WO2000054838A1 - Composition contenant du calcium - Google Patents

Composition contenant du calcium Download PDF

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Publication number
WO2000054838A1
WO2000054838A1 PCT/GB2000/000986 GB0000986W WO0054838A1 WO 2000054838 A1 WO2000054838 A1 WO 2000054838A1 GB 0000986 W GB0000986 W GB 0000986W WO 0054838 A1 WO0054838 A1 WO 0054838A1
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WIPO (PCT)
Prior art keywords
composition
vitamin
calcium
triglyceride
emulsion
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PCT/GB2000/000986
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English (en)
Inventor
Jan Yngvar Piene
Original Assignee
Nycomed Pharma As
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Publication date
Application filed by Nycomed Pharma As filed Critical Nycomed Pharma As
Priority to AU33050/00A priority Critical patent/AU3305000A/en
Publication of WO2000054838A1 publication Critical patent/WO2000054838A1/fr

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    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
    • A23L2/385—Concentrates of non-alcoholic beverages
    • 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
    • A23L33/16—Inorganic salts, minerals or trace elements
    • 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
    • A23L5/00—Preparation or treatment of foods or foodstuffs, in general; Food or foodstuffs obtained thereby; Materials therefor
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61P3/02—Nutrients, e.g. vitamins, minerals
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to a calcium and vitamin D formulation in liquid form, for example a syrup or a liquid concentrate, and to a process for its manufacture .
  • Calcium carbonate tablets are widely used as a source of the essential nutrient calcium, especially for individuals in periods of rapid growth (e.g. in infancy or adolescence) , or those suffering from or at risk of osteoporosis .
  • Calcium uptake is reduced in patients with vitamin D deficiency and accordingly calcium carbonate is often formulated together with vitamin D, e.g. as in the Orocal-Vitamin D 3 tablets of Theramex (Monaco) .
  • the calcium dosage desired for an individual may vary depending on age and condition, and since the calcium tablets available commercially are rather large (e.g. about 1.7 to 2.5g m weight per tablet) , it is desirable to provide such calcium and vitamin D supplements m an acceptable liquid form, e.g. as a syrup or as a liquid concentrate for dilution before consumption.
  • an acceptable liquid form e.g. as a syrup or as a liquid concentrate for dilution before consumption.
  • Formulating calcium and vitamin D m a liquid composition however provides its own problems, m particular related to the stability of the vitamin D. Thus typically vitamin D activity de. content) of such liquid compositions deteriorates rapidly.
  • Calcium and vitamin D supplement products need to be storage stable for prolonged periods m order to be commercially viable and m order for the user to receive tne desired dosages of calcium and vitamin D.
  • vitamin D deterioration may be compensated for by use of an "overage", a higher initial vitamin D content; however, the overage must De relatively small (e.g. 10% or less) otherwise doses received when using relatively fresh product would be above the desired levels .
  • the invention provides a liquid emulsion composition having a continuous aqueous phase containing a viscosity modifier and a dissolved physiologically tolerable calcium compound, and a discontinuous triglyceride phase comprising vitamin D and an edible triglyceride, said emulsion composition further containing at least one emulsifying agent selected from edible phospholipids and fatty acid esters .
  • the edible triglyceride is preferably a fish oil or more preferably a plant oil, optionally wholly or partially hydrogenated, e.g. coconut oil, soybean oil, rape seed oil, sunflower oil, safflower oil, mustard seed oil, olive oil, etc.
  • the oil will be one rich m relatively short fatty acid chains, e.g. having a high abundance of C 6 to C 18 or more preferably C 8 to C 12 fatty acid residues.
  • the weight average fatty acid carbon content is m the range C 8 to C 12 .
  • Fatty acid profiles can be adjusted as desired by fractionating plant oil or by mixing plant oils from different sources. Highly unsaturated fatty acids are m general not preferred.
  • the edible triglyceride preferably constitutes up to 5% by weight of the total composition, more preferably up to 3% by weight, still more preferably up to 1% by weight, e.g. 0.1 to 0.5% by weight.
  • the edible triglyceride is preferably used m a ratio of 1000 000 IU vitamin D to 50 to 400g, more preferably 175 to 300g, especially 190 to 250g, more especially 200 to 225g triglyceride.
  • fatty acid ester emulsifying agents may be used, e.g. esters of fatty acids (e.g. C 16 _ 22 , especially C 18 fatty acids) and polyhyd ⁇ c alcohols (especially C 6 alcohols) or polyoxyethylated derivatives thereof, in particular the span and tween non-ionic surfactants, especially polysorbate 80 (i.e. Tween 80).
  • esters of fatty acids e.g. C 16 _ 22 , especially C 18 fatty acids
  • polyhyd ⁇ c alcohols especially C 6 alcohols
  • polyoxyethylated derivatives thereof in particular the span and tween non-ionic surfactants, especially polysorbate 80 (i.e. Tween 80).
  • polysorbate 80 i.e. Tween 80
  • the phospholipid used m the compositions of the invention is preferably a glycerophospholipid, a lysophospholipid or a sphmgophospholipid, e.g. a sphmgomyelin (SPH) , cerebroside or ganglioside.
  • a glycerophospholipid e.g. a sphmgomyelin (SPH) , cerebroside or ganglioside.
  • SPH sphmgomyelin
  • glycerophospholipids examples include phosphatidic acids (PA) , phosphatidylethanola mes (PE) , phosphatidylcholmes (PC) , phosphatidyl-glycero- phosphates , N-acyl-phosphatidyl-ethanolammes , pnosphati ⁇ ylsermes (PS) , phosphatidylmositols (PI) , pnosphatidylglycerols, diphosphatidylglycerols and plasmalogens .
  • PA phosphatidic acids
  • PE phosphatidylethanola mes
  • PC phosphatidylcholmes
  • PS phosphatidyl-glycero- phosphates
  • N-acyl-phosphatidyl-ethanolammes pnosphati ⁇ ylsermes
  • PS phosphatidylmositols
  • PI phosphatidylmosito
  • lysophospholipids examples include lysophosphatidylcholmes , lysophosphotidylethanolammes , lysophosphatidylmositols, lysophosphatidylsermes, lysophosphatidylglycerols , lysophosphatidylglycerophosphates, lysodiphosphatidylglycerols, lyso-N-acyl- phosphatidylethanolammes and lysophosphatidic acids
  • Glycerophospholipids for example phosphatidylcholmes, are particularly preferred.
  • the phospholipid may be naturally occurring, synthetic or semisynthetic; however arian egg phospholipids or plant -derived natural phospholipids such as lecithins are especially preferred, e.g. soybean, sunflower, rapeseed, corn or peanut lecithins.
  • semisynthetic phospholipids is meant a natural phospholipid which has been sub ected to chemical modification, e.g. hydrolysis, for example enzymatic hydrolysis with phospholipases such as phospholipase A l7 A 2 , B, C, or D, especially phospholipase A 2 .
  • Single phospholipids or combinations of two or more phospholipids may be used.
  • Plant derived lecithins generally contain a mixture of phospholipids, e.g. PC together with one or more of PE, PI, PS, PA and SPH.
  • phospholipids e.g. PC together with one or more of PE, PI, PS, PA and SPH.
  • Emultop available from Lucas Meyer GmbH, Hamburg, DE
  • Lecithins are also particularly preferred for use as the phospholipids due to their tocopherol content and inherent antioxidative properties.
  • the phospholipids or fatty acid ester emulsifiers are preferably used at a weight ratio relative to the triglyceride of 1:10 to 1:60, more preferably 1:20 to 1:40, especially 1:25 to 1:35.
  • the phospholipid or fatty acid ester provides the triglyceride droplets m the emulsion with an at least partial surface membrane which serves to promote stability both of the emulsion and of the vitamin D dispersed m the triglyceride droplets.
  • the protection of the vitamin D may arise as a result of reduced oxygen diffusion across the oil -water interface of the emulsion droplets and desirably the vitamin D concentration the oil phase is relatively low m order to have a low ratio between vitamin D-m-oil concentration and oil -water interface surface area.
  • the vitamin D used the compositions of the invention may be any one of its various active forms including metabolites and bioprecursors , e.g. cholecalciferol (vitamin D 3 ) , ergocalciferol (vitamin D 2 ) , l ⁇ , 25-dihydroxy vitamin D, 25-hydroxy vitamin D, l ⁇ - hydroxy vitamin D, etc. Ergocalciferol and, even more so, cholecalciferol are preferred.
  • Vitamin D 3 is readily available commercially an edible oil base, e.g. from Roche.
  • Such forms may include edible t ⁇ glycerides and it should be noted that the total quantity of edible triglycerides m the composition may include some deriving from the vitamin D mix.
  • the calcium compound used the compositions of the invention may be any calcium compound capable of acting as a calcium source on oral administration.
  • the compound may be in dissolved or dissolved and suspended form in the final composition; while soluble calcium salts are preferred, insoluble calcium salts may be included to further increase the calcium concentration of the compositions.
  • insoluble calcium salts are used, t is desirable to use them finely divided form, e.g. with a mean particle size below 5 ⁇ m, to prevent sedimentation during storage and to avoid any "gritty" taste on consumption.
  • soluble is meant soluble the continuous aqueous phase of the composition.
  • Examples of calcium sources include calcium carbonate, calcium lactate, calcium gluconate, calcium citrate, calcium malate, calcium hydroxide, calcium glycerophosphate, calcium phosphate, calcium hydrogen phosphate (m tribasic, dibasic and monobasic forms, le.
  • a soluble calcium salt calcium lactate (e.g. calcium lactate pentahydrate) which has a mild, neutral taste is preferred.
  • an insoluble calcium salt calcium carbonate is preferred.
  • the calcium concentration should be selected to be below its solubility limit, a limit which may be pH and temperature dependant and may be dependant on the presence or absence of other components m the aqueous pnase, e.g. acidifiers. If for any particular formulation, a precipitation or flocculation problem occurs, this can readily be remedied by increasing the water content, i.e. by reducing the calcium concentration m the aqueous phase.
  • the calcium salt may be formed m the production of the compositions of the invention, e.g. by reaction of calcium carbonate or calcium hydroxide with an acid source of the desired counte ⁇ on, e.g. lactic acid, malic acid or citric acid (especially (+) -lactic acid) for the preparation of calcium lactate) .
  • an acid source of the desired counte ⁇ on e.g. lactic acid, malic acid or citric acid (especially (+) -lactic acid) for the preparation of calcium lactate) .
  • the calcium content will preferably be 1000 mg Ca per 200-1200 IU vitamin D, more preferably 1000 mg/400-1000 IU, most especially about 1000 mg/700-900 IU.
  • the composition, concentrate or syrup form will contain 0.5 to 10% w/w of calcium and 0.5 to 100 IU/g vitamin D, preferably 1 to 6% w/w calcium and 1 to 50 IU/g, more preferably 1 to 5% w/w calcium and 9 to 40 IU/g.
  • the emulsion may be taken neat or may first be diluted, e.g. with water or a selected beverage, for example m a 1 part emulsion to 2 to 10 parts, more especially 5 parts, water ratio.
  • compositions according to the invention may, and indeed generally will, contain other physiologically tolerable components, for example sweeteners, viscosity modifiers (e.g. gelling agents, gums, starches, and other thickeners), antioxidants (e.g. tocopherols, such as d, 1- ⁇ -tocopherol , and ascorbyl palmitate) , essential nutrients (e.g. vitamins other than vitamin D (e.g.
  • vitamins A, B, C, E and K vitamins A, B, C, E and K
  • lsoflavones e.g., betacarotene, lycopene, soluble and insoluble fibre and minerals other than calcium
  • colouring agents pharmaceuticals
  • pH modifiers e.g. buffering agents or acidifiers, for example citric acid, lactic acid, malic acid, etc.
  • preservatives e.g. benzoates and sorbates
  • flavours etc .
  • compositions of the invention also contain a viscosity modifier, le. a material which increases the viscosity of the aqueous phase, most preferably the combination of a thickener and a gelling agent, for example agar agar and an edible gum such as locust bean gum, guar gum, xanthan gum, gum arable, or gum tragacanth.
  • a viscosity modifier will generally be used at total concentrations of 0.01 to 5% w/w of the total liquid emulsion composition, more preferably 0.05 to 3% w/w, especially 0.3 to 1.5% w/w.
  • the viscosity modifiers serve to enhance the physical stability of the emulsion and advantageously at least one of the viscosity modifiers used is a gelling agent, le. a material capable of forming a gel on dissolution water.
  • the gelling agent is preferably used at a concentration of 0.05 to 1% w/w of the total composition, more preferably 0.06 to 0.4% w/w, especially 0.07 to 0.3% w/w.
  • One particularly preferred gelling agent is agar agar and this is especially preferably used together with one or more edible gums, e.g. locust bean gum and guar gum.
  • the thickener is preferably used at a concentration of 0.05 to 3% by weight of the total composition.
  • compositions of the invention are intended for oral mgestion and thus desirably contain sweeteners and flavours to enhance their acceptability to the consumer.
  • the sweeteners used may be natural sweeteners, e.g. mono, di and polysacch ⁇ des, for example sucrose, fructose, fructooligosaccharides (oligofructoses) , glucose, glucose syrup, invert sugar, maltodextrms or sugar alcohols such as sorbitol, mannitol, xylitol, isomalt, etc., or artificial sweeteners.
  • intense artificial sweeteners, and especially non- cariogenic sweeteners are preferred.
  • Examples include aspartame, acesulfam K, neohespe ⁇ dme dihydrochalcone , thaumat , saccharin, saccharin salts and cyclamates .
  • a single sweetener or a combination of two or more sweeteners may be used.
  • Preferred natural sweeteners are sugar and fructose conveniently used as syrups with 70% solids (on drying), and fructooligosaccharides .
  • a particularly preferred combination is aspartame and acesulfam K, e.g. a 2:1 to 1:2 weight ratio, especially a 0.9:1 to 1:0.9 ratio.
  • a combination of aspartame, acesulfam and mul and/or fructooligosacche ⁇ des is used as the combination has a synergistic taste effect, relatively effectively mimicking the sweetening effect of sugar and masking any harsh taste of the artificial sweeteners.
  • Fructooligosaccharides can be obtained by partial hydrolysis of mulm and are available under the trade name Raftilose from Orafti SA, Tienen, Belgium, which firm also supplies ulins under the trade name Raftilme.
  • Fructooligosaccharides are also available under the trade name Actilight from Beghm-Meiji Industries, Neuilly-sur-Seme, France.
  • the mulm or fructooligosaccharide will be used m 100-5000 parts by weight per 2 parts by weight of aspartame and acesulfam.
  • sweetener m the compositions of the invention will depend upon the particular sweeteners used and on whether the composition is to be diluted before consumption. Thus the sweetener content will be chosen so as to give a pleasant sweetness on consumption. Typically the sweetener content will be 0.05 to 1% w/w where intense artificial sweeteners are used, e.g. about 0.1% w/w. Where natural sweeteners (e.g. invert sugar or fructose) are used, they can typically make up 20-50% w/w, more preferably 30-50% w/w of the overall composition on a dry solids basis.
  • natural sweeteners e.g. invert sugar or fructose
  • polyols such as sorbitol, mannitol, xylitol and isomalt may be used as mentioned above, these may result in a laxative effect if used in large quantities and they are thus less preferred than the intense artificial sweeteners.
  • the use of prebiotics such as mulm and fructooligosaccharides is also preferred as it appears that they serve as a substrate for the bifidobacteria m the colon, resulting in certain circumstances in improved uptake of calcium.
  • the use of fructooligosaccharides m oral calcium compositions is novel and forms a further aspect of the present invention.
  • the invention provides an orally admmistrable calcium supplement comprising a physiologically tolerable calcium compound, a prebiotic (e.g. fructooligosaccharide or mulm) and preferably also a vitamin D.
  • Such supplements may be m any convenient form, e.g. tablets (for example as described m WO96/09036 (Innothera), powders, capsules, dispersions, emulsions, syrups, gels, etc.
  • natural sweeteners may be preferred over artificial sweeteners.
  • artificial sweeteners may be preferred.
  • flavouring agents useful m the compositions of the invention include fruit (e.g. pineapple or citrus) concentrates and concentrated aqueous or non-aqueous flavours such as flavour oils, e.g. citrus oils, for example cold pressed orange oil (B.P.) .
  • Orange concentrate e.g. 65 B ⁇ x orange concentrate is particularly suitable.
  • the flavouring agent will be used at a concentration sufficient to give the composition, optionally after dilution, a pleasant taste.
  • 65 B ⁇ x orange concentrate may be used at a concentration of 1 to 20% w/w relative to the total emulsion, preferably 2 to 15% w/w.
  • cold pressed orange oil BP may be used at a concentration of 0.04 to 0.3% w/w, preferably 0.06 to 0.2% w/w, relatively to the total emulsion.
  • flavours or acidifiers which are soluble m the aqueous phase may affect the solubility of the calcium compound m that phase and that it may be necessary in such cases to dilute the aqueous phase to prevent precipitation.
  • acidifiers such as lactic acid and water-msoluble flavours such as citrus oils or water-soluble flavours such as strawberry, raspberry, passion fruit, exotic fruit, peach and apricot flavours and other non-citrus flavours such as pineapple concentrate are preferred.
  • flavour oil it may be dispersed in the triglyceride together with the vitamin D or alternatively and preferably it and the vitamin D are separately dispersed in the overall emulsion - in this way any effect of the flavour oil on vitamin D stability may be minimized.
  • a phospholipid or another emulsifier is preferably dissolved in the flavour oil and two oil phases, one containing flavour oil and the other containing vitamin D are intensively mixed with the aqueous phase.
  • Suitable preservatives for use in the compositions of the invention include food grade preservatives, for example the potassium and sodium salts of sorbic, benzoic and parahydroxybenzoic acids . Potassium sorbate is especially preferred.
  • the preservative will generally be used at concentrations of 0.05 to 1.5% w/w relative to the total emulsion, preferably 0.1 to 0.3 w/w.
  • Vitamin C is desirably included in the compositions of the invention, e.g. at a concentration of 1-3 mg/mL, especially 1.5-2.0 mg/mL.
  • beta-carotene may for example be used.
  • Beta-carotene gives the emulsion an orange colour which matches the orange flavour where an orange flavour is used.
  • Cold-water soluble beta-carotene is preferred as it disperses easily in the aqueous phase.
  • Beta-carotene 7% CWS from Roche, which gives the product a clear transparent orange colour is especially preferred.
  • Acidifying agents e.g. lactic or malic acid
  • Lactic acid available in 80% solution as Purac 80 from Purac biochem bv is preferred.
  • the pH of the emulsion should be adjusted to below 6, more preferably below 5, e.g. in the range 3 to 5.
  • the particular pH selected should be sufficient to maintain all or the desired fraction of the calcium compound in solution.
  • fructooligosaccharides are used in the compositions of the invention, the pH is desirably kept above 4 to avoid hydrolysis .
  • compositions of the invention are oil-in-water emulsions, preferably with a narrow oil (triglyceride) droplet size distribution with the mean droplet size (measured for example by light microscopy and comparison with a 1 to 10 ⁇ m scale) in the range 1 to 5 ⁇ m, more preferably 1 to 4 ⁇ m.
  • Emulsification is preferably effected in such a way as to have only a small oversize fraction of droplets, ie. droplets above 5 ⁇ m in diameter.
  • This may be achieved by mixing the aqueous phase and the oil phase using a high intensity mixer, for example a high shear rotor stator mixer, available for example from Ystral GmbH, Dottingen, DE .
  • a suitable mixer is the Diax 600 with a 20G or 20F shaft.
  • An in-line dispersion chamber eg Diax 600, type 22/Z is preferably used as this can ensure that little or no air is introduced into the emulsion.
  • the preparation of the emulsion of the invention forms a further aspect of the invention.
  • the invention provides a process for the preparation of a liquid emulsion composition according to the invention, said process comprising: forming an aqueous composition comprising an aqueous solution of a viscosity modifier; forming a triglyceride composition comprising a solution of a Vitamin D and at least one emulsifying agent selected from edible phospholipids and fatty acid esters ; mixing said triglyceride composition with at least part of said aqueous composition whereby to form an oil- m-water emulsion; and if necessary mixing further components with said emulsion whereby to form said liquid emulsion composition, e.g.
  • compositions containing a physiologically tolerable calcium compound, sweeteners, a further viscosity modifier (e.g. a gelling agent), further vitamins or minerals, flavours, colours, preservatives etc .
  • the process of the invention preferably involves preparing at least two, and more preferably at least three, aqueous compositions and at least one, preferably two, non-aqueous compositions.
  • the first aqueous composition comprises a solution of a thickening agent (e.g. a vegetable gum or a mixture of vegetable gums, e.g. galactomannans) and a portion of this may be used for the preparation of the emulsion, the remainder being combined with a second aqueous composition which is an aqueous solution of a gelling agent (e.g. agar agar) .
  • a thickening agent e.g. a vegetable gum or a mixture of vegetable gums, e.g. galactomannans
  • the calcium compound may be dissolved or dispersed m either of the first or second aqueous solutions or m the combined aqueous composition; preferably however the calcium compound is dispersed m a third aqueous composition, optionally together with further components such as sweeteners and preservatives, and this third aqueous composition is mixed m with the combined aqueous composition before or preferably after which the emulsion is also mixed m.
  • an oil component such as a flavour oil which has the potential to reduce vitamin D stability
  • the first oil composition is preferably emulsified with the portion of the first aqueous composition that has been set aside for emulsion formation whereafter the second oil composition may be intensively mixed m with the resultant emulsion.
  • the overall volume of water used is preferably kept to the minimum required to keep the calcium compound stably m solution.
  • the proportions of this water used to prepare the different aqueous compositions will generally be selected to be at least the minimum required to produce compositions which can be poured and mixed together, the total desired water content can be made up by addition of aqueous solutions of further components (such as vitamin C) or of water. In this way evaporation losses can be compensated for.
  • composition production and handling is carried out under an inert (e.g. nitrogen or inert (e.g. noble) gas) atmosphere, under a partial vacuum or with nitrogen injection so as to minimize the oxygen contact with the vitamin D.
  • oxygen contact may be reduced by preparing the vitamin D- triglyce ⁇ de composition, and emulsifying this with the thickener solution under an inert atmosphere.
  • sweeteners e.g. acesulfam and aspartame
  • preservatives e.g. potassium sorbate
  • liquid (E) to liquid (D) keeping the temperature of the resulting mixture above the gel point, e.g at 50°C.
  • the calcium lactate will dissolve to yield a clear solution.
  • acidifier e.g. lactic acid
  • the containers used may be single dose containers, e.g. bottles, sachets, vials, etc; however multi-dose containers are preferred, e.g. 50 to 1000 mL bottles, preferably 500 mL bottles.
  • the containers are light transmitting, they are preferably brown-coloured, e.g. brown coloured PET.
  • the head space above the emulsion may if desired be flushed with an oxygen-free gas, e.g. nitrogen.
  • deaeration or nitrogen injection is preferably used during the preparation of the emulsion product to exclude oxygen.
  • the emulsion is preferably administered (optionally after dilution) m doses containing 100 to 1500 mg Ca, preferably 200 to 500 mg Ca, with sufficient doses being taken over the day to provide a 200 to 1200 mg Ca daily dosage, more preferably a 500 to 1000 mg Ca daily dosage.
  • the daily dosage is preferably 400 to 600 mg Ca, more preferably 500 mg Ca while for therapeutic use, e.g. m osteoporosis, the daily dosage is preferably 900 to 1100 mg Ca, more preferably 1000 mg Ca .
  • Individual doses preferably contain 500 mg Ca or less m order to optimise calcium uptake .
  • the vitamin D dosage is preferably 100 to 1000 IU per day, more preferably 300 to 500 IU/day for prophylactic use and 700 to 900 IU/day for therapeutic use.
  • the calcium to vitamin D ratio is preferably 500 mg Ca: 150-500 IU, more preferably 500 mg Ca : 200-450 IU, especially 500 mg Ca : 200-220 IU and 500 mg Ca : 400- 450 IU for prophylactic and therapeutic use respectively.
  • the calcium content of the emulsion according to the invention is preferably 10-27.5 mg Ca/mL, especially 12.5 or 25 mg Ca/mL.
  • Such emulsions may conveniently be diluted 1 part with 5 parts by volume of diluent, e.g. tap water or mineral water, milk, fruit juice, or any other alcohol -free beverage. Where water is used the resultant diluted composition may be a clear liquid with an acceptable flavour.
  • Doses of the composition of the invention may be taken between meals or with meals and are suitable for older people with reduced gastric acid secretion.
  • compositions of the invention may be used m therapeutic or prophylactic treatment and this forms a further aspect of the invention.
  • the invention provides a method of treatment of a human or non-human mammal subject to combat conditions associated with calcium deficiency (e.g. osteoporosis), said method comprising orally administering said subject a composition or supplement according to the invention, optionally following dilution thereof m a physiologically tolerable aqueous liquid.
  • Betacarotene (7% CWS) 170mg
  • Vitamin D 3 (1 MlU/g from Roche) 22mg
  • the agar agar is mixed with 350 ml of purified water with an intensive mixer and heated up until dissolved at a temperature of 95 °C.
  • locust bean gum and guar gum are mixed together with 900 mL of purified water at a temperature of 70°C. 70 mL of this mixture is removed and diluted to 150 L with purified water and set aside for use in emulsification.
  • the agar agar solution and the remaining gum solution are mixed and kept above 50°C to form the main solution.
  • Aspartame, acesulfam K and potassium sorbate are added to 600 ml of purified water and dissolved by the aid of an intensive mixer. 175 gram of calcium lactate pentahydrate is then gradually added to form a suspension by the aid of the same intensive mixer.
  • the suspension is transferred to the mam solution where calcium lactate dissolves completely to form a clear solution.
  • Lactic acid (80%) and betacarotene 7% CWS are added and the container is placed m a waterbath for cooling while continuously being stirred by a slow moving stirrer.
  • the triglyceride and 190 mg lecithin are heated up until approximately 50°C until a solution is achieved.
  • the clear brown solution is then cooled down to approximately 30°C whereupon vitamin D is added.
  • the orange oil and 125 mg lecithin are mixed; only slight heating is necessary m this case m order to dissolve the lecithin.
  • the triglyceride phase is then emulsified mto the 150 ml diluted gum solution with an intensive mixer at nigh speed to produce an emulsion.
  • the orange oil is then emulsified mto the same 150 ml.
  • the emulsion is then added to the mam solution when the temperature m this solution is at approximately 28 °C.
  • the temperature is further brought down below 20°C at which the volume is corrected with purified water to 2000 ml.
  • the product is then filled mto coloured 250 - 1000 ml PET or glass bottles.
  • the resulting beverage concentrate contains 250 mg of elemental calcium and 220 IU of vitamin D 3 per 20 ml of serving.
  • the beverage concentrate has the following properties : Viscosity (Brookfield): 1280 mPa . s
  • Purified water to 2500 ml The beverage concentrate is prepared analogously to Example 1.
  • the fructooligosaccharide is added at the time when the cooling down process starts in order to avoid unnecessary exposure to high temperatures.
  • the beverage concentrate contains 250 mg of elemental calcium, 220 IU of vitamin D 3 and 1.5 grams of fructo oligosaccharides per 25 ml of serving.
  • the beverage concentrate has the following properties:
  • Viscosity (Brookfield): 916 mPa . s
  • the beverage concentrate is prepared analogously to Example 2 , except that vitamm C is dissolved in approximately 100 ml of purified water and added at the end of the process together with the triglyceride and orange oil emulsion.
  • the beverage concentrate contains 250 mg of elemental calcium, 220 IU of vitamm D , 39 mg of vitamm C and 1.5 grams of fructooligosaccharides per 25 ml of serving.
  • the beverage concentrate has the following properties:
  • Viscosity (Brookfield) : 1130 mPa . s
  • a stability study was carried out m order to investigate the physical and chemical stability of the liquid calcium composition product.
  • a 2 3 factorial design was set up m order to demonstrate the effect of three formulation variables. These were the type of emulsifying agent, presence of vitamm C and presence of oligofructose .
  • the following combinations of formulation variables were used m all together 8 combinations and executed m a random order: 00/54838
  • Batches 9 and 10 were identical to batch 8 and were produced in order to demonstrate the variability of the analytical methods employed.
  • the type of emulsifying agent was investigated for influence on the stability of vitamin D 3 and effect on the physical stability of the emulsion. Effects on physical stability investigated included any evidence of creaming or phase separation as well as the measurement of the mean droplet size as a function of time.
  • the calcium content per dosage of 20 or 25 ml was 200 mg of elemental calcium and the content of vitamin D 3 was 4 ⁇ g (160 IU) per dosage (i.e. 4.4 ⁇ g (176 IU) including overage (10%) ) .
  • the amount of the gelling agent (agar-agar) and the thickeners (locust bean gum and guar gum) was selected in order to maintain a satisfactory viscosity in the product .
  • the low level of vitamin C (2 mg) was added to the formulations in order to function as an antioxidant to prevent the discolouring of betacarotene.
  • the vitamin D 3 and the orange oil were separately emulsified into two different pre-emulsions and added after each other into the main solution at a temperature of 28°C.
  • the emulsion was homogenised with a Diax 600 high intensity mixer for two minutes after the volume correction at the very end of the production.
  • Guar gum 5.40 g 5.40 g 6.7 g 5.40 g 6.7 g 5.40 g 6.7 g 6.7 g 6.7 g
  • Acesulfam K 1.20 g 1.20 g 1.50 g 1.20 g 1.50 g 1.20 g 1.50 g 1.20 g 1.50 g 1.50 g 1.5 g 1.50 g
  • Lactic acid (80%) 9.60 g 9.60 g 12.0 g 9.60 g 12.0 g 9.60 g 12.0 g 9.60 g 12.0 g 12.0 g 12.0 g 12.0 g
  • Lecithin (Emultop) 432 mg 432 mg 516 mg 516 mg 516 mg 516 mg 516 mg 516 mg
  • Vitamin D 3 (1 mill IU/g) 21.1 mg 21.1 mg 26.4 mg 21.1 mg 26.4 mg 21.1 mg 26.4 mg 21.1 mg 26.4 mg 26.4 mg 26.4 mg 26.4 mg 26.4 mg
  • Vitamin D 3 per dosage 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 ⁇ g 4.4 g 4.4 g
  • the emulsions were filled into 200 ml amber glass bottles with a screw cap and set aside for the stability trial.
  • the stability conditions were chosen to be 25°C and 60% relative humidity as this would closely resemble the actual storage conditions in a retail situation.
  • the 10 batches were analysed initially and after 2, 4 and 6 months with respect to the content of vitamin D 3 , emulsion droplet size and appearance. Two of the formulations were analysed at 3 months instead of 2 months with respect to vitamin D 3 . Viscosity, microbiological quality, pH, oxygen content and taste were analysed initially and after 6 months.
  • Vitamin D 3 content analysis was carried out by a single one-step extraction of the fat-soluble vitamins from a product sample into hexane, followed by solid phase extraction (SPE) to further purify and enrich the vitamin D 3 .
  • SPE solid phase extraction
  • Vitamin D 3 was then analysed on a reversed phase Supelcosil HPLC column using a mobile phase containing acetonitrile and methanol for the separation.
  • the method of measuring the droplet size was changed before the 4 month measurement point .
  • the new method included a more accurate and statistically better method for calculating the mean droplet size involving determining the mean for 10 to 25 droplets from a 4Ox microscope picture. There was no evidence of creaming or phase separation in any of the batches at the various time points during the stability trial.
  • the pH for the formulations are all in the region of 4.4 to 4.6 and no significant changes over time were seen.
  • the amount of dissolved oxygen in the batches were measured with a Moca 3600 oxygen sensor from Orbisphere Laboratories .
  • the mean values for the oxygen content were 2.55 and 2.14 ppm respectively for the initial analysis and after 6 months.

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Abstract

L'invention concerne une composition à émulsion liquide possédant une phase aqueuse continue qui contient un modificateur de viscosité et, sous forme dissoute, un composé à base de calcium physiologiquement tolérable ainsi qu'une vitamine D contenant une phase triglycéride discontinue et un triglycéride comestible, ladite composition à émulsion contenant aussi au moins un agent émulsifiant sélectionné entre les phospholipides comestibles et les esters d'acides gras.
PCT/GB2000/000986 1999-03-16 2000-03-16 Composition contenant du calcium WO2000054838A1 (fr)

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AU33050/00A AU3305000A (en) 1999-03-16 2000-03-16 Calcium-containing composition

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GB9906009.7 1999-03-16

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035769A1 (fr) * 1999-11-18 2001-05-25 The Procter & Gamble Company Produits pourvus d'un systeme de conservation contenant de l'isothiocyanate et procedes d'utilisation
EP1228764A1 (fr) * 2001-02-01 2002-08-07 EnergyBalance AG Calcium composition avec oligofructose
WO2002024165A3 (fr) * 2000-09-20 2002-12-27 Nycomed Pharma As Preparation d'emulsions et de concentres de ces dernieres
WO2003034832A1 (fr) * 2001-10-19 2003-05-01 Unilever N.V. Emulsion d'eau dans l'huile comestible avec calcium
WO2007104774A1 (fr) * 2006-03-14 2007-09-20 Routin Sa Boisson aromatisée concentrée sans sucre, son procédé de préparation et ses utilisations
WO2008031188A1 (fr) * 2006-09-14 2008-03-20 Vieth Reinhold W Compositions à base de vitamine d et procédé d'administration à un être humain
FR2917976A1 (fr) * 2007-06-29 2009-01-02 Galderma Sa Composition dermatologique comprenant des vehicules lipidiqu lipidiques de calcitriol, son procede de preparation et son utilisation
WO2011057731A1 (fr) * 2009-11-10 2011-05-19 Cognis Ip Management Gmbh Composition comprenant un lipide approprié à la consommation humaine
US8043648B2 (en) * 2007-04-16 2011-10-25 Conopco Inc. Edible emulsions with mineral
US8293299B2 (en) 2009-09-11 2012-10-23 Kraft Foods Global Brands Llc Containers and methods for dispensing multiple doses of a concentrated liquid, and shelf stable Concentrated liquids
WO2013101494A1 (fr) * 2011-12-30 2013-07-04 Abbott Laboratories Composition nutritionnelle mélangeable à deux phases comprenant de la gomme de caroube
US20130281404A1 (en) * 2010-09-30 2013-10-24 Meiji Co., Ltd. Composition containing 2-acyl-lysophosphatidylserine and method for producing the same
WO2014078509A1 (fr) * 2012-11-14 2014-05-22 Abbott Laboratories Compositions nutritionnelles liquides stabilisées comprenant des sels de calcium insolubles
US9095164B2 (en) 2005-02-09 2015-08-04 Kevin Meehan Animal feed composition for increased production of glutathione peroxidase and superoxide dismutase
JP2018531917A (ja) * 2015-09-09 2018-11-01 アレルギー リサーチ グループ，エルエルシー 精子の運動性および生存性強化のためのリン脂質組成物およびその使用
EP3334434A4 (fr) * 2015-09-09 2019-03-06 Allergy Research Group, LLC Compositions de phospholipides et leur utilisation pour améliorer la viabilité et la mobilité des spermatozoïdes
US11013248B2 (en) 2012-05-25 2021-05-25 Kraft Foods Group Brands Llc Shelf stable, concentrated, liquid flavorings and methods of preparing beverages with the concentrated liquid flavorings
WO2021115850A1 (fr) * 2019-12-09 2021-06-17 Société des Produits Nestlé S.A. Pâte pour boisson
EP3796917A4 (fr) * 2018-05-21 2022-06-22 Agthia Eau enrichie en vitamine d et son procédé de fabrication
WO2023198528A1 (fr) * 2022-04-12 2023-10-19 Société des Produits Nestlé S.A. Boisson comprenant de la vitamine d ou ses dérivés ayant une stabilité améliorée
WO2023198529A1 (fr) * 2022-04-12 2023-10-19 Société des Produits Nestlé S.A. Émulsion comprenant de la vitamine d ou ses dérivés ayant une stabilité améliorée
CN117503708A (zh) * 2023-09-27 2024-02-06 济南维瑞医药科技开发有限公司 一种佝偻病患儿专用补钙剂及其制备方法

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US5545411A (en) * 1994-12-16 1996-08-13 Bristol-Myers Squibb Company Method for lowering viscosity by use of gum acacia
WO1996031130A2 (fr) * 1995-04-07 1996-10-10 Abbott Laboratories Supplements calciques et boissons a teneur en calcium contenant de la vitamine d
US5785990A (en) * 1995-07-10 1998-07-28 Merrick's, Inc. Feed fortifier and enhancer for preruminant calves and method of using same
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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001035769A1 (fr) * 1999-11-18 2001-05-25 The Procter & Gamble Company Produits pourvus d'un systeme de conservation contenant de l'isothiocyanate et procedes d'utilisation
US6361812B1 (en) 1999-11-18 2002-03-26 The Procter & Gamble Co. Products comprising an isothiocyanate preservative system and methods of their use
US6558723B2 (en) 1999-11-18 2003-05-06 The Procter & Gamble Co. Products comprising an isothiocyanate preservative system and methods of their use
US7105190B2 (en) 1999-11-18 2006-09-12 The Procter & Gamble Company Products comprising an isothiocyanate preservative system and methods of their use
WO2002024165A3 (fr) * 2000-09-20 2002-12-27 Nycomed Pharma As Preparation d'emulsions et de concentres de ces dernieres
EP1228764A1 (fr) * 2001-02-01 2002-08-07 EnergyBalance AG Calcium composition avec oligofructose
WO2003034832A1 (fr) * 2001-10-19 2003-05-01 Unilever N.V. Emulsion d'eau dans l'huile comestible avec calcium
US9095164B2 (en) 2005-02-09 2015-08-04 Kevin Meehan Animal feed composition for increased production of glutathione peroxidase and superoxide dismutase
WO2007104774A1 (fr) * 2006-03-14 2007-09-20 Routin Sa Boisson aromatisée concentrée sans sucre, son procédé de préparation et ses utilisations
WO2008031188A1 (fr) * 2006-09-14 2008-03-20 Vieth Reinhold W Compositions à base de vitamine d et procédé d'administration à un être humain
AU2007295888B2 (en) * 2006-09-14 2012-07-12 Elaine Vieth Vitamin D compositions and method of administration to a human being
CN101969958B (zh) * 2006-09-14 2015-04-08 R·W·菲特 维生素d组合物以及给人类施用的方法
US9066958B2 (en) 2006-09-14 2015-06-30 Reinhold W. Vieth Vitamin D compositions and method of administration to a human being
KR101437706B1 (ko) * 2006-09-14 2014-09-03 레인홀드 더블유 비스 비타민 ｄ 조성물 및 인간에의 투여 방법
US8043648B2 (en) * 2007-04-16 2011-10-25 Conopco Inc. Edible emulsions with mineral
FR2917976A1 (fr) * 2007-06-29 2009-01-02 Galderma Sa Composition dermatologique comprenant des vehicules lipidiqu lipidiques de calcitriol, son procede de preparation et son utilisation
WO2009007622A3 (fr) * 2007-06-29 2009-05-22 Galderma Sa Composition dermatologique comprenant des vésicules lipidiques de calcitriol, son procédé de préparation et son utilisation
US8293299B2 (en) 2009-09-11 2012-10-23 Kraft Foods Global Brands Llc Containers and methods for dispensing multiple doses of a concentrated liquid, and shelf stable Concentrated liquids
US8603557B2 (en) 2009-09-11 2013-12-10 Kraft Foods Group Brands Llc Containers and methods for dispensing multiple doses of a concentrated liquid, and shelf stable concentrated liquids
WO2011057731A1 (fr) * 2009-11-10 2011-05-19 Cognis Ip Management Gmbh Composition comprenant un lipide approprié à la consommation humaine
US20130281404A1 (en) * 2010-09-30 2013-10-24 Meiji Co., Ltd. Composition containing 2-acyl-lysophosphatidylserine and method for producing the same
US9290781B2 (en) * 2010-09-30 2016-03-22 National University Corporation Tokyo University Of Marine Science And Technology Composition containing 2-acyl-lysophosphatidylserine and method for producing the same
WO2013101494A1 (fr) * 2011-12-30 2013-07-04 Abbott Laboratories Composition nutritionnelle mélangeable à deux phases comprenant de la gomme de caroube
US11013248B2 (en) 2012-05-25 2021-05-25 Kraft Foods Group Brands Llc Shelf stable, concentrated, liquid flavorings and methods of preparing beverages with the concentrated liquid flavorings
WO2014078509A1 (fr) * 2012-11-14 2014-05-22 Abbott Laboratories Compositions nutritionnelles liquides stabilisées comprenant des sels de calcium insolubles
JP2018531917A (ja) * 2015-09-09 2018-11-01 アレルギー リサーチ グループ，エルエルシー 精子の運動性および生存性強化のためのリン脂質組成物およびその使用
EP3334434A4 (fr) * 2015-09-09 2019-03-06 Allergy Research Group, LLC Compositions de phospholipides et leur utilisation pour améliorer la viabilité et la mobilité des spermatozoïdes
EP3796917A4 (fr) * 2018-05-21 2022-06-22 Agthia Eau enrichie en vitamine d et son procédé de fabrication
WO2021115850A1 (fr) * 2019-12-09 2021-06-17 Société des Produits Nestlé S.A. Pâte pour boisson
WO2023198528A1 (fr) * 2022-04-12 2023-10-19 Société des Produits Nestlé S.A. Boisson comprenant de la vitamine d ou ses dérivés ayant une stabilité améliorée
WO2023198529A1 (fr) * 2022-04-12 2023-10-19 Société des Produits Nestlé S.A. Émulsion comprenant de la vitamine d ou ses dérivés ayant une stabilité améliorée
CN117503708A (zh) * 2023-09-27 2024-02-06 济南维瑞医药科技开发有限公司 一种佝偻病患儿专用补钙剂及其制备方法

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