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WO2025012339A1 - Préparations solides de vitamine a - Google Patents

Préparations solides de vitamine a Download PDF

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Publication number
WO2025012339A1
WO2025012339A1 PCT/EP2024/069548 EP2024069548W WO2025012339A1 WO 2025012339 A1 WO2025012339 A1 WO 2025012339A1 EP 2024069548 W EP2024069548 W EP 2024069548W WO 2025012339 A1 WO2025012339 A1 WO 2025012339A1
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WO
WIPO (PCT)
Prior art keywords
vitamin
weight
solid preparation
beadlets
component
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PCT/EP2024/069548
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English (en)
Inventor
Cosima HIRSCHBERG
Kristin MUNKERUP
Jesper Feldthusen Jensen
Stephanie NACHTIGALL
Kathrin Meyer
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BASF SE
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BASF SE
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Publication of WO2025012339A1 publication Critical patent/WO2025012339A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • 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

Definitions

  • the present invention relates to solid preparations of vitamin A in the form of beadlets which contain a high amount of vitamin A.
  • Vitamin A is a fat-soluble vitamin, hence an essential nutrient.
  • Vitamin A encompasses a group of chemically related organic compounds that includes retinol, its esters, retinal (also known as retinaldehyde) and retinoic acid.
  • Vitamin A has multiple functions: essential in embryo development for growth, maintaining the immune system, and healthy vision, where it combines with the protein opsin to form rhodopsin - the light-absorbing molecule necessary for both low-light (scotopic vision) and colour vision.
  • Vitamin A is primarily used for animal feed, but also in food, in prescription medication and as dietary supplement. Most of the vitamin A in the market is produced synthetically.
  • Vitamin A is insoluble in water, however soluble in fats and oils.
  • an oil is not suitable for the use in various solid vitamin supplements such as dry premixes, food premixes and different forms of dietary supplements, especially tablets.
  • Beadlets are a special form of powder preparations. They have typically a core which contains an active, e. g. vitamin A and matrix materials and optionally a covering or coating, which reduces the sticking of the particles. Beadlets are usually obtained by providing an emulsion or dispersion of the respective active, here an emulsion of vitamin A, in water and/or a volatile organic solvent with a colloid, stirring/emulsifying it to the desired droplet size and then spray-drying the emulsion together with additional matrix material. Beadlets have typically a medium particle size (d(0,5)) 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.).
  • d(0,5) medium particle size 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.).
  • WO 2021/165288 describes powders of fat-soluble vitamins, such as vitamin A esters, which besides the fat soluble vitamin contain a hydrocolloid, a starch hydrolysate such as maltodextrin, tocopherol and sodium ascorbate.
  • the powders of WO 2021/165288 provide an improved stability to the vitamin A against degradation, in particular oxidative degradation due to the high amount of sodium ascorbate and tocopherol.
  • the stabilization of vitamin A provided by the powders of WO 2021/165288 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 stability problem becomes even more prominent, when the content of the vitamin A in the beadlet core is 10% by weight or higher than 10% by weight, in particular at least 15% by weight.
  • vitamin A 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.
  • 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, alginates, gums, such as gum arabic (synonym of acacia gum), guar gum, caroub 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, alginates, gums, such as gum arabic (synonym of acacia gum), guar gum,
  • 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 usually 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 quality 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 vitamin A.
  • the total amount of the components a.2 and a.3 is at least 50% 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.1, in particular the vitamin A esters is preferably at least 0.9:1 in particular at least 1.0:1 and especially at least 1.2:1, preferably in the range of 0.9: 1 to 5.0:1, in particular in the range of 1.0: 1 to 4.5: 1 , especially in the range of 1.2: 1 to 4.0: 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 weight ratio of isomalt to the component a.3, in particular the modified starch is preferably at least 0.8:1, in particular at least 1.0:1 and especially at least 1.2:1, preferably in the range of .8: 1 to 5.0:1, in particular in the range of 1.0: 1 to 3.5: 1 , especially in the range of 1.2: 1 to 3.0: 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 vitamin A particles.
  • the beadlet core may contain one or more antioxidants in order to increase the stability of the vitamin A.
  • 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 0.1 to 10% by weight, preferably 0.5 to 7% by weight, especially 1 to 6% 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.
  • 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
  • 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. If the beadlets have a coating, 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 EP 1938807 or WO 2021/165288 by a process comprising i) providing an aqueous emulsion containing vitamin A droplets, in particular droplets of one or more vitamin A esters, in the in the aqueous phase and at least a portion of the further ingredients of the beadlet core which are dissolved, emulsified and/or dispersed in the aqueous phase of the aqueous emulsion; ii) converting the aqueous emulsion 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.
  • Step i) can be carried out by analogy to the methods described in EP 1938807 or WO 2021/165288.
  • the vitamin A in particular one or more vitamin A esters, is/are usually emulsified 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 vitamin A, 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.
  • molten vitamin A in particular a melt of one or more vitamin A esters, optionally in combination with an organic stabilizing agent, such as tocopherol, is introduced into an aqueous solution of at least a portion of the component a.3 and optional of the component a2) at a temperature, were the vitamin A, in particular the ester remains in its molten state.
  • the solution of the component a.3 and optionally a.2 is typically preheated to a temperature in the range of +/-20 0 C of the melt.
  • the emulsion is typically carried out at a temperature in the range of at least 50°C, e. g. in the range of 50 to 100°C.
  • the emulsification can be carried out in a manner known per se, for example using mixing devices which apply shear forces to the emulsion, such as stirrers, homogenizers or by pumping.
  • mixing devices which apply shear forces to the emulsion
  • This entails, depending on the type of mixing device, emulsification until the droplets of the vitamin A have an average particle size D[4.3] determined by Fraunhofer diffraction of at most 5 pm, preferably at most 2 pm, particularly at most 1 pm.
  • D[4.3] refers to the volume-weighted average diameter (see Handbook for Malvern Mastersizer S, Malvern Instruments Ltd., UK).
  • the emulsification 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 emulsion followed by the addition of the molten vitamin A to obtain a first aqueous dispersion.
  • the first emulsion is then homogenized to the desired droplet size outlined above. The emulsification can moreover take place both in the presence and in the absence of isomalt.
  • step ii) of the process the aqueous emulsion 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 , EP 1938807 or WO 2021/165288.
  • 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 droplet size range below 1 pm.
  • the solid preparations of vitamin A 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.
  • 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 sulphate and magnesium oxide; • Binders, such as glucose, lactose, cellulose derivatives, e. g. methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, polivyl pyrrolidone (povidone), sodium alginate;
  • Binders such as glucose, lactose, cellulose derivatives, e. g. methylcellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl 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 sulphate, sodium benzoate, polyethylene glycols;
  • Glidants such as colloidal silicon dioxide, cornstarch, talc
  • Ant-adherents such as talc.
  • Further ingredients of solid dosage forms may be present, if necessary. Suitable further ingredients, include e. g. preservatives, antioxidants, antiirritants, chelating agents, coating auxiliaries, odour masking agents and taste corrigents.
  • the solid dosage forms contain
  • the respective beadlet preparation of the present invention containing the vitamin A, preferably such that the solid dosage form contains 1000 to 20000 I U/g of vitamin A or from 1000 to 20000 III per dosage unit;
  • Suitable solid dosage forms include tablets, gelatine capsules, powders and granules for oral administration.
  • 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.
  • the vitamins A 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 hydrogen phosphate, calcium hydrogen phosphate dihydrate, croscarmellose sodium, stearic acid, magnesium stearate.
  • the vitamin A provided by the beadlet composition is particularly stable against degradation.
  • said multivitamin tablets are characterized by a vitamin A 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).
  • 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 a 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 vitamin A acetate was melted at 65-70°C under a N2 cover until it is fully liquid.
  • DL-a- tocopherol was added to the molten vitamin A acetate and distributed in the molten vitamin A acetate to obtain a homogeneous molten oil phase.
  • the protective colloid and partially the water-soluble antioxidants were dissolved with constant stirring at 60°C.
  • the molten oil phase was then pumped into the aqueous solution in an amount such that a dry matter content of 55 to 70% was achieved.
  • Emulsification was carried out with stirring at 55-65°C until the vitamin A acetate was dispersed finely in the emulsion.
  • the remaining ingredients such as additional water- soluble antioxidants and isomalt, were then added to the emulsions.
  • the emulsion was then diluted with water to a viscosity of 50-250 mPas, as determined by a modular rotational rheometer (RheolabQC, AntonPaar) at 60°C.
  • the emulsion was then 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 (tricalcium phosphate (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 general overall composition of the beadlets is given in the following table 1.
  • the mean particle diameter of the beadlets was about 150 to 250 pm.
  • the beadlets had a bulk density (untapped) according to European Pharmacopoeia of 0.65-0.75 g/cm 2 .
  • the term “Quantum satis” is understood in its pharmacological meaning and in particular refers to an amount of 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.
  • Example 1 Preparation of vitamin A acetate beadlets with isomalt.
  • the beadlets of the example 1 were prepared according to the general protocol given above using isomalt and vitamin A acetate.
  • the overall composition of the beadlets is given in the following table 1.
  • the mean particle diameter of the beadlets was about 162 pm.
  • the beadlets had a bulk density (untapped) according to European Pharmacopoeia of 0.73 g/cm 2 .
  • Comparative example 1 Preparation of vitamin A beadlets with sucrose.
  • the beadlets of the comparative example 1 were prepared according to the general protocol given above using isomalt and vitamin A acetate.
  • the overall composition of the beadlets is given in the following table 2.
  • the mean particle diameter of the beadlets was about 177 pm.
  • the beadlets had a bulk density (untapped) according to European Pharmacopoeia of 0.72 g/cm 2 .
  • 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 hydrogen phosphate, calcium hydrogen phosphate 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 A acetate beadlets was tested by means of multi-vitamin mineral tablets having a content of about 4000 I U/g of vitamin A 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.
  • the vitamin A was analyzed in each case after storage for 1, 2, 3 and 6 months. The results are summarized in table 3a.
  • the content of vitamin A acetate in the tablet was spectrophotometrically assessed via LIV/VIS.
  • the tablet is dissolved in 10% by weight of ethanolic KOH to reflux for 30 minutes.
  • the obtained solution is cooled to ambient temperature diluted with water and extracted with a defined heptane to obtain a theoretical concentration of about 20 lll/mL.
  • Table 3a Storage stability of vitamin A beadlets in multivitamin (MVM) tablets
  • Table 3b Storage stability of vitamin A beadlets in bulk
  • Examples 2 to 4 and Comparative examples 6 to 8 Preparation of vitamin A acetate beadlets with varying amount of isomalt and different sugars.
  • Trehalose dihydrate was obtained from Sigma Aldrich and had a treaholose content of min 98 % by weight
  • Maltodextrin 1 Glucidex 19 of Roquette having a DE value of 18-20
  • Maltodextrin 2 Glucidex 29 of Roquette having a DE value of 27-31
  • Maltodextrin 3 Glucidex 47 of Roquette having a DE value of 43-47
  • the beadlets of the were prepared according to the protocol of the general procedure with the overall composition given in the following table 4.
  • the mean particle diameter of the beadlets was about 210-240 pm and a tapped bulk density of about 0.70-0.71 g/cm 3 .
  • the beadlets of the were prepared according to the protocol of the general procedure with the overall composition given in the following table 6.
  • the mean particle diameter of the beadlets was about 210-240 pm and a tapped bulk density of about 0.70-0.71 g/cm 3
  • the storage stability was assessed as described above.
  • Table 6 Composition of the beadlet:
  • the beadlets of the were prepared according to the protocol of the general procedure with the overall composition given in the following table 8.
  • the storage stability was assessed as described above using the tablet compositions (a) and (b) given in the following table 9.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des préparations solides de vitamine A se présentant sous la forme de granules, et comprenant a) un noyau de granule contenant a.1 de la vitamine A en tant que composant a.1 ; a.2 de l'isomalt en tant que composant a.2 ; a.3 au moins un colloïde protecteur en tant que composant a.3, la quantité relative de chaque composant se rapportant au poids sec total du noyau de granule, et b) éventuellement un revêtement. La présente invention concerne des formes posologiques solides à administrer par voie orale contenant une préparation solide telle que définie dans la description et un ou plusieurs excipients, en particulier des comprimés minéraux multivitaminés. La présente invention concerne l'utilisation d'isomalt dans une préparation solide de vitamine A sous forme de granules comprenant des noyaux de granule pour augmenter la stabilité chimique de l'acétate de vitamine A dans lesdites granules.
PCT/EP2024/069548 2023-07-10 2024-07-10 Préparations solides de vitamine a Pending WO2025012339A1 (fr)

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EP23184514.0 2023-07-10
EP23184514 2023-07-10

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WO2025012339A1 true WO2025012339A1 (fr) 2025-01-16

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0864326A2 (fr) * 1997-03-12 1998-09-16 Knoll Ag Préparation multiphasique comprenant un agent actif
WO2006032399A2 (fr) * 2004-09-21 2006-03-30 Basf Aktiengesellschaft Procede de production de poudres seches d'un ou de plusieurs carotenoides
EP1938807A1 (fr) 2006-12-22 2008-07-02 Basf Se Poudrage réactive
WO2018210981A1 (fr) * 2017-05-19 2018-11-22 Dsm Ip Assets B.V. Particules solides
WO2021165288A1 (fr) 2020-02-18 2021-08-26 Basf Se Poudres de vitamine liposoluble stables

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
EP0864326A2 (fr) * 1997-03-12 1998-09-16 Knoll Ag Préparation multiphasique comprenant un agent actif
WO2006032399A2 (fr) * 2004-09-21 2006-03-30 Basf Aktiengesellschaft Procede de production de poudres seches d'un ou de plusieurs carotenoides
EP1938807A1 (fr) 2006-12-22 2008-07-02 Basf Se Poudrage réactive
WO2018210981A1 (fr) * 2017-05-19 2018-11-22 Dsm Ip Assets B.V. Particules solides
WO2021165288A1 (fr) 2020-02-18 2021-08-26 Basf Se Poudres de vitamine liposoluble stables

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields", 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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