, pages 713 - 718, XP009139633
J. C. LINM. Y. LEEM. H. CHANY. C. CHENH. H. CHEN: "Betaine enhances antidepressant-like, but blocks psychotomimetic effects of ketamine in mice", PSYCHOPHARMACOL. (BERL., vol. 233, 2016, pages 3223 - 3235, XP036027444, DOI: doi:10.1007/s00213-016-4359-x
S. MEYERS: "Use of neurotransmitter precursors for treatment of depression", ALTERN. MED. REV., vol. 5, 2000, pages 64 - 71

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114732132A (en) * 2020-12-21 2022-07-12 北京朗迪制药有限公司 Calcium-magnesium niacin liquid nutrient supplement for improving sleep and preparation method thereof
WO2022204561A1 (en) * 2021-03-25 2022-09-29 Brain Luxury Inc. A stable, emulsion-forming liquid composition comprising amino acids
WO2023209730A1 (en) * 2022-04-25 2023-11-02 Bhookhahaathi Hospitality Private Limited A nutraceutical composition of caffeine-free coffee and process to prepare the same

Similar Documents

Publication Publication Date Title
RU2524645C2 (en) Orally soluble and/or effervescent compositions, containing at least one s-adenosylmethyonine (sam)
RU2333660C1 (en) Improved cocoa-containing mixtures
EP1782803B1 (en) Coenzyme q10-containing composition
ES2345067T3 (en) METHOD FOR USING GUAYABA EXTRACT AND COMPOSITION THAT INCLUDES GUAYABA EXTRACT.
RU2368248C1 (en) Mixture with reduced glycemic content and its containing product (versions)
WO2020011629A1 (en) Composition of powderous instant drink, its preparation and use
US20050276839A1 (en) Appetite satiation and hydration beverage
US20040071825A1 (en) Agglomerated granular protein-rich nutritional supplement
WO1993020718A1 (en) Food composition which inhibits formation of intestinal putrefaction product
US10441535B2 (en) Nutraceutical confectionary composition containing caffeine and L-theanine
EP2008531A1 (en) Composition for foods and drinks having improved hygroscopicity
US20190133147A1 (en) Confectionery product
WO2008022105A2 (en) Compositions and methods for nutrition supplementation
US20110123654A1 (en) Synergistic enhancement of cellular ergogenic nutrient uptake, like creatine or carnitine, with tarragon
US20070248648A1 (en) High protein, fatigue reducing powder
JP5224680B2 (en) Anti-fatigue
ES2263886T5 (en) Procedure for the manufacture of an enteral food containing isomaltulose
US20020150627A1 (en) Composition containing creatine and phosphorus
US20200129464A1 (en) Method and Composition for Increasing the Bioavailability of Carnitine
EP4309515A1 (en) Composition for promoting glp-1 secretion
EP4021508A1 (en) Formulations comprising arginine and/or a pharmaceutically acceptable salt thereof and an acid active ingredient with a pka of 1 -5
CA3188397A1 (en) Compositions and methods using xanthan gum to stabilize at least one urolithin in an aqueous matrix
CN117915902A (en) Nutritional composition
AU2002228484A1 (en) Composition containing creatine and phosphorus

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19739537

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19739537

Country of ref document: EP

Kind code of ref document: A1