WO2009056247A1 - Composition comprising polyunsaturated fatty acids and activated charcoal - Google Patents

Composition comprising polyunsaturated fatty acids and activated charcoal Download PDF

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Publication number
WO2009056247A1
WO2009056247A1 PCT/EP2008/008882 EP2008008882W WO2009056247A1 WO 2009056247 A1 WO2009056247 A1 WO 2009056247A1 EP 2008008882 W EP2008008882 W EP 2008008882W WO 2009056247 A1 WO2009056247 A1 WO 2009056247A1
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WO
WIPO (PCT)
Prior art keywords
composition
acid
pufa
tablet
activated charcoal
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2008/008882
Other languages
French (fr)
Inventor
Catherine Kabaradjian
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Consumer Care AG
Original Assignee
Bayer Consumer Care AG
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
Priority to PL08845987T priority Critical patent/PL2214638T3/en
Priority to AU2008317920A priority patent/AU2008317920B2/en
Priority to ES08845987T priority patent/ES2379034T3/en
Priority to BRPI0818568 priority patent/BRPI0818568A2/en
Priority to RU2010121714/15A priority patent/RU2485940C2/en
Priority to AT08845987T priority patent/ATE541560T1/en
Application filed by Bayer Consumer Care AG filed Critical Bayer Consumer Care AG
Priority to CA2703816A priority patent/CA2703816C/en
Priority to EP08845987A priority patent/EP2214638B1/en
Priority to MX2010003703A priority patent/MX2010003703A/en
Publication of WO2009056247A1 publication Critical patent/WO2009056247A1/en
Anticipated expiration legal-status Critical
Priority to US12/799,744 priority patent/US20100260893A1/en
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
    • A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
    • 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
    • A61K33/44—Elemental carbon, e.g. charcoal, carbon black
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • Composition comprising polyunsaturated fatty acids and activated charcoal
  • the present invention relates to an oral composition without bad odour, smell or taste comprising polyunsaturated fatty acids (PUFA) and activated charcoal, its process for preparation and its use as nutritional supplement or as dietary supplement for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases.
  • PUFA polyunsaturated fatty acids
  • Polyunsaturated fatty acids are the active ingredients e.g. in fish oil and are responsible for significant low blood lipid levels and low incidence of hypertension which was shown in a epidemiological study with Inuits (M.H. Davidson, P. R. Liebson, Cardiovascular Reviews&Reports 1986, 7, 461-472).
  • LDL low density lipoprotein cholesterol
  • HDL high density lipoprotein cholesterol
  • Coronary heart disease (CHD) is the major cause of death in the western countries and high plasma cholesterol levels, more specifically the LDL/HDL ratio, is highly correlated with the risk of CHD (Willett and Sacks, N. Eng. J. Med. 1991, 121, 324).
  • the PUFA found in fish oil have carbon chains of 18, 20 or 22 atoms and can be classified in n-3 omega and n-6 omega fatty acids which are essential for the human body.
  • omega-3 fatty acids eicosapentenoic acid (EPA) and docosahexenoic acid (DHA) are only found in fish and other marine life. Fish oil is therefore the most important food source for omega-3 fatty acids.
  • Standard nutritional supplement of PUFA is achieved by a daily administration of 500-1000 mg liquid fish oil.
  • the fish oil is normally administered in capsules in order to prevent the fishy smell and odour. Nevertheless some people experience gastrointestinal upset of the fishy smell even hours after the fish oil is taken. The reason is that after decomposition of the galantine wall in the gastro-intestinal tract, the voluminous dosage of the fish oil is released as a macroscopic drop which interfere with the resorption of the fish oil.
  • the problems of bad smell, odour and resorption can be solved in part by microdispersed fish oil preparations as pulverulent or aqueous matrix as described in EP 0 276 772. However, even the microdispersed fish oil granule or powder has a remaining fishy smell when pressed in simple tablets, so that flavours or antioxidants are needed to be added to the formulations.
  • flavours are used to domineer over the fishy smell of the fish oil as described e.g. in JP 08092587 or JP 08228678.
  • Taste masking is also achieved by adding milk products to the fish oil formulation as described e.g. in US 2003/0198728 or JP 2002-204656 or by coating or encapsulating the PUFA as described e.g. in WO 2004/016720 and WO 2005/029978.
  • the reason for the fishy smell of the fish oil is based on the oxidation of the unsaturated part of the PUFA.
  • antioxidants e.g. tocopherol can be added to the formulation as described e.g. in DE 20105126 or EP 1 155 620.
  • the object of the present invention is to provide an oral composition containing PUFA, having no bad odour or smell and avoiding a complex and expensive taste masking technology.
  • Subject of the present invention is an oral composition comprising polyunsaturated fatty acids (PUFA) and activated charcoal.
  • PUFA polyunsaturated fatty acids
  • the oral composition according to the invention has not a fishy or bad smell, odour or taste.
  • polyunsaturated fatty acids include, but are not limited to, fish oil, perilla oil, omega-3 fatty acids, omega-6-fatty acids, arachidonic acid, linoleic acid, alpha-linoleic acid, dihomogammalinoleic acid, eicosapentenoic acid (EPA), docosahexenoic acid (DHA) and mixtures thereof.
  • fish oil containing eicosapentenoic acid (EPA) and docosahexenoic acid (DHA) is used.
  • the composition according to the invention comprises PUFA, in particular fish oil powder or granulate, in an amount of 5 % to 70%, more preferable 40 % to 60 % by weight of the composition.
  • the total amount of the PUFA, in particular fish oil powder or granulate, used in the composition is 100 mg - 1000 mg, preferably 400 mg - 900 mg.
  • the composition according to the invention comprises eicosapentenoic acid (EPA) in an amount of 0.5 % to 10 %, preferably 1.5 % to 4 % by weight of the composition or in an amount of 1 % to 20 %, preferably 3 % to 8 % by weight of the fish oil powder or granulate contained in the composition.
  • EPA eicosapentenoic acid
  • the total amount of EPA in the composition is 10 mg - 100 mg, preferably 15 mg - 50 mg.
  • the composition according to the invention comprises docosahexenoic acid (DHA) in an amount of 0.5 % to 10 %, preferably 1 % to 4 % by weight of the composition or in an amount of 1 % to 20 %, preferably 2 % to 6 % by weight of the fish oil powder or granulate contained in the composition.
  • DHA docosahexenoic acid
  • the total amount of DHA in the composition is 10 mg - 50 mg, preferably 15 mg - 30 mg.
  • the PUFA in particular the fish oil containing eicosapentenoic acid (EPA) and docosahexenoic acid (DHA), is used preferably in a microdispersed form as a granulate or powder, in a pulverulent or aqueous matrix as described in EP 0 276 772. Preference is given to a fish oil granulate or powder.
  • EPA eicosapentenoic acid
  • DHA docosahexenoic acid
  • the pulverulant matrix of the fish oil powder or granulate comprises at least a homogenous protective colloid, a surfactant, optionally a diluent, stabilizer and further pharmaceutical excipients.
  • a homogenous protective colloid e.g., a surfactant, optionally a diluent, stabilizer and further pharmaceutical excipients.
  • the mentioned ingredients are used as an aqueous solution.
  • the protective colloids of the pulverulant matrix include but are not limited to polypeptides such as gelatine, casein, caseinate, polysaccharides such as starch, dextrin, pectin, Arabic gum, milk, milk powder, polyvinyl alcohols, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate-copolymers, acrylic acid- and methacrylic acid-copolymers with acrylic acid- or methacrylic acid esters, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginates or mixtures thereof.
  • polypeptides such as gelatine, casein, caseinate, polysaccharides such as starch, dextrin, pectin, Arabic gum, milk, milk powder, polyvinyl alcohols, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate-copolymers, acrylic acid- and methacrylic acid-copolymers with acrylic acid- or methacrylic acid
  • Diluents of the pulverulant matrix include but are not limited to sugar or sugar alcohols e.g. saccharose, lactose, invert sugar, sorbit, mannit or glycerine.
  • sugar or sugar alcohols e.g. saccharose, lactose, invert sugar, sorbit, mannit or glycerine.
  • Stabilizers of the pulverulant matrix include but are not limited to tocopherol, t-butyl hydroxytoluol, t-butyl hydroxyanisol and ethoxyquine.
  • Surfactants of the pulverulant matrix include but are not limited to esters of long chain fatty acids and ascorbic acid, esters of mono- and diglycerin and fatty acids and oxethylated derivatives thereof, esters of mono fatty acid glycerides with acetic acid, citric acid, lactic acid, diacetyltartrate, salts of 2-(2'-stearoyllactyl) lactic acid, poly glycerine fatty acid esters, sorbitan fatty acid esters, porpylenglycol-fatty acid esters, ascorbylpalmitate and lecithin.
  • the pulverulant matrix comprises fish oil in the amount of 5 % to 70 %, preferably 50 % to 60 %, one or more surfactants in an amount of 1 % to 30 %, preferably 5 % to 15 %, a protective colloid in an amount of 5 % to 50 %, preferably 10 % to 40 %, a diluent in an amount of 0 % to 70 %, preferably 3 % to 35 %, by weight of the dry mass of the fish oil powder or granulate.
  • the pulverulant matrix comprises the fish oil in small particles having an average particle size of less then 10 ⁇ m, more preferably less then 1 ⁇ m, most preferably less then 0.5 ⁇ m.
  • the fish oil powder or granulate can be prepared as described in EP 0 276 772.
  • the composition according to the invention comprises activated charcoal in an amount of 0.1 % up to 10 %, preferably 1 % up to 5 %, by weight of the composition.
  • the total amount used in the composition is 5 mg up to 200 mg, preferably 10 mg up to 100 mg.
  • the particles of the activated charcoal according to the present invention have preferably a portion of at least 90 % of particles having a particle size of less then 100 ⁇ m.
  • the function of the activated charcoal according to the invention is to adsorb the bad or fishy smell, odor or taste.
  • composition according to the invention can comprise further active ingredients such as vitamins and minerals.
  • Vitamins include, but are not limited to, vitamin A, beta carotene, vitamin C (ascorbic acid), vitamin D3 (cholecalcipherol), vitamin E (tocopherol acetate), vitamin Bl (thiamine), vitamin B2 (riboflavin), nicotinamide, vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), folic acid, vitamin B 12 (cyanocobalamin), vitamin Kl, vitamin K2, especially menaquinone 7-10, and biotin.
  • Minerals include, but are not limited to, iron salts, copper salts, calcium salts such as calcium carbonate, calcium phosphate, calcium glycerophosphate; magnesium salts such as magnesium phosphate, magnesium sulphate (dihydrate) or magnesium oxide; zinc salts such as zinc citrate; selenium salts such as sodium selenate; potassium iodide; manganese salts such as manganese sulphate; molybdate salts such as sodium molybdate; chromium salts such as chromium chloride; sodium chloride and potassium chloride.
  • the composition according to the present invention can be used as nutritional supplement or as dietary supplement for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases in a patient.
  • the inventive composition can also be used as nutritional or as dietary supplement for developing and maintaining the cognitive functions connected with e.g. eyes, memory, language etc. or for alleviating and/or preventing blood vessel diseases, cardiovascular, cerebrovascular and nervous diseases such as e.g. hypertension, cardiac infarction, Alzheimer, Parkinson and depression, or for alleviating hormonal, immunologic disorders or obesity.
  • it can be used as nutritional or dietary supplement to support treatments of diabetes, cancer and/or inflammatory affections.
  • a patient, for the purpose of this invention is a mammal, including a human.
  • the use as a nutritional or dietary supplement is especially preferred for pregnant women, children and elderly persons.
  • a further aspect of the invention is a method for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases, for developing and maintaining the cognitive functions connected with e.g. eyes, memory, language etc., for alleviating and/or preventing blood vessel diseases, cardiovascular, cerebrovascular and nervous diseases such as e.g. hypertension, cardiac infarction, Alzheimer, Parkinson and depression, or for alleviating hormonal, immunologic disorders or obesity or for supporting treatments of diabetes, cancer and/or inflammatory affections by administering the inventive composition as nutritional supplement or as dietary supplement to a patient which is, for the purpose of this invention, a mammal, including a human, especially pregnant women, children and elderly persons.
  • composition according to the invention is administered orally one or more, preferably up to three, more preferably up to two times per day. With each administration the number of dosage forms taken in at the same time should not exceed two.
  • ingredients of the oral dosage form are those which are accepted for pharmaceuticals and nutritional supplements and physiologically unobjectionable, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders (e.g. polyvinylpyrrolidone, gelatin, starch derivatives and cellulose derivatives), and all other excipients required to produce formulations of pharmaceuticals and nutritional supplements of the desired properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g.
  • lubricants magnesium stearate
  • disintegrants e.g.
  • crosslmked polyvinylpyrrolidone, sodium carboxymethylcellulose e.g. wetting agents (e.g. sodium lauryl sulphate), e.g. release-slowing agents (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. coloured pigments, e.g. effervescent couples.
  • wetting agents e.g. sodium lauryl sulphate
  • release-slowing agents e.g. cellulose derivatives, polyacrylic acid derivatives
  • coloured pigments e.g. effervescent couples.
  • composition according to the invention includes a tablet, a coated tablet, a multilayer tablet, a tablet with coated granules, a core tablet, a coat-core tablet or immediate, slow and timed release preparations. - o -
  • the composition is a tablet wherein the activated charcoal is dispersed in the matrix of the tablet, a three-layer tablet wherein the activated charcoal is in the two outer layers, or a coated tablet wherein the activated charcoal is in the coating.
  • Fig. 1 shows a three-layer tablet wherein the activated charcoal is in the two outer layers (1) and the PUFA is in the inner layer (2).
  • composition mentioned herein is produced by general standard processes.
  • tablets can be produced by mixing and/or granulating the active ingredients together with the excipients to form a blend which is finally pressed to tablets.
  • different blends containing different ingredients and excipients can be premixed and combined to a final blend which is then pressed to tablets, or the premixtures can be pressed to a multilayer tablet.
  • the acid/base couple can be added e.g. to final blend or the acid and the base are added at different times to the blend. Also the base and the acid can be added to different blends which are finally combined.
  • composition of the present invention is that there is not any bad or fishy smell, odor or taste, even after storage of several weeks, and the inventive composition can do without any flavour or antioxidant.
  • composition according to the present invention shows a good and/or fast resorption of the PUFA after administration of the composition. Furthermore, the composition facilitates a quick intake, optionally without water or drink.
  • composition according to the invention shows an acceptable hardness and friability to be manufactured without affecting the beadlet integrity, i.e. no PUFA exudates from the tablet matrix.
  • composition of the present invention is that for the preparation of the composition a complex and expensive taste masking technology known in the prior art such as coating of granules, adding of antioxidants, or putting the PUFA into a capsule is not needed.
  • the composition of the present invention can be prepared by simple and well-known standard procedures.
  • Another well-known taste masking method is the addition of flavours in order to cover and mask the bad smell. This taste masking method is normally restricted to only a few applicable flavours which have to be selected in each case.
  • flavouring ingredients are not needed for taste masking in the composition of the present invention. Examples:
  • a three-layered tablet according to Fig. 1 consisting of the two outer layers A and the inner layer B wherein the inner layer B consists of:
  • the ingredients of layer B are mixed together in a tumble mixer for 20 min. and 5 min. before the end the lubricant magnesium stearate is added to give the final blend 1 which is than filled into the feeder 1 of the device for multilayer tablet.
  • the ingredients of layer A are mixed together in a tumble mixer for 20 min. to give the final blend 2 which is than filled into the feeder 2 and 3 of the device for multilayer tablet.
  • the threelayer tablet is than pressed by a rotary press. - o -
  • a tablet consisting of:
  • a coated tablet consisting of a core consisting of: • 600 mg of dry fish oil powder (omega-3, 18:12) including 28.2 mg of EPA and 20 mg of DHA
  • All ingredients of the core are mixed together in a tumble mixer for 20 min. and optionally 5 min. before the end the lubricant magnesium stearate is added.
  • the blend is pressed into tablets with a rotary press. Thereafter the tablets are coated with a coating suspension consisting of activated charcoal, shellac, hydroxypropylmethylcellulose, triacetine and purified water
  • Examples 1, 2 and 3 do not show any bad or fishy taste or smell.

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Abstract

The present invention relates to an oral composition without bad odour, smell or taste comprising polyunsaturated fatty acids (PUFA) and activated charcoal, its process for preparation and its use as nutritional supplement or as dietary supplement for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases.

Description

Composition comprising polyunsaturated fatty acids and activated charcoal
The present invention relates to an oral composition without bad odour, smell or taste comprising polyunsaturated fatty acids (PUFA) and activated charcoal, its process for preparation and its use as nutritional supplement or as dietary supplement for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases.
Polyunsaturated fatty acids (PUFA) are the active ingredients e.g. in fish oil and are responsible for significant low blood lipid levels and low incidence of hypertension which was shown in a epidemiological study with Inuits (M.H. Davidson, P. R. Liebson, Cardiovascular Reviews&Reports 1986, 7, 461-472). In particular the blood concentration of the low density lipoprotein cholesterol (LDL) is lowered and that of the high density lipoprotein cholesterol (HDL) is increased. Coronary heart disease (CHD) is the major cause of death in the western countries and high plasma cholesterol levels, more specifically the LDL/HDL ratio, is highly correlated with the risk of CHD (Willett and Sacks, N. Eng. J. Med. 1991, 121, 324).
The PUFA found in fish oil have carbon chains of 18, 20 or 22 atoms and can be classified in n-3 omega and n-6 omega fatty acids which are essential for the human body. In particular the omega-3 fatty acids eicosapentenoic acid (EPA) and docosahexenoic acid (DHA) are only found in fish and other marine life. Fish oil is therefore the most important food source for omega-3 fatty acids.
Standard nutritional supplement of PUFA is achieved by a daily administration of 500-1000 mg liquid fish oil. The fish oil is normally administered in capsules in order to prevent the fishy smell and odour. Nevertheless some people experience gastrointestinal upset of the fishy smell even hours after the fish oil is taken. The reason is that after decomposition of the galantine wall in the gastro-intestinal tract, the voluminous dosage of the fish oil is released as a macroscopic drop which interfere with the resorption of the fish oil. The problems of bad smell, odour and resorption can be solved in part by microdispersed fish oil preparations as pulverulent or aqueous matrix as described in EP 0 276 772. However, even the microdispersed fish oil granule or powder has a remaining fishy smell when pressed in simple tablets, so that flavours or antioxidants are needed to be added to the formulations.
The flavours are used to domineer over the fishy smell of the fish oil as described e.g. in JP 08092587 or JP 08228678. Taste masking is also achieved by adding milk products to the fish oil formulation as described e.g. in US 2003/0198728 or JP 2002-204656 or by coating or encapsulating the PUFA as described e.g. in WO 2004/016720 and WO 2005/029978. The reason for the fishy smell of the fish oil is based on the oxidation of the unsaturated part of the PUFA. In order to prevent oxidation and to stabilize the PUFA antioxidants e.g. tocopherol can be added to the formulation as described e.g. in DE 20105126 or EP 1 155 620.
The object of the present invention is to provide an oral composition containing PUFA, having no bad odour or smell and avoiding a complex and expensive taste masking technology.
Surprisingly it is found that a bad or fishy smell of the composition according to the present invention can be avoided.
Subject of the present invention is an oral composition comprising polyunsaturated fatty acids (PUFA) and activated charcoal. The oral composition according to the invention has not a fishy or bad smell, odour or taste.
According to the present invention polyunsaturated fatty acids (PUFA) include, but are not limited to, fish oil, perilla oil, omega-3 fatty acids, omega-6-fatty acids, arachidonic acid, linoleic acid, alpha-linoleic acid, dihomogammalinoleic acid, eicosapentenoic acid (EPA), docosahexenoic acid (DHA) and mixtures thereof. Preference is given to fish oil, omega-3 fatty acids, eicosapentenoic acid (EPA), docosahexenoic acid (DHA) and mixtures thereof. Most preferably fish oil containing eicosapentenoic acid (EPA) and docosahexenoic acid (DHA) is used.
In a preferred embodiment the composition according to the invention comprises PUFA, in particular fish oil powder or granulate, in an amount of 5 % to 70%, more preferable 40 % to 60 % by weight of the composition. The total amount of the PUFA, in particular fish oil powder or granulate, used in the composition is 100 mg - 1000 mg, preferably 400 mg - 900 mg.
In a most preferred embodiment the composition according to the invention comprises eicosapentenoic acid (EPA) in an amount of 0.5 % to 10 %, preferably 1.5 % to 4 % by weight of the composition or in an amount of 1 % to 20 %, preferably 3 % to 8 % by weight of the fish oil powder or granulate contained in the composition. The total amount of EPA in the composition is 10 mg - 100 mg, preferably 15 mg - 50 mg.
In a most preferred embodiment the composition according to the invention comprises docosahexenoic acid (DHA) in an amount of 0.5 % to 10 %, preferably 1 % to 4 % by weight of the composition or in an amount of 1 % to 20 %, preferably 2 % to 6 % by weight of the fish oil powder or granulate contained in the composition. The total amount of DHA in the composition is 10 mg - 50 mg, preferably 15 mg - 30 mg. The PUFA, in particular the fish oil containing eicosapentenoic acid (EPA) and docosahexenoic acid (DHA), is used preferably in a microdispersed form as a granulate or powder, in a pulverulent or aqueous matrix as described in EP 0 276 772. Preference is given to a fish oil granulate or powder.
In a preferred embodiment the pulverulant matrix of the fish oil powder or granulate comprises at least a homogenous protective colloid, a surfactant, optionally a diluent, stabilizer and further pharmaceutical excipients. In the case of the aqueous matrix the mentioned ingredients are used as an aqueous solution.
The protective colloids of the pulverulant matrix include but are not limited to polypeptides such as gelatine, casein, caseinate, polysaccharides such as starch, dextrin, pectin, Arabic gum, milk, milk powder, polyvinyl alcohols, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate-copolymers, acrylic acid- and methacrylic acid-copolymers with acrylic acid- or methacrylic acid esters, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginates or mixtures thereof.
Diluents of the pulverulant matrix include but are not limited to sugar or sugar alcohols e.g. saccharose, lactose, invert sugar, sorbit, mannit or glycerine.
Stabilizers of the pulverulant matrix include but are not limited to tocopherol, t-butyl hydroxytoluol, t-butyl hydroxyanisol and ethoxyquine.
Surfactants of the pulverulant matrix include but are not limited to esters of long chain fatty acids and ascorbic acid, esters of mono- and diglycerin and fatty acids and oxethylated derivatives thereof, esters of mono fatty acid glycerides with acetic acid, citric acid, lactic acid, diacetyltartrate, salts of 2-(2'-stearoyllactyl) lactic acid, poly glycerine fatty acid esters, sorbitan fatty acid esters, porpylenglycol-fatty acid esters, ascorbylpalmitate and lecithin.
The pulverulant matrix comprises fish oil in the amount of 5 % to 70 %, preferably 50 % to 60 %, one or more surfactants in an amount of 1 % to 30 %, preferably 5 % to 15 %, a protective colloid in an amount of 5 % to 50 %, preferably 10 % to 40 %, a diluent in an amount of 0 % to 70 %, preferably 3 % to 35 %, by weight of the dry mass of the fish oil powder or granulate.
In a preferred embodiment the pulverulant matrix comprises the fish oil in small particles having an average particle size of less then 10 μm, more preferably less then 1 μm, most preferably less then 0.5 μm.
The fish oil powder or granulate can be prepared as described in EP 0 276 772. The composition according to the invention comprises activated charcoal in an amount of 0.1 % up to 10 %, preferably 1 % up to 5 %, by weight of the composition. The total amount used in the composition is 5 mg up to 200 mg, preferably 10 mg up to 100 mg.
The particles of the activated charcoal according to the present invention have preferably a portion of at least 90 % of particles having a particle size of less then 100 μm.
The function of the activated charcoal according to the invention is to adsorb the bad or fishy smell, odor or taste.
The composition according to the invention can comprise further active ingredients such as vitamins and minerals. Vitamins include, but are not limited to, vitamin A, beta carotene, vitamin C (ascorbic acid), vitamin D3 (cholecalcipherol), vitamin E (tocopherol acetate), vitamin Bl (thiamine), vitamin B2 (riboflavin), nicotinamide, vitamin B5 (pantothenic acid), vitamin B6 (pyridoxine), folic acid, vitamin B 12 (cyanocobalamin), vitamin Kl, vitamin K2, especially menaquinone 7-10, and biotin. Minerals include, but are not limited to, iron salts, copper salts, calcium salts such as calcium carbonate, calcium phosphate, calcium glycerophosphate; magnesium salts such as magnesium phosphate, magnesium sulphate (dihydrate) or magnesium oxide; zinc salts such as zinc citrate; selenium salts such as sodium selenate; potassium iodide; manganese salts such as manganese sulphate; molybdate salts such as sodium molybdate; chromium salts such as chromium chloride; sodium chloride and potassium chloride.
The composition according to the present invention can be used as nutritional supplement or as dietary supplement for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases in a patient. The inventive composition can also be used as nutritional or as dietary supplement for developing and maintaining the cognitive functions connected with e.g. eyes, memory, language etc. or for alleviating and/or preventing blood vessel diseases, cardiovascular, cerebrovascular and nervous diseases such as e.g. hypertension, cardiac infarction, Alzheimer, Parkinson and depression, or for alleviating hormonal, immunologic disorders or obesity. Furthermore, it can be used as nutritional or dietary supplement to support treatments of diabetes, cancer and/or inflammatory affections. A patient, for the purpose of this invention, is a mammal, including a human. The use as a nutritional or dietary supplement is especially preferred for pregnant women, children and elderly persons.
A further aspect of the invention is a method for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases, for developing and maintaining the cognitive functions connected with e.g. eyes, memory, language etc., for alleviating and/or preventing blood vessel diseases, cardiovascular, cerebrovascular and nervous diseases such as e.g. hypertension, cardiac infarction, Alzheimer, Parkinson and depression, or for alleviating hormonal, immunologic disorders or obesity or for supporting treatments of diabetes, cancer and/or inflammatory affections by administering the inventive composition as nutritional supplement or as dietary supplement to a patient which is, for the purpose of this invention, a mammal, including a human, especially pregnant women, children and elderly persons.
The composition according to the invention is administered orally one or more, preferably up to three, more preferably up to two times per day. With each administration the number of dosage forms taken in at the same time should not exceed two.
Nevertheless, it may in some cases be advantageous to deviate from the amounts specified, depending on body weight, individual behaviour toward the active ingredient, type of preparation and time or interval over which the administration is effected. For instance, less than the aforementioned minimum amounts may be sufficient in some cases, while the upper limit specified has to be exceeded in other cases.
Ingredients of the oral dosage form are those which are accepted for pharmaceuticals and nutritional supplements and physiologically unobjectionable, for example: as fillers cellulose derivatives (e.g. microcrystalline cellulose), sugars (e.g. lactose), sugar alcohols (e.g. mannitol, sorbitol), inorganic fillers (e.g. calcium phosphates), binders (e.g. polyvinylpyrrolidone, gelatin, starch derivatives and cellulose derivatives), and all other excipients required to produce formulations of pharmaceuticals and nutritional supplements of the desired properties, e.g. lubricants (magnesium stearate), e.g. disintegrants (e.g. crosslmked polyvinylpyrrolidone, sodium carboxymethylcellulose), e.g. wetting agents (e.g. sodium lauryl sulphate), e.g. release-slowing agents (e.g. cellulose derivatives, polyacrylic acid derivatives), e.g. coloured pigments, e.g. effervescent couples.
Excipients for pharmaceuticals and nutritional supplements familiar to the skilled person are also described for example in the following handbook: "Handbook of Pharmaceutical Excipients", Rowe R.C., Sheskey PJ. & Weller, P.J., American Pharmaceutical Association, Washington, 4th edition 2003.
The composition according to the invention includes a tablet, a coated tablet, a multilayer tablet, a tablet with coated granules, a core tablet, a coat-core tablet or immediate, slow and timed release preparations. - o -
Preference is given to a tablet, a coated tablet or a multilayer tablet. Most preferably the composition is a tablet wherein the activated charcoal is dispersed in the matrix of the tablet, a three-layer tablet wherein the activated charcoal is in the two outer layers, or a coated tablet wherein the activated charcoal is in the coating.
Fig. 1 shows a three-layer tablet wherein the activated charcoal is in the two outer layers (1) and the PUFA is in the inner layer (2).
The composition mentioned herein is produced by general standard processes. E.g. tablets can be produced by mixing and/or granulating the active ingredients together with the excipients to form a blend which is finally pressed to tablets. Optionally different blends containing different ingredients and excipients can be premixed and combined to a final blend which is then pressed to tablets, or the premixtures can be pressed to a multilayer tablet. In the case of an effervescent formulation the acid/base couple can be added e.g. to final blend or the acid and the base are added at different times to the blend. Also the base and the acid can be added to different blends which are finally combined.
Advantage of the composition of the present invention is that there is not any bad or fishy smell, odor or taste, even after storage of several weeks, and the inventive composition can do without any flavour or antioxidant.
The composition according to the present invention shows a good and/or fast resorption of the PUFA after administration of the composition. Furthermore, the composition facilitates a quick intake, optionally without water or drink.
The composition according to the invention shows an acceptable hardness and friability to be manufactured without affecting the beadlet integrity, i.e. no PUFA exudates from the tablet matrix.
Advantage of the composition of the present invention is that for the preparation of the composition a complex and expensive taste masking technology known in the prior art such as coating of granules, adding of antioxidants, or putting the PUFA into a capsule is not needed. The composition of the present invention can be prepared by simple and well-known standard procedures. Another well-known taste masking method is the addition of flavours in order to cover and mask the bad smell. This taste masking method is normally restricted to only a few applicable flavours which have to be selected in each case. However, flavouring ingredients are not needed for taste masking in the composition of the present invention. Examples:
Example 1:
A three-layered tablet according to Fig. 1 consisting of the two outer layers A and the inner layer B wherein the inner layer B consists of:
• 600 mg of dry fish oil powder (omega-3, 18:12) including 28.2 mg of EPA and 20 mg of
DHA
• 64 mg of anhydrous dibasic calcium phosphate
• 40 mg of cyclodextrin
• 40 mg ofhydroxypropylcellulose
• 40 mg of bentonite
• 4 mg of silicon dioxide
• 4 mg of magnesium stearate
• 8 mg of desodorized rosemary extract
and the two outer layer A consists each of:
» 25 mg of activated charcoal (90% of the particles have a particle size less then 100 μm, loss on ignition at 6000C: .=1%, loss on drying: <10%)
• 25 mg of hydroxypropylcellulose
• 50 mg of microcrystalline cellulose
manufacturing process of example 1:
The ingredients of layer B are mixed together in a tumble mixer for 20 min. and 5 min. before the end the lubricant magnesium stearate is added to give the final blend 1 which is than filled into the feeder 1 of the device for multilayer tablet. The ingredients of layer A are mixed together in a tumble mixer for 20 min. to give the final blend 2 which is than filled into the feeder 2 and 3 of the device for multilayer tablet. The threelayer tablet is than pressed by a rotary press. - o -
Example 2:
A tablet consisting of:
• 600 mg of dry fish oil powder (omega-3, 18:12) including 28.2 mg of EPA and 20 mg of DHA
• 64 mg of anhydrous dibasic calcium phosphate
• 40 mg of cyclodextrin
• 40 mg of hydroxypropylcellulose
• 40 mg of bentonite
» 4 mg of silicon dioxide
• 4 mg of magnesium stearate
• 8 mg of desodorized rosemary extract
• 50 mg of activated charcoal (90% of the particles have a particle size less then 100 μm, loss on ignition at 6000C: ^ %, loss on drying: <10%)
• 50 mg of hydroxypropylcellulose
• lOO mg of microcrystalline cellulose
manufacturing process of example 2:
Direct compression process :
All ingredients are mixed together in a tumble mixer for 20 min. and optionally 5 min. before the end the lubricant magnesium stearate is added. The final blend is pressed into tablets with a rotary press.
Example 3:
A coated tablet consisting of a core consisting of: • 600 mg of dry fish oil powder (omega-3, 18:12) including 28.2 mg of EPA and 20 mg of DHA
• 348 mg of anhydrous dibasic calcium phosphate
• 48 mg of cyclodextrin
» 60 mg of hydroxypropylcellulose
• 60 mg of bentonite
• 60 mg of povidone (kollidon VA 60 fine)
• 6 mg of silicon dioxide
• 6 mg of magnesium stearate
» 12 mg of desodorized rosemary extract
and a coating consisting of:
• 15.5 mg of activated charcoal(90% of the particles have a particle size less then 100 μm, loss on ignition at 6000C: ≤%, loss on drying: ≤10%)
• 15 mg of schellac
• 22.5 mg of hydroxypropylmethylcellulose
• 9 mg of triacetine
manufacturing process of example 3:
All ingredients of the core are mixed together in a tumble mixer for 20 min. and optionally 5 min. before the end the lubricant magnesium stearate is added. The blend is pressed into tablets with a rotary press. Thereafter the tablets are coated with a coating suspension consisting of activated charcoal, shellac, hydroxypropylmethylcellulose, triacetine and purified water
Results:
Examples 1, 2 and 3 do not show any bad or fishy taste or smell.

Claims

What is claimed is:
1. Oral composition comprising polyunsaturated fatty acids (PUFA) and activated charcoal.
2. Composition of claim 1 without fishy or bad smell, odour or taste.
3. Composition of claim 1 or 2, wherein the PUFA are fish oil, perilla oil, omega-3 fatty acids, omega-6-fatty acids, arachidonic acid, linoleic acid, alpha-linoleic acid, dihomogammalinoleic acid, eicosapentenoic acid (EPA), docosahexenoic acid (DHA) or mixtures thereof.
4. Composition of claim 1 or 3, wherein the PUFA are fish oil containing eicosapentenoic acid (EPA) and docosahexenoic acid (DHA).
5. Composition of claim 1 or 4, wherein the PUFA are fish oil powder or granulate.
6. Composition of any of claims 1 to 5, wherein the amount of the PUFA is of 5 % to 70% by weight of the composition.
7. Composition of any of claims 1 to 6, wherein the amount of the PUFA in the composition is 100 mg - 1000 mg.
8. Composition of any of claims 1 to 7 comprising at least one further mineral and/or vitamin.
9. Composition of any of claims 1 to 8 which is an oral nutritional or dietary supplement.
10. Composition of any of claims 1 to 9 which is a tablet, a coated tablet or a multilayer tablet.
11. Composition of any of claims 1 to 10 which is a tablet wherein the activated charcoal is dispersed in the matrix of the tablet.
12. Composition of any of claims 1 to 11 which is a three-layer tablet wherein the activated charcoal is in the two outer layers.
13. Composition of any of claims 1 to 12 which is a coated tablet wherein the activated charcoal is in the coating.
14. Process for manufacturing of the composition according to any of claims 1 to 13.
15. Use of a composition according to any of claims 1 to 13 as nutritional supplement or as dietary supplement for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases, for developing and maintaining the cognitive functions, for alleviating and/or preventing blood vessel diseases, cardiovascular, cerebrovascular and nervous diseases, for alleviating hormonal, immunologic disorders or obesity, for supporting treatments of diabetes, cancer and/or inflammatory affections.
16. Method for balancing the blood lipid level, preventing or reducing the risk of the development of atherosclerotic changes, disorders or diseases, for developing and maintaining the cognitive functions, for alleviating and/or preventing blood vessel diseases, cardiovascular, cerebrovascular and nervous diseases, for alleviating hormonal, immunologic disorders or obesity, for supporting treatments of diabetes, cancer and/or inflammatory affections wherein the composition according to any of claims 1 to 13 is administered as nutritional supplement or as dietary supplement.
PCT/EP2008/008882 2007-10-30 2008-10-21 Composition comprising polyunsaturated fatty acids and activated charcoal Ceased WO2009056247A1 (en)

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BRPI0818568 BRPI0818568A2 (en) 2007-10-30 2008-10-21 Composition comprising polyunsaturated fatty acids and activated carbon, their manufacturing process and their uses
RU2010121714/15A RU2485940C2 (en) 2007-10-30 2008-10-21 Composition containing polyunsaturated fatty acids and activated carbon
PL08845987T PL2214638T3 (en) 2007-10-30 2008-10-21 Composition comprising polyunsaturated fatty acids and activated charcoal
MX2010003703A MX2010003703A (en) 2007-10-30 2008-10-21 Composition comprising polyunsaturated fatty acids and activated charcoal.
AT08845987T ATE541560T1 (en) 2007-10-30 2008-10-21 COMPOSITION WITH POLYUNSATURATED FATTY ACIDS AND ACTIVATED CHARCOAL
EP08845987A EP2214638B1 (en) 2007-10-30 2008-10-21 Composition comprising polyunsaturated fatty acids and activated charcoal
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CN105919946A (en) * 2016-05-31 2016-09-07 福格森（武汉）生物科技股份有限公司 Preparation method of DHA pellet
WO2018109059A1 (en) * 2016-12-15 2018-06-21 Dsm Ip Assets B.V. Blend formulation comprising silicate and microbial and / or plant cells comprising a polyunsaturated fatty acid having at least 20 carbon atoms (lc-pufa)
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ES2379034T3 (en) 2012-04-20
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RU2010121714A (en) 2011-12-10
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AR070759A1 (en) 2010-05-05
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TW200942229A (en) 2009-10-16

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