Solid preparations of vitamin a

Abstract

The present invention relates to solid preparations of vitamin A in the form of beadlets, comprising a) beadlet core containing 5 a.1 vitamin A as a component a.1; a.2 isomalt as a component a.2; a.3 at least one protective colloid as a component a.3, where the relative amount of each component refers to the total dry weight of beadlet core, and b) optionally a coating. The present invention relates to solid oral dosage forms containing a solid preparation as defined herein and one or more excipients, in particular to multivitamin mineral tablets. The present invention relates to the use of isomalt in a solid preparation of Vitamin A in the form of beadlets comprising core beadlets for increasing the chemical stability of Vitamin A acetate in said beadlets.

Description

[0001] Solid preparations of vitamin A

[0002] The present invention relates to solid preparations of vitamin A in the form of beadlets which contain a high amount of vitamin A.

[0003] 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.

[0004] Vitamin A is insoluble in water, however soluble in fats and oils. The high sensitivity of vitamin A to oxidation stand in the way of direct use of the straight Vitamin A oily products obtained by chemical synthesis. Moreover, 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.

[0005] These problems can in principle be overcome by solid powder preparations in which the vitamin A is present in finely dispersed droplet form and the fine droplets of vitamin A are embedded in a solid matrix containing one or more water-soluble carbohydrates and / or protective colloids as main matrix components and are thus protected against degradation in particular oxidation.

[0006] 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.).

[0007] 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. However, 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.

[0008] It was surprisingly found that the stability of 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.

[0009] Therefore, the present invention relates to solid preparations of vitamin A in the form of beadlets, comprising a) a beadlet core, which contains a.1) vitamin A as a component a.1 ; a.2) isomalt as a component a.2; a.3) at least one protective colloid from the group of polysaccharides and modified polysaccharides as a component a.3, and optionally b) a beadlet coating.

[0010] The solid preparations of the present invention provide superior stability to vitamin A, 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 using beadlet formulations which are easily to handle.

[0011] Therefore, 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.

[0012] Yet a further aspect of the present invention relates to the use of isomalt in the solid preparation of vitamin A as defined herein for increasing the chemical stability of vitamin A in said the solid preparation.

[0013] In particular, the present invention relates the use of isomalt in the solid preparation of vitamin A in the form of beadlets, in particular in the solid preparation as defined herein for increasing the chemical stability of vitamin A 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. Here and in the following, the term vitamin A refers to the group of retinol (vitamin A alcohol), the retinol esters, such as retinol acetate, retinol propionate, retinol myristate, retinol palmitate, retinol stearate and retinol oleate, retinal and retinoic acid.

[0014] Here and in the following, the stability of vitamin A refers to its stability against degradation, in particular degradation caused by oxidative stress, which vitamin A typically suffers upon storage of solid dosage forms containing solid preparations of vitamin A.

[0015] According to the present invention, the solid preparation of vitamin A is in the form of beadlets, which means that the solid preparation essentially consists of beadlets. In this context, 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.

[0016] Here and throughout the specification, the term “beadlet” refers to particles, which are formed by the beadlet core and the optional coating. In other words, the term “solid preparation of vitamin A in the form of beadlets” refers to compositions in the form of beadlets which have

[0017] (a) a beadlet core that contains the components a.1 , a.2 and a.3 and optionally further components; and optionally

[0018] (b) coating.

[0019] Here and throughout the specification, the term “beadlet core” refers to the beadlet without the optional coating.

[0020] In particular, the beadlet and also the beadlet core are spherical or almost spherical particles. The term “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.

[0021] Typically, the beadlets of the solid preparation have a medium diameter (d(0,5) value) in the range of 50 to 1000 pm, in particular in the range of 100 to 500 pm, especially in the range of 180 to 350 pm, as determined by sieving according to European Pharmacopeia (Ph. Eur.).

[0022] Here and in the following, 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.

[0023] In this context, 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. In the context of the particle distribution of the beadlets, 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.

[0024] According to the invention, the beadlet core typically contains the components a.1, a.2 and a.3 and optionally further components. Typically, the components of the beadlet core are are evenly distributed within the beadlet core.

[0025] According to the invention, the beadlet core contains vitamin A as the component a.1. The relative amount of vitamin A is usually in the range of 10 to 50% by weight, in particular in the range of 15 to 40% by weight, especially in the range of 20 to 30% by weight, based on the total dry weight of beadlet core. Typically the content of vitamin A of the beadlet core, expressed in International units per gram (I U / g) is in the range of 250.000 to 575.000 I U / g. For example 1 IU of vitamin A corresponds to 0.300 pg of retinol, 0.344 pg of retinylacetate or 0.546 pg of retinyl palmitate (see e. g. Opinion of the Scientific Committee on Food (SCF) on the Tolerable Upper Intake Level of Preformed Vitamin A (retinol and retinyl esters) 2002 and D-A-CH Referenzwerte fur die Nahrstoffzufuhr (Reference Values for Nutrient intake) , 1stEd., Umschau Braus GmbH Verlagsgesellschaft, 2000). The amount of vitamin A in the beadlet core can be determined by standard analytical methods, e. g. by HPLC as described in the European Pharmacopeia, 11.3 (01 / 2018:0218, p. 5294 f.) or by the procedure described in the examples.

[0026] Here and throughout the specification, the term “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.

[0027] Typically, the vitamin A is present in the beadlets in the form of fine dispersed oil droplets, having generally a droplet 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).

[0028] The vitamin A of component a.1 is in particular a retinol ester, which is also frequently termed vitamin A ester. In particular retinol ester is an ester of retinol with an aliphatic monocarboxylic acid, i. e. an alkanoic acid or an alkenoic acid having usually 2 to 20 carbon atoms, such as retinyl acetate, retinyl propionate, retinyl myristate, retinyl palmitate, retinyl stearate and retinyl oleate. The retinol ester may be a synthetic retinol ester obtained by classical organic syntheses or by biochemical syntheses, mostly by fermentation. Typically, the synthetic retinol ester 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.

[0029] According to the invention, 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). 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.

[0030] The relative amount of isomalt is usually in the range of 20 to 75% by weight, in particular in the range of 30 to 60% by weight, especially in the range of 30 to 55% by weight or 30 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. In other words, the analytical content of GPS and GPM in the beadlet core may be somewhat smaller than the amount used for production.

[0031] According to the invention, 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.

[0032] Here and throughout the specification, the term “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.

[0033] Here and throughout the specification, the term “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. Generally, the 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. Typically, 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. For further details we refer to the experimental part.

[0034] Examples of 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).

[0035] Preference is given to modified starches, gums, in particular gum arabic, and mixtures thereof as the component a.3. Preference is given to components a.3, which comprise or consists of a modified starch. Particular preference is given to components a.3, wherein 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.

[0036] Especially, 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.

[0037] Typically, 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.

[0038] 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. In particular, 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. For further details we refer to the experimental part.

[0039] Examples of octenyl succinate starches 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.

[0040] 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.

[0041] Due to the comparatively high relative weight of the components a.2 and a.3 compared to the vitamin A of component a.1, 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. Typically, 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. 55 to 80% by weight or 55 to 79.9% by weight, in particular 60 to 80% by weight or 60 to 79.5% by weight, especially to 65 to 80% by weight or 65 to 79% by weight, where the total amount of the components a.2 and a.3 refers to the total dry weight of beadlet core.

[0042] For the stability of the vitamin A it was found beneficial that 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.

[0043] For the stability of the vitamin A it was found beneficial that 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.

[0044] In addition to the aforementioned components a.1 to a.3, the beadlet core may contain one or more further components, conventionally used in the preparation of vitamin A particles.

[0045] For example, the beadlet core may contain one or more antioxidants in order to increase the stability of the vitamin A. Examples of 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.

[0046] The beadlet core may contain water. Preferably, 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.

[0047] 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.

[0048] 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. Suitable coating agents are well known in the art, e. g. from WO 91 / 06292.

[0049] 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.

[0050] A skilled person will immediately recognize that some anti-caking agents may act as flow aids and vice versa, e. g. silicon dioxide and tricalcium phosphate.

[0051] In particular, the coating is essentially formed by one or more coating agents selected from powdering agents, anticaking-agents, flow aids and combinations thereof. With respect to the coating, 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.

[0052] In particular, the coating of the beadlets, if present, 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.

[0053] 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.

[0054] Step i) can be carried out by analogy to the methods described in EP 1938807 or WO 2021 / 165288.

[0055] In step i), 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. It is immediately apparent to a skilled person that for the production of the beadlet preparation of the present invention, 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.

[0056] For this, usually 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. For this, the solution of the component a.3 and optionally a.2 is typically preheated to a temperature in the range of + / -200C 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. 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. The term D[4.3] refers to the volume-weighted average diameter (see Handbook for Malvern Mastersizer S, Malvern Instruments Ltd., UK). Preferably the emulsification of step i) is carried out in the presence of at least portion of the protective colloid of component a.3. For example, 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.

[0057] In 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.

[0058] If the preparation of the present invention contains a coating, a step iii) is carried out. Step iii) may be carried out separately after step iii) or preferably steps ii) and iii) are carried out. In this case, 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.

[0059] 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.

[0060] The present invention relates to solid oral dosage forms containing a solid preparation according to present invention and one or more excipients.

[0061] 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 Gebiete [Encyclopedia of auxiliary substances for pharmacy, cosmetics and related fields], 5thedition, 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:

[0062] 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;

[0063] • Lubricants, such as stearic acid and its salts, e. g. magnesium stearate or calcium stearate, talc, paraffin, sodium lauryl sulphate, sodium benzoate, polyethylene glycols;

[0064] • Glidants, such as colloidal silicon dioxide, cornstarch, talc;

[0065] • Ant-adherents, such as talc.

[0066] • Superdesintegrants, such as crosslinked carboxymethyl cellulose sodium, (XL- CMC, Croscarmellose sodium, AC-Di-sol), crosslinked polyvinylpyrrolidone (Crospovidone) and sodium starch glycolate.

[0067] In addition the a aforementioned excipients, the solid formulations may contain further ingredients typically used in solid dosage forms, including active ingredients, such as vitamins, e. g. vitamin B1 (thiamine 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.

[0068] 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.

[0069] Typically, the solid dosage forms contain

[0070] 0.5 to 5% by weight, based on the total weight of the solid dosage form, of 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;

[0071] 70 to 99.5% by weight, based on the total weight of the solid dosage form, of one or more conventional excipients; and

[0072] 0 to 29.5 % by weight, based on the total weight of the solid dosage forms, of one or more further ingredients, such as vitamins, trace elements and / or minerals.

[0073] Suitable solid dosage forms include tablets, gelatine capsules, powders and granules for oral administration.

[0074] 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.

[0075] In a particular embodiment, 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. In the multivitamin mineral tablet, the vitamin A from the beadlet preparation and the other the vitamins are typically contained in the ranges of recommended daily dosage. In the multivitamin mineral tablet, the minerals and trace elements are typically contained in the ranges of recommended daily dosage.

[0076] Typically, the multivitamin mineral tablet comprises

[0077] • 0.5 to 5% by weight, based on the total weight of the solid dosage forms, of the respective beadlet preparation of the present invention containing the vitamin A;

[0078] • 95-99.5 % by weight of a mineral / vitamin composition containing the following ingredients:

[0079] - 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.

[0080] In the multivitamin mineral tablets of the present invention the vitamin A provided by the beadlet composition is particularly stable against degradation. In particular, 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. Abbreviations: b.w. by weight

[0081] Comp. Comparative

[0082] GPC Gel Permeation Chromatography

[0083] HPLC High Performance Liquid Chromatography

[0084] MALS Multi Angle Light Scattering Detection

[0085] OSA octenyl succinate starch

[0086] Q. S. quantum satis

[0087] RH Relative Humidity

[0088] Rl Refractive Index

[0089] TCP Tricalcium phosphate

[0090] TP Time point (the number in brackets indicate the month)

[0091] Examples

[0092] Analytics of the beadlets:

[0093] 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).

[0094] General Procedure: Preparation of vitamin A acetate beadlets with isomalt or other sugar / sugar alcohol

[0095] 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.

[0096] 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.

[0097] In a separate vessel, 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.

[0098] 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 / cm2.

[0099] Table 1 :

[0100] Here and in all other examples, 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.

[0101] Example 1 : Preparation of vitamin A acetate beadlets with isomalt.

[0102] The beadlets of the example 1 were prepared according to the general protocol given above using isomalt and vitamin A acetate.

[0103] 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 / cm2.

[0104] 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.

[0105] 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 / cm2.

[0106] Table 2: Composition of the vitamin A acetate beadlet:

[0107] 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.

[0108] The respective beadlet preparations were compacted in multivitamin mineral tablets having the following overall composition

[0109] 1.4% by weight of the respective vitamin A acetate beadlets

[0110] 98.6% by weight of a mineral / vitamin composition containing the following ingredients:

[0111] - 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.

[0112] 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.

[0113] In the same way, the stability of vitamin A acetate in the vitamin A acetate beadlets was tested by storing the beadlets 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 3b.

[0114] The content of vitamin A acetate in the tablet was spectrophotometrically assessed via LIV / VIS. For this, 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. The obtained solution is subjected to quantitative HPLC against a standard using LiChromosorb CN 5 pm column (L = 250 mm, i.d. 4.0 mm) with UV detection at 325 nm using 1% pentanol in heptane as a mobile phase.

[0115] Table 3a: Storage stability of vitamin A beadlets in multivitamin (MVM) tablets

[0116] Table 3b: Storage stability of vitamin A beadlets in bulk

[0117] Examples 2 to 4 and Comparative examples 6 to 8: Preparation of vitamin A acetate beadlets with varying amount of isomalt and different sugars.

[0118] 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 / cm3.

[0119] The storage stability was assessed as described above. The results are summarized in table 5.

[0120] Table 4: Composition of the beadlet:

[0121] 1 ) see definition in table 1

[0122] Table 4: continued:

[0123] 2) see definition in table 1

[0124] Table 4: continued:

[0125] 3) see definition in table 1

[0126] Table 5

[0127] Examples 5 to 9: Preparation of vitamin A acetate beadlets with varying amount of isomalt and vitamin A acetate

[0128] 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 / cm3 The storage stability was assessed as described above. The results are summarized in table 7. Table 6: Composition of the beadlet:

[0129] 1 ) see definition in table 1

[0130] Table 7 Example 10 and Comparative example 9: Investigation of vitamin A acetate beadlets in different tablet matrices

[0131] 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.

[0132] The results are summarized in table 10. Table 8: Composition of the beadlet:

[0133] 1 ) see definition in table 1 The respective beadlet preparations were compacted in tablets a 450 mg (diameter 9 mm) having the following compositions (a) and (b) summarized in table 8. In case of composition (a) a compaction force of 15 kN in case of composition (b) a compaction force of 10 kN was applied. Table 9

[0134] Table 10

Claims

Claims1. A solid preparation of vitamin A in the form of beadlets, comprising a) a beadlet core containing a.1 vitamin A as a component a.1 ; a.2 isomalt as a component a.2; a.3 at least one protective colloid as a component a.3, where the relative amount of each component refers to the total dry weight of beadlet core, and b) optionally a coating.

2. The solid preparation according to claim 1 , where the beadlet core comprises a.1 10 to 50%, by weight, in particular 15 to 40% by weight, especially 20 to30% by weight of vitamin A as a component a.1 ; a.2 20 to 75% by weight, in particular 30 to 60% by weight, especially 30 to55% by weight of isomalt as a component a.2; a.3 5 to 70% by weight, in particular 10 to 35% by weight, especially 15 to35% by weight of at least one protective colloid as a component a.3, where the relative amount of each component refers to the total dry weight of beadlet core.

3. The solid preparation according to any one of the preceding claims, wherein the weight ratio of isomalt to the component a.3 is in the range of 1.0:1 to 3.0:1, in particular in the range of 1.1 :1 to 2.5:1, especially in the range of 1 :2:1 to 2.2:1.

4. The solid preparation according to any one of the preceding claims, wherein the component a.3 is selected from the group of polysaccharides and modified polysaccharides5. The solid preparation according to claim 4, wherein the component a.3 is selected from modified starches and gums, such as acacia gum.

6. The solid preparation according to claim 5, wherein the modified starches are selected from alkyl succinate modified starch and alkenyl succinate modified starch, such as octenyl succinate modified starches.

7. The solid preparation according to claim 6, wherein the alkyl succinate modified starch and alkenyl succinate have a weight average molecular weight in the range of 5,000 to 1 ,000,000 g / mol as determined by gel permeation chromatography and / or a degree of substitution in the range of 1 to 3% with respect to the glucose units of the starch.

8. The solid preparation according to any one of the preceding claims, wherein the vitamin A is selected from vitamin A esters, in particular vitamin A acetate, vitamin A propionate, vitamin A palmitate and mixtures thereof.

9. The solid preparation according to any one of the preceding claims, wherein the beadlets have a medium diameter in the range of 50 to 1000 pm, in particular in the range of 100 to 500 pm, especially in the range of 180-350 pm, as determined by sieving according to European Pharmacopeia (Ph. Eur.).

10. The solid preparation according to any one of the preceding claims, wherein the coating is essentially formed by one or more coating agents selected from powdering agents, anticaking agents, flow aids and combinations thereof.

11. The solid preparation according to claim 10, wherein the coating agent is selected from native starches, earth alkali phosphate, silica based flow aids earth alkali carbonates and combinations thereof.

12. The solid preparation according to any one of the preceding claims, wherein the total amount of the coating agent is in the range of 5 to 30% by weight, in particular 8 to 25% by weight, based on the dry weight of the beadlet.

13. A solid oral dosage form containing a solid preparation according to any one of the preceding claims and one or more excipients.

14. The solid oral dosage form of claim 13 which is a tablet obtained by compaction of a mixture of the solid preparation and the one or more excipients.

15. The solid oral dosage form of claim 14 which is a tablet, in particular a multivitamin mineral tablet.

16. The use of isomalt in a solid preparation of Vitamin A in the form of beadlets comprising core beadlets for increasing the chemical stability of Vitamin A acetate in said beadlets.

17. The use of isomalt in the solid preparation of vitamin A as defined in any one of claims 1 to 12 for increasing the chemical stability of vitamin A in said the solid preparation and / or in solid dosage forms containing said solid preparation.

18. The use according to claim 17, wherein said solid composition has been compacted to multivitamin mineral tablets having a vitamin A retention over time (timespan months, 40°C, 75 RH (relative humidity)) of 80% or more after 3 months.

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