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WO2025008385A1 - Préparations solides de bêta-carotène - Google Patents

Préparations solides de bêta-carotène Download PDF

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Publication number
WO2025008385A1
WO2025008385A1 PCT/EP2024/068702 EP2024068702W WO2025008385A1 WO 2025008385 A1 WO2025008385 A1 WO 2025008385A1 EP 2024068702 W EP2024068702 W EP 2024068702W WO 2025008385 A1 WO2025008385 A1 WO 2025008385A1
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WO
WIPO (PCT)
Prior art keywords
weight
carotene
solid preparation
component
range
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PCT/EP2024/068702
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English (en)
Inventor
Cosima HIRSCHBERG
Jesper Feldthusen Jensen
Julia WIEBE
Christian Koepsel
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BASF SE
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BASF SE
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/15—Vitamins
    • A23L33/155—Vitamins A or D
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to solid preparations of p-carotene in the form of beadlets which contain a high amount of p-carotene.
  • P-Carotene is an organic, strongly colored red-orange pigment. Dietary p-carotene is a provitamin A compound, converting in the body to retinol (vitamin A). p-Carotene is frequently used as a vitamin A source in vitamin supplements and for coloring food.
  • B-Carotene is insoluble in water and its solubility in fats and oils is found to be only low, as well. This limited solubility and the great sensitivity of B-carotene to oxidation stand in the way of direct use of the relatively coarse particle products obtained by chemical synthesis. Moreover, the bioavailability of coarse-particle B-carotene is quite poor and not suitable for the use in vitamin supplements. Apart from that, coarse particle B-carotene provide only poor coloring results.
  • Beadlets are a special form of powder preparations. They have typically a core which contains an active, e. g. B-carotene and matrix materials and optionally a covering or coating, which reduces the sticking of the particles. Beadlets are usually obtained by providing a dispersion of the respective active, here B-carotene, in water and/or a volatile organic solvent, grinding it to the desired particle size if necessary and then spray-drying suspension together with the matrix material. Beadlets have typically a medium particle size (d50) in the range of 50 pm to 1000 pm, in particular 100 to 500 pm as determined by sieving according to European Pharmacopeia (Ph. Eur.).
  • d50 medium particle size
  • WO 2006/032399 describes dry powders of carotenoids, such as B-carotene, which contain a combination of isomalt and a protective colloid as a matrix material.
  • the powders of WO 2006/032399 provide an improved stability to the B-carotene against degradation, in particular oxidative degradation, when the powder is formulated in a solid dosage form, such as a tablet, in comparison to powders wherein the isomalt was replaced by another carbohydrate, such as sucrose, or by a sugar alcohol, such as mannitol.
  • the stabilization of B-carotene provided by the powders of WO 2006/032399 in solid dosage forms, in particular in solid dosage forms obtained by compacting mixture of the powder with one or more excipients such as tablets is not entirely satisfactory.
  • the powder when the powder is incorporated into a solid dosage form, in particular into solid dosage forms obtained by compacting mixture of the powder with one or more excipients such as tablets.
  • the stability problem becomes even more prominent, when the content of the B-carotene in the beadlet core is higher than 15% by weight, in particular at least 20% by weight.
  • B-carotene in solid dosage forms such as tablets can be further improved by providing beadlets containing a combination of isomalt and at least one protective colloid from the group of polysaccharides and modified polysaccharides with balanced relative amounts of isomalt and the at least one protective colloid.
  • the present invention relates to solid preparations of p-carotene in the form of beadlets, comprising a) a beadlet core, which contains a.1) 20 to 40% by weight, in particular 20 to 35% by weight, especially 25 to 30% by weight of p-carotene as a component a.1 ; a.2) 30 to 75% by weight, in particular 40 to 60% by weight, especially 40 to 50% by weight of isomalt as a component a.2; a.3) 5 to 50% by weight, in particular 10 to 35% by weight, especially 25 to 35% by weight of at least one protective colloid from the group of polysaccharides and modified polysaccharides as a component a.3, where the relative amount of each component refers to the total dry weight of beadlet core, and optionally b) a beadlet coating.
  • the solid preparations of the present invention provide superior stability to B-carotene, in particular, when the solid preparations are used in solid dosage forms, especially in solid dosage forms which are obtained by compaction of the solid preparation in mixture with one or more excipients.
  • the solid dosage forms can be easily prepared by well-known techniques for preparing beadlet formulations and are easily to handle.
  • a further aspect of the present invention relates to solid oral dosage forms containing a solid preparation according to present invention and one or more excipients.
  • Yet a further aspect of the present invention relates to the use of isomalt in the solid preparation of p-carotene as defined herein for increasing the chemical stability of p- carotene in said the solid preparation.
  • the present invention relates the use of isomalt in the solid preparation of p-carotene as defined herein for increasing the chemical stability of p-carotene in solid dosage forms containing said solid preparation, in particular in solid dosage forms which have been obtained by compaction of a mixture of the solid preparation and one or more excipients.
  • the stability of B-carotene refers to its stability against degradation, in particular degradation caused by oxidative stress, which B-carotene typically suffers upon storage of solid dosage forms containing solid preparations of B- carotene.
  • the solid preparation of p-carotene is in the form of beadlets, which means that the solid preparation essentially consists of beadlets.
  • the term “essentially consists” means that the total amount of the beadlets within the preparation is typically at least 90% by weight, in particular at least 95% by weight, based on the total weight of the preparation.
  • beadlet refers to particles, which are formed by the beadlet core and the optional coating.
  • solid preparation of p-carotene in the form of beadlets refers to compositions in the form of beadlets which have
  • beadlet core refers to the beadlet without the optional coating.
  • the beadlet and also the beadlet core are spherical or almost spherical particles.
  • spherical is understood that for a particular beadlet the largest diameter does not deviate more than 50% of the smallest diameter, i. e. the ratio of the largest diameter to the smallest diameter of a particular beadlet does not exceed a value of 1.5.
  • the particle diameter of the beadlets refers to the medium particle diameter which is also referred to as the d(0,5) value of the particle size distribution of the beadlets.
  • the particle size distribution of the beadlets, and, hence, their medium particle diameter can be determined by sieving, e. g. according to the European Pharmacopeia (Ph. Eur.).
  • the d(0,9) value of the particle size distribution of the beadlets is typically not higher than 1000 pm, in particular not higher than 500 pm.
  • the d(0, 1 ) value of the particle size distribution of the beadlets is typically not smaller than 10 pm, in particular not smaller than 50 pm.
  • the d(0,5) value refers to the beadlet size below which 50% by weight of the beadlets fall. It is also referred to a median particle size.
  • the d(0,9) value refers to the beadlet size below which 90% by weight of the beadlets fall.
  • the d(0, 1 ) value denotes the beadlet size that is undercut by 10% by weight of the beadlets.
  • the beadlet core typically contains the components a.1, a.2 and a.3 and optionally further components.
  • the components of the beadlet core are are evenly distributed within the beadlet core.
  • total dry weight of the beadlet core refers to the total weight of the components contained in the core, except for the volatile components, such as water.
  • the B-carotene is present in the form of fine particles, having generally a particle size of less than 10 pm, in particular less than 5 pm or even less than 2 pm as determined by Fraunhofer diffraction according to ISO 13320 or by transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • the B-carotene may be a synthetic B-carotene obtained by classical organic syntheses or by biochemical syntheses, mostly by fermentation, or a B-carotene isolated from plants or algae.
  • the synthetic B-carotene is food grade or pharma grade and has a purity of at least 95% according to Ph.Eur. requirements and actual values are typically in the range 97-98 % as determined by HPLC.
  • the beadlet core contains isomalt as the component a.2.
  • Isomalt is a mixture of the two sugar alcohols 6-O-a-D-glucopyranosyl-D-sorbitol (GPS, isomaltit) und 1-O-a-D-glucopyranosyl-D-mannitol dihydrate (GPM).
  • GPS 6-O-a-D-glucopyranosyl-D-sorbitol
  • GPM 1-O-a-D-glucopyranosyl-D-mannitol dihydrate
  • the total content of GPS and GPM in isomalt is typically at least 85% by weight, based on the total anhydrous weight, i. e. the weight except for water. It may contain up to 15% by weight, based on the total anhydrous weight, of one or more hydrogenated mono- and disaccharides other than GPS and GPM, such as mannitol and sorbitol.
  • the relative amount of isomalt is in the range of 30 to 75% by weight, in particular in the range of 40 to 60% by weight, especially in the range of 40 to 50% by weight, based on the total dry weight of beadlet core.
  • the amount of isomalt in the beadlet core can be quantified by standard analytical methods, e. g. by high performance liquid chromatography, HPLC, as described e. g. in European Pharmacopeia 11.0 monograph, pages 3137-3139 for “Isomalt”.
  • the relative amounts of isomalt given here refer to a standard quality of isomalt, i. e. an isomalt containing at least 85% by weight, based on the total anhydrous weight, of GPS and GPM.
  • the analytical content of GPS and GPM in the beadlet core may be somewhat smaller than the amount used for production.
  • the beadlet core contains one or more protective colloids as the component a.3.
  • the protective colloid is selected from the group of polysaccharides and modified polysaccharides.
  • polysaccharide means a polymer made of at least 3 saccharide units, in particular at least 5 saccharide unites (weight average), which are connected by glycosidic bonds.
  • modified polysaccharide means a polymer made of at least 3 saccharide units, in particular at least 5 saccharide unites (weight average), which are connected by glycosidic bonds, where at least a portion of the hydroxyl groups of the saccharide units have been etherified or esterified.
  • degree of substitution in the modified polysaccharide at most 3%, e. g. 0.5 to 3%, especially 1.5 to 2.5% with respect to the saccharide units, which means that on average at most 3 mol-%, e. g. 0.5 to 3 mol-%, especially 1.5 to 2.5 mol-% of saccharide units have been etherified or esterified.
  • the polysaccharides and modified polysaccharides suitable as protective colloids have a weight average molecular weight (Mw) in the range of 5,000 to 1,000,000 g/mol, in particular in the range of 20,000 to 300,000 g/mol, as determined by gel permeation chromatography (GPC) e. g. using i) a Suprema GPC column from the company Polymer Standards Service GmbH and ii) a MALS- as well as an Rl detector.
  • Mw weight average molecular weight
  • suitable protective colloids include e. g. degraded native starches such as maltodextrin having a DE of not more than 15, modified starches, such as alkyl succinate modified starches and alkenyl succinate modified starches, dextrins, pectin, gums, such as gum arabic (synonym of acacia gum) and cellulose derivatives, such as methyl cellulose (MC), ethyl cellulose (EC) carboxymethyl cellulose (CMC), hydroxypropyl cellulose (HPC) and hydroxypropyl methyl cellulose (HPMC).
  • degraded native starches such as maltodextrin having a DE of not more than 15
  • modified starches such as alkyl succinate modified starches and alkenyl succinate modified starches, dextrins, pectin, gums, such as gum arabic (synonym of acacia gum) and cellulose derivatives, such as methyl cellulose (MC), ethyl cellulose (
  • modified starches Preference is given to modified starches, gums, such as gum arabic, and mixtures thereof as the component a.3.
  • the modified starch is the main constituent of the component a.3 and in particular contributes at least 70% by weight, especially at least 90% by weight to the total weight of the component a.3.
  • the modified starches are selected from alkyl succinate modified starch and alkenyl succinate modified starch.
  • the alkyl and alkenyl groups in these modified starches typically have 4 to 20 carbon atoms, in particular 6 to 12 carbon atoms, e. g. 8 carbon atoms.
  • the degree of substitution in the alkyl succinate modified starch and alkenyl succinate modified starch is the range of 0.5 to 3%, in particular in the range of 1 to 3% and especially 1.5 to 2.5% with respect to the glucose units, which means that on average 0.5 to 3 mol-%, in particular 1 to 3 mol-% especially 1.5 to 2.5 mol-% of the glucose units bear an alkyl succinate moiety and/or an alkenyl succinate moiety.
  • a particular preferred example of such a modified starch is an octenyl succinate starch, in particular an octenyl succinate starch of a waxy maize starch.
  • the octenyl succinate starch has a degree of substitution in the range 1.5-2.5 %. and a weight average molecular weight in the range of 20,000 to 300,000 g/mol, especially 80,000- 120,000 g/mol as determined by gel permeation chromatography (GPC) e. g. using i) a Suprema GPC column from the company Polymer Standards Service GmbH and ii) a MALS- as well as a Rl detector.
  • GPC gel permeation chromatography
  • octenyl succinate starches examples include the commercial products, such as the CAPSLIL® grades of National Starch, such as CAPSLIL® HF, HiCap® 100 of Ingredion, PurityGum® Grades of National Starch, such as PurityGum® 2000, EmCap grades of Cargill, such as EmCap 12633 and EmCap 12635, and the Cleargum® grades of Roquette, such as Cleargum® CO 01, Cleargum® CO A1 or Cleargum® CO03.
  • the commercial products such as the CAPSLIL® grades of National Starch, such as CAPSLIL® HF, HiCap® 100 of Ingredion, PurityGum® Grades of National Starch, such as PurityGum® 2000, EmCap grades of Cargill, such as EmCap 12633 and EmCap 12635, and the Cleargum® grades of Roquette, such as Cleargum® CO 01, Cleargum® CO A1 or Cleargum® CO03.
  • the relative amount of the protective colloid of component a.3 is in the range of 5 to 55% by weight, in particular in the range of 10 to 35% by weight, especially in the range of 15 to 35% by weight, based on the total dry weight of beadlet.
  • the relative amounts of component a.3 given here refer to a standard qualities of the protective colloids of component a.3. They apply in particular to the preferred protective colloids of component a.3 and especially to the alkyl and alkenyl succinate starches.
  • the components a.2 and a.3 and the optional further components contained in the beadlet core form a matrix which surrounds or embeds the B-beta carotene.
  • the total amount of the components a.2 and a.3 is at least 55% by weight, in particular at least 60% by weight, and typically at least 70% by weight, e. g.
  • the total amount of the components a.2 and a.3 refers to the total dry weight of beadlet core.
  • the weight ratio of isomalt to the component a.3, in particular the modified starch is at least 1.4:1 , in particular at least 1.45:1 and especially at least 1.48:1, e. g. in the range of 1.4:1 to 3.0:1, in particular in the range of 1.45: 1 to 2.5: 1 , especially in the range of 1 :48: 1 to 2.2: 1.
  • These ratios apply in particular to the preferred protective colloids of component a.3 and especially to the alkyl and alkenyl succinate starches.
  • the beadlet core may contain one or more further components, conventionally used in the preparation of B-carotene particles.
  • the beadlet core may contain one or more antioxidants in order to increase the stability of the B-carotene.
  • antioxidants include but are not limited to DL- [alpha]-tocopherol, D-[alpha]-tocopherol, mixed tocopherols, t-butylhydroxytoluene, t- butylhydroxyanisole, citric acid, sodium citrate, ascorbic acid, sodium ascorbate, ascorbyl palmitate and ethoxyquin and combinations thereof.
  • Preferred antioxidants include DL- [alpha]-tocopherol ascorbic acid, sodium ascorbate, and combinations thereof. If present, the antioxidant is usually present in the beadlet core in a concentration of from 0.05 to 10% by weight, preferably 0.1 to 7% by weight, based on the dry mass of the beadlet core.
  • the beadlet core may contain water.
  • the amount of water does not exceed 5% by weight, based on the total weight of the beadlet core, i. e. based on the dry weight of the beadlet core + water.
  • the beadlets of the preparation of the present invention may further comprise a coating.
  • the coating surrounds the beadlet core and may improve the handling and/or the mechanical stability of the beadlet core. It may also serve for reducing the caking of the beadlet particles in the composition and improve the flow characteristics of the composition.
  • the coating may principally any coating suitable for the coating including hydrophobic coatings, such as wax coatings or fat coatings, or in particular hydrophilic coatings, such as coatings based on minerals and/or native starches.
  • hydrophobic coatings such as wax coatings or fat coatings
  • hydrophilic coatings such as coatings based on minerals and/or native starches.
  • Suitable coating agents are well known in the art, e. g. from WO 91/06292.
  • Suitable hydrophilic coating agents include in particular powdering agent, such as native starches, e. g. potato starch, wheat starch and maize starch, including also waxy starches, anti-caking agents, e. g. earth alkali metal phosphates, such as tricalcium phosphate, earth alkali metal carbonates, such as magnesium carbonate or calcium carbonate, glidants or flow aids, in particular silica based flow aids, such as colloidal silicon dioxides, pyrogenic silica, silicates, e. g. talcum.
  • anti-caking agents may act as flow aids and vice versa, e. g. silicon dioxide and tricalcium phosphate.
  • the coating is essentially formed by one or more coating agents selected from powdering agents, anticaking-agents, flow aids and combinations thereof.
  • the term “essentially formed” means that the total amount of the respective coating agent is at least 90% by weight, based on the dry weight of the coating.
  • the coating of the beadlets is formed by a combination of at least one native starch and at least one coating agent of the group of anti-caking agents and glidants or flow aids and combinations thereof.
  • the total amount of the coating i. e. t the total amount of the coating agent that forms the coating, is generally in the range of 5 to 30% by weight, in particular in the range of 8 to 25% by weight, based on the dry weight of the beadlet core.
  • the preparation of the present invention can be produced by analogy to standard methods in the art as described e. g. in WO 91/06292, WO 94/19411 and WO 2006/032399 by a process comprising i) providing an aqueous dispersion or suspension containing solid B-carotene particles dispersed in the in the aqueous phase and at least a portion of the further ingredients of the beadlet core which are dissolved and/or dispersed in the aqueous phase of the aqueous suspension/dispersion; ii) converting the aqueous suspension into core beadlets and iii) optionally applying a coating to the core beadlets, where steps ii) and iii) can be carried out simultaneously or subsequently.
  • suspension and dispersion are used synonymously. Even though a skilled person may consider the term “dispersion” may require the presence of a protective colloid while the term “suspension” means its absence, here and throughout the specification, the terms suspension and dispersion include both the absence and the presence of a protective colloid.
  • Step i) can be carried out by analogy to the methods described in WO 91/06292, WO 94/19411 and WO 2006/032399 but also by the micronization technique described in EP 065193.
  • the B-carotene is usually suspended in water or a mixture of water and a water miscible solvent optionally together with at least a portion of the components a.2 and/or a.3 and optionally further components forming the beadlet core.
  • the relative amounts of the B-carotene, the components a.2 and a.3 and any optional further components forming the beadlet core are chosen such that they essentially correspond to the final relative amounts of the beadlet core.
  • the dispersion is subjected to a grinding process. The grinding can be carried out in a manner known per se, for example using a ball mill.
  • D[4.3] refers to the volume-weighted average diameter (see Handbook for Malvern Mastersizer S, Malvern Instruments Ltd., UK).
  • the grinding of step i) is carried out in the presence of at least portion of the protective colloid of component a.3.
  • a portion or total amount of the protective colloid and the optional antioxidant may be previously dissolved in water followed by the addition of the B-carotene to obtain a first aqueous dispersion.
  • the first dispersion is then grinded to the desired particle size outlined above.
  • the grinding of the aqueous grinded can moreover take place both in the presence and in the absence of isomalt.
  • the suspension can also be provided by analogy to the methods described in EP 065193.
  • This procedure typically comprises the following steps: i-1) dissolving the B-carotene in a water-miscible organic solvent or in a mixture of water and a water-miscible organic solvent or in a water immiscible organic solvent; i-2) mixing the solution obtained as in i-1) with an aqueous molecular or colloidal solution of a mixture of isomalt and at least one protective colloid, resulting in the hydrophobic phase of the carotenoid as nanodisperse phase.
  • the water-miscible solvents used in stage i-1) are, in particular, water-miscible, thermally stable, volatile solvents comprising only carbon, hydrogen and oxygen, such as alcohols, ethers, esters, ketones and acetals.
  • the solvents expediently used are those which are at least 10% water-miscible, have a boiling point below 200°C. They typically have fewer than 10 carbons.
  • Those particularly preferably used are methanol, ethanol, n-propanol, isopropanol, 1,2-butanediol 1 -methyl ether, 1 ,2-propanediol 1-n-propyl ether, propylene carbonate, tetrahydrofuran or acetone.
  • a water-immiscible organic solvent means for the purpose of the present invention an organic solvent with a solubility in water of at most 10 g/dl at 20°C under atmospheric pressure.
  • Possible solvents in this connection are, inter alia, halogenated aliphatic hydrocarbons such as, for example, methylene chloride, chloroform and tetrachloromethane, organic carbonates, such as dimethyl carbonate, diethyl carbonate, ethyl formate, methyl, ethyl or isopropyl acetate and ethers such as methyl tert-butyl ether.
  • Preferred water-immiscible organic solvents are the following compounds from the group consisting of dimethyl carbonate, ethyl formate, ethyl acetate, isopropyl acetate and methyl tert-butyl ether.
  • the dissolution of the B-carotene is typically carried out at elevated temperatures of above 30° C, preferably in the range of 50° C to 240° C, in particular 100° C to 200° C, particularly preferably 140° C to 180° C, if appropriate under pressure.
  • the dissolving of the carotenoid(s) is carried out as quickly as possible, for example in the region of seconds, e.g. in 0.1 to 10 seconds, particularly preferably in less than 1 second.
  • elevated pressure e.g. in the range from 20 bar to 80 bar, preferably 30 to 60 bar.
  • the molecular solution obtained in this way is subsequently mixed directly with the aqueous molecular or colloidal solution, which is cooled if appropriate, of the mixture of isomalt and at least one protective colloid.
  • mixing is carried out such a way that a mixing temperature of about 35°C to 80°C is set up. During this, the solvent component is transferred into the aqueous phase, and the hydrophobic phase of the carotenoid(s) results as nanodisperse phase.
  • step ii) of the process the aqueous dispersion obtained in step i) is converted to core beadlets by removing the water and any other volatile components.
  • the conversion into core beadlets can be carried out inter alia by spray drying, spray cooling, modified spray drying, freeze drying or drying in a fluidized bed, e .g. by analogy to the methods described in WO 91/06292, WO 94/19411 and WO 2006/032399.
  • step iii) is carried out.
  • Step iii) may be carried out separately after step iii) or preferably steps ii) and iii) are carried out.
  • step ii) is carried in the presence of a coating material as described above, e. g. by spray drying or spray cooling in the presence of a coating material.
  • the solid preparations of the invention are free flowing powders. They can be easily redispersed without problems in aqueous systems to result in a uniform fine distribution of the active substance in the particle size range below 1 pm.
  • the solid preparations of B- carotenoid of the invention are suitable inter alia as additive to food formula and food supplements, e. g. as means for producing pharmaceutical and cosmetic preparations, and for the production of dietary supplement products, for example of multivitamin products in the human and animal sectors, and also for coloring food products such as beverages.
  • the present invention relates to solid oral dosage forms containing a solid preparation according to present invention and one or more excipients.
  • Suitable excipients for solid dosage forms in particular those for dosage forms obtained by compaction, such as tablets, are known in the art, e. g. in Fiedler, H. P., Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende füre [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 5 th edition, Aulendorf: ECV-Editio- Kantor- Verlag, 2001.
  • a summary of suitable excipients for tablets can be found in the review of K. Varma, Research an Reviews: Journal of Chemistry (RRJCHEM) Vol. 5 (2), June 2016, pp 143-154 (p-ISSN: 2322-00).
  • Examples of typical excipients for solid dosage forms include, but are not limited to:
  • Fillers or diluents such as lactose, micro crystalline cellulose, mannitol, such as Pearlitol SD200 and 25C, sorbitol, dibasic calcium phosphate, dehydrate, calcium sulfate and magnesium oxide;
  • Binders such as as glucose, lactose, cellulose derivatives, e. g. methylcellulose, ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, carboxymethyl cellulose, polivyl pyrrolidone (povidone), sodium alginate;
  • Lubricants such as stearic acid and its salts, e. g. magnesium stearate or calcium stearate, talc, paraffin, sodium lauryl sulfate, sodium benzoate, polyethylene glycols;
  • Glidants such as colloidal silicon dioxicde, conrstarch, talc
  • Ant-adherents such as talc.
  • Superdesintegrants such as crosslinked carboxymethyl cellulose sodium, (XL- CMC, Croscarmellose sodium, AC-Di-sol), crosslinked polyvinylpyrrolidone (Crospovidone) and sodium starch glycolate.
  • the solid formulations may contain further ingredients typically used in solid dosage forms, including active ingredients, such as vitamins, e. g. vitamin B1 (thiamin mononitrate), vitamin B2 (riboflavin), vitamin B3 (niacin), nicotinamide, vitamin B5 (calcium D-pantothenat), vitamin B6 (pyroxidin hydrochloride), vitamin B12 (cobalamin), vitamin E, vitamin C, and further nutrition supplements, such as minerals or trace elements, e. g. Mg, Ca, Fe, Cu, Mn, Zn and/or Se in the form of their salts and/or oxides.
  • active ingredients such as vitamins, e. g. vitamin B1 (thiamin mononitrate), vitamin B2 (riboflavin), vitamin B3 (niacin), nicotinamide, vitamin B5 (calcium D-pantothenat), vitamin B6 (pyroxidin hydrochloride), vitamin B12 (cobalamin), vitamin E, vitamin C, and further nutrition supplements, such as minerals
  • Further ingredients of solid dosage forms may be present, if necessary. Suitable further ingredients, include e. g. preservatives, antioxidants, antiirritants, chelating agents, coating auxiliaries, odor masking agents and taste corrigents.
  • the solid dosage forms contain
  • Suitable solid dosage forms include tablets, gelatine capsules, powders and granules for oral administration.
  • the benefit of the present invention is in particular achieved in solid dosage forms obtained by compaction of a mixture comprising the solid preparation of the present invention and at least one or more excipients and optionally further ingredients, such as minerals, trace elements and/or vitamins.
  • Solid dosage forms obtained by compaction of a mixture comprising the solid preparation of the present invention and at least one or more excipients and optionally further ingredients are in particular tablets.
  • the form of the tablet is not particularly limited.
  • the tablets may be uncoated or coated, e. g. with sucrose, a cellulose derivative or another suitable substance or be treated otherwise in order to display a prolonged or delayed activity and in order to release a predetermined amount of the active basic ingredient continuously.
  • the tablet is a multivitamin mineral tablet.
  • a multivitamin mineral tablet is understood as a tablet, which besides the beadlet preparation of the present invention contains at least one further vitamin in particular e. g. 2, 3, 4, 5 or all of the following vitamins, such as vitamin B1 , vitamin B2, vitamin B3, nicotinamide, vitamin B5, vitamin B6, vitamin B12, vitamin E and/or vitamin C, and at least one mineral nutrition supplement comprising preferably at least one mineral and/or trace element suitable as nutritional supplement, such as Mg, Ca, Fe, Cu, Mn, Zn and/or Se in the form of their salts and/or oxides.
  • vitamins such as vitamin B1 , vitamin B2, vitamin B3, nicotinamide, vitamin B5, vitamin B6, vitamin B12, vitamin E and/or vitamin C
  • at least one mineral nutrition supplement comprising preferably at least one mineral and/or trace element suitable as nutritional supplement, such as Mg, Ca, Fe, Cu, Mn, Zn and/or Se in the form of their salts and
  • the B-carotene from the beadlet preparation and the other the vitamins are typically contained in the ranges of recommended daily dosage.
  • the minerals and trace elements are typically contained in the ranges of recommended daily dosage.
  • the multivitamin mineral tablet comprises
  • vitamins comprising at least two, e. g. 2, 3, 4, 5 or all of the following: vitamin B1 , vitamin B2, vitamin B3, nicotinamide, vitamin B5, vitamin B6, vitamin B12, vitamin E and/or vitamin C; minerals comprising at least two, e. g. 2, 3, 4, 5 or all of the following: magnesium oxide, copper-ll-oxide, iron fumarate, manganese-ll-sulfate monohydrate, potassium chloride, zinc oxide; excipients comprising at least two, e. g. 2, 3, 4 or all of the following: calcium hydrogenphosphate, calcium hydrogenphosphate dihydrate, croscarmellose sodium, stearic acid, magnesium stearate.
  • the B-carotene provided by the beadlet composition is particularly stable against degradation.
  • said multivitamin tablets are characterized by a p-carotene retention over time (timespan months), 40°C, 75 RH of 80% or more after 3 months.
  • Particle size of the beadlets was determined by sieving according to DIN 66165-2:2016-08 using an analytical vibrating sieve shaker (type Retsch AS 200 control).
  • Example 1 Preparation of p-carotene beadlets with isomalt
  • the protective colloid was a commercial octenyl succinate starch (OSA; Capsul HF) having a degree of substitution in the range 1.5-2.5 mol-%. and an weight average molecular weight of approx. 100,000 (typically 80,000-120,000 g/mol measured by GPC using i) a Suprema GPC column from the company Polymer Standards Service GmbH and ii) a MALS and/or a Rl detector.
  • OSA commercial octenyl succinate starch
  • Capsul HF Capsul HF
  • the protective colloid and 50% by weight of the water-soluble antioxidants were dispersed in water and are stirred for 1 h at 60°C.
  • the crystalline p-carotene was dispersed in the aqueous solution and stirred to achieve a wettening of the hydrophopic crystals.
  • the aqueous suspension of the p-carotene was then milled in a wet ball mill until the desired primary particle size of p-carotene, corresponding to an E 1/1 of 90, at temperatures below 60°C was reached. This is to prevent the dispersion from thickening.
  • the E1/1 value defines the specific extinction of a aqueous dispersion of 5 ppm B-carotene in a 1 cm cuvette at the absorption maximum.
  • the isomalt and remaining antioxidants were then added and the dispersion was spray dried in a spray tower at a minimum temperature of 100° C, typically 100-150°C, (temperature in the spray tower) in the presence of powdering agent (corn starch) and flow aid (tricalciumphosphate (TCP)) according to the protocol described on page 6 of WO 91/06292.
  • the spray-dried particles were then post-dried in an integrated fluidized bed drier at a minimum temperature of 40°C, typically 40-70°C, for 5h. At last the particles are sieved to separate fines/dust and oversized/agglomerated particles from the final beadlet composition.
  • the overall composition of the beadlets is given in the following table 1.
  • the mean particle diameter of the beadlets was about 250 pm.
  • the beadlets had a bulk density (untapped) according to European Pharmacopoeia of 0.65 g/cm 2 .
  • Comparative example 1 Preparation of p-carotene beadlets with sucrose.
  • the beadlets of the comparative example were prepared according to the protocol given for example 1, with the only exception that isomalt was replaced by the same amount of sucrose.
  • the overall composition of the beadlets is given in the following table 1.
  • the mean particle diameter of the beadlets was about 250 pm.
  • the beadlets had a bulk density (untapped) according to European Pharmacopoeia of 0.65 g/cm 2 .
  • Table 1 Composition of the beadlet: 1 ) Determined based on the used weights of the ingredients in the formulation manufacturing, the water content was determined after the powder was dried using a gravimetric analysis (105°C - Ph.Eur.). The relative amounts of the components of the core beadlet formulation add to 100% by weight.
  • Q. S. quantitative satis
  • TCP in the range of 0.1 -1% by weight, especially 0.3- 0.5% by weight and to an amount of corn starch in the range of 5-20% by weight, based on the total weight of the beadlet.
  • vitamins vitamin B1 , vitamin B2, nicotinamide, vitamin B5, vitamin B6, vitamin E and vitamin C - the vitamins are contained in the ranges of recommended daily dosage minerals: magnesium oxide, copper-ll-oxide, iron fumarate, manganese-ll-sulfate monohydrate, potassium chloride, zinc oxide - the minerals are contained in the ranges of recommended daily dosage tablet fillers: calcium hydrogenphosphate, calcium hydrogenphosphate dihydrate, croscarmellose sodium, stearic acid, magnesium stearate - listed in descending order (by weight %)
  • Oblong tablets were compacted with an average weight of approx. 1200 mg per tablet.
  • the tablets were produced by subjecting the thoroughly mixed in ingredients in a tableting apparatus at 20°C applying compaction pressure of 20-25 kN.
  • the stability of the vitamin p-carotene beadlets was tested by means of multi-vitamin mineral tablets having a content of about 3mg of p-carotene per tablet.
  • the tablets were packaged in HDPE containers whose lid was sealed with heat sealed aluminum foil.
  • the tablets were stored at 40°C and 75% relative humidity (RH) for 1, 2, 3 and 6 months.
  • RH relative humidity
  • the P-carotene was analyzed in each case after storage for 1, 2, 3 and 6 months.
  • the content of B-Carotene in the tablet was spectrophotometically assessed via LIV/VIS.
  • the tablet is dissolved in 3N aqueous KOH at 65°C for 15 minutes.
  • the obtained solution is cooled to ambient temperature and extracted with a defined amount of cyclohexane which after extraction is diluted with a defined amount of isopropanol.
  • the obtained solution is subjected to LIV/VIS spectrometry and the intensity at peak maximum (452 +/- 5 nm) is measured.
  • Table 2 Storage stability of p-carotene beadlets in multivitamin (MVM) tablets
  • Examples 2 to 5 and Comparative examples 2 and 3 Preparation of p-carotene beadlets with varying amount of isomalt
  • the beadlets of the were prepared according to the protocol given for example 1 , with the overall composition given in the following table 3.
  • the mean particle diameter of the beadlets was about 250 pm.
  • the beadlets of the were prepared according to the protocol given for example 1, with the overall composition given in the following table 4.
  • the mean particle diameter of the beadlets was about 250 pm.
  • Table 5 Storage stability of p-carotene beadlets in multivitamin mineral (MVM) tablets, depending on the isomalt content

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Abstract

La présente invention concerne des préparations solides de β-carotène sous forme de petites billes, comprenant a) un cœur de petite bille contenant a.1 20 à 40 % en poids de β-carotène en tant que composant a.1 ; a.2 30 à 75 % en poids d'isomalt en tant que composant a.2 ; a.3 5 à 55 % en poids d'au moins un colloïde protecteur du groupe des polysaccharides et des polysaccharides modifiés en tant que composant a.3, la quantité relative de chaque composant se rapportant au poids sec total du cœur de petite bille, et b) éventuellement un enrobage. La présente invention concerne également une forme posologique orale solide contenant une préparation solide telle que décrite ici et un ou plusieurs excipients.
PCT/EP2024/068702 2023-07-03 2024-07-03 Préparations solides de bêta-carotène Pending WO2025008385A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0065193A2 (fr) 1981-05-15 1982-11-24 BASF Aktiengesellschaft Procédé de fabrication de préparations pulvérulentes, finement divisées, de compositions caroténoides ou rétinoides
WO1991006292A1 (fr) 1989-11-02 1991-05-16 Danochemo A/S Procede de preparation d'un solide hydrophobe ou aerophile dispersible dans l'eau
WO1994019411A1 (fr) 1993-02-19 1994-09-01 Danochemo A/S Procede d'obtention d'une preparation pulverulente de carotenoide hydro-dispersible
WO2006032399A2 (fr) 2004-09-21 2006-03-30 Basf Aktiengesellschaft Procede de production de poudres seches d'un ou de plusieurs carotenoides
CN116268416A (zh) * 2023-04-28 2023-06-23 西藏多欣健康科技有限公司 含麦芽糊精和结晶果糖的组合物及其制备方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0065193A2 (fr) 1981-05-15 1982-11-24 BASF Aktiengesellschaft Procédé de fabrication de préparations pulvérulentes, finement divisées, de compositions caroténoides ou rétinoides
WO1991006292A1 (fr) 1989-11-02 1991-05-16 Danochemo A/S Procede de preparation d'un solide hydrophobe ou aerophile dispersible dans l'eau
EP0498824A1 (fr) 1989-11-02 1992-08-19 Danochemo As Procede de preparation d'un solide hydrophobe ou aerophile dispersible dans l'eau.
WO1994019411A1 (fr) 1993-02-19 1994-09-01 Danochemo A/S Procede d'obtention d'une preparation pulverulente de carotenoide hydro-dispersible
WO2006032399A2 (fr) 2004-09-21 2006-03-30 Basf Aktiengesellschaft Procede de production de poudres seches d'un ou de plusieurs carotenoides
CN116268416A (zh) * 2023-04-28 2023-06-23 西藏多欣健康科技有限公司 含麦芽糊精和结晶果糖的组合物及其制备方法

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
"European Pharmacopeia", article "Isomalt", pages: 3137 - 3139
"Ullmann's Encyclopedia of Industrial Chemistry", 2000, article "Wet Grinding"
FIEDLER, H. P.: "Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete", 2001, ECV-EDITIO-KANTOR-VERLAG
K. VARMA, RESEARCH AN REVIEWS: JOURNAL OF CHEMISTRY (RRJCHEM, vol. 5, no. 2, June 2016 (2016-06-01), pages 143 - 154, ISSN: 2322-00

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