Water Soluble Silicon-Containing Granulate

Abstract

A water-soluble silicon-containing granulate comprising a silicon compound of the formula Y.sub.xSi(OH).sub.4-x or an oligomer thereof, wherein Y is optionally substituted (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)-alkenyl, (C.sub.1-C.sub.4)-alkoxy, amino, and wherein x is 0-2, and a cold-water soluble starch material.

Claims

1. A water-soluble silicon-containing granulate comprising a silicon compound of the formula Y.sub.xSi(OH).sub.4-x or an oligomer thereof, wherein Y is optionally substituted (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)-alkenyl, (C.sub.1-C.sub.4)-alkoxy, amino, and wherein x is 0-2; and a cold-water soluble starch material.

2. The water-soluble granulate of claim 1, further comprising a stabilizing agent inhibiting polymerisation of the silicon compound.

3. The water soluble granulate of claim 2, wherein the stabilizing agent is chosen from the group of amino acids, peptides, organic acids, phenol and polyphenolic compounds, polyalcohols such as maltodextrine, quaternary ammonium compounds and aldehydes, preferably wherein the stabilizing agent is or comprises a quaternary ammonium compound, such as choline.

4. The water-soluble granulate of claim 3, wherein the silicon compound is chosen from the group of orthosilicic acid or an oligomer thereof (x=0 in the formula), and mono(C.sub.1-C.sub.4)alkyl-trisilanol and combinations thereof, and preferably the silicon compound is orthosilicic acid or an oligomer thereof.

5. The water-soluble granulate of claim 1, wherein the granulate is a fluidized granulate, obtainable from fluidized bed granulation.

6. The water-soluble granulate of claim 1, wherein the granulate has a density in the range of 0.30-0.60 g/cm.sup.3.

7. The water-soluble granulate of claim 1, wherein at least 90 wt % and preferably at least 95 wt % of the granules has a diameter of at most 600 μm, and preferably at least 80 wt %, more preferably at least 90 wt % of the granules has a diameter of at least 100 μm.

8. The water-soluble granulate of claim 1, wherein the cold-water soluble starch material comprises a starch that has been chemically modified.

9. The water-soluble granulate as claimed in claim 8, wherein the starch has been chemically modified with an organic acid into an esterified starch or a salt thereof, for instance to octyl succinate starch or an alkali salt thereof.

10. The water-soluble granulate of claim 9, wherein the cold-water soluble starch material comprises a dextrine or a maltodextrine.

11. The water-soluble granulate of claim 1, wherein the silicon concentration is in the range of 0.5-2.0 wt %, based on the total weight of the granulate.

12. A method of preparing a water-soluble silicon containing granulate comprising the steps of: providing a liquid formulation of a silicon compound of the formula Y.sub.xSi(OH).sub.4-x or an oligomer thereof, wherein Y is optionally substituted (C.sub.1-C.sub.4)alkyl, (C.sub.2-C.sub.5)-alkenyl, (C.sub.1-C.sub.4)-alkoxy, amino, and wherein x is 0-2, and preferably x=0; providing a cold-water soluble starch material; and mixing the liquid formulation and the cold-water soluble starch material, so that the silicon compound adsorbs onto the starch material and silicon containing granules are formed.

13. The method as claimed in claim 12, wherein the liquid formulation further comprises a stabilizing agent inhibiting polymerisation of the silicon compound, said stabilizing agent preferably being chosen from the group of amino acids, peptides, organic acids, phenol and polyphenolic compounds, polyalcohols such as maltodextrine, quaternary ammonium compounds and aldehydes, more preferably wherein the stabilizing agent is or comprises a quaternary ammonium compound, such as choline.

14. The method as claimed in claim 12, wherein the starch material is provided into a fluidized bed granulator to be fluidized, and wherein the liquid formulation is sprayed into the fluidized bed granulator during operation thereof, wherein starch material particles agglomerate to granules with the liquid formulation acting as a binder.

15. A granulate obtainable with the method of claim 12.

16. A galenic or nutritional composition such as a package or dosage form, comprising the granulate as claimed in claim 1.

17. A food supplement or feed supplement comprising the galenic or nutritional composition as claimed in claim 16 after dissolution and/or dispersion with water, beverage and/or other aqueous solution or dispersion.

18. A method for the prevention, inhibition and/or treatment of bone-loss and cartilage degeneration related diseases, loss of hair nail quality, alopecia, and skin ageing diseases comprising orally administering a solution of the composition of claim 16.

Description

BRIEF INTRODUCTION OF THE FIGURES

[0041] These and other aspects of the invention will be further elucidated with reference to the Examples and Figures, wherein

[0042] FIG. 1A shows the silicon concentration of dissolution medium measured by GFAAS (elemental silicon). 500 mg stabilized silicic acid granules (lot 1-160713) are incubated in a dissolution apparatus, using 500 ml dissolution medium, at 37° C. and 1000 rpm mixing speed. The silicon concentration after 240 minutes is 1.01% (GFAAS) w/v;

[0043] FIG. 1B shows the silicon concentration of dissolution medium measured by the colorimetric molybdenum blue method (specific for monomeric silicic acid). 500 mg stabilized silicic acid granules (lot 1-160713) are incubated in a dissolution apparatus, using 500 ml dissolution medium, at 37° C. and 1000 rpm mixing speed. The silicon concentration after 240 minutes is 0.95% (colorimetry) w/v.

EXAMPLES

[0044] In all examples, percentages refer to weight percentages unless otherwise expressed.

Example 1

[0045] Choline chloride is treated with dry hydrochloric acid. Silicon (IV) tetrachloride is added to the formed choline solution (ratio SiCl4 versus choline chloride: 1 mol per 1 to 5 mol). The resulting solution is hydrolyzed by adding water (ice/ice water) while cooling within a temperature range of −10 to −30° C. The solution is neutralized by adding sodium hydroxide and maintaining the temperature below 0° C. The final pH is between 1-1.5. The pH was measured with a pH analyser commercially available from Stratos, type MS A405, Knick, equipped with a Memosens pH electrode with a Ag/AgCl2 reference system and liquid KCl electrolyte. Following purification by active carbon, the precipitate is removed by filtration together with the active carbon. The water concentration is reduced by distillation under vacuum until a preparation is obtained containing 2.0-4% silicon by volume and 60-80% choline chloride by weight and 15-30% water by weight. Precipitation which is formed during distillation is removed by filtration.

[0046] A mixture of 65,67% sodium starch octenyl succinate (Emarusta Al, Matsutani Chemical Industry Co. Ltd., Japan) and 1% tricalciumphosphate is added to a Flow coater FLO-120 (Freund Bldg, Japan) fluidized bed system. A fluid bed granulation process is started by setting the temperature of the inlet air at 85° C. and spraying 33,33% liquid choline-stabilized silicic acid on the modified starch when the product has reached a temperature of 50° C. Following spraying, drying is automatically started of the fluidized granules in the FLO-120 unit at a product temperature of 50° C. until a water content of less than 3% is obtained in the granules. An example of the particle size distribution, measured by sieving analysis, is given in table 1, illustrating that 96% of the particles have a size smaller than 595 μm (30 mesh). The density is between 0.408 and 0.525 g/ml. The dried granules have an elemental silicon concentration between 0.75% and 1.5% (w/w) as measured by graphite furnace atomic absorption spectrometry (GFAAS).

TABLE-US-00001 TABLE 1 Sieve analysis of choline stabilized silicic acid granules containing only sodium starch octenyl succinate as the carrier. Mesh (micron) % of particles retained on sieve 16 (1190) 0 22 (761) 1 30 (595) 3 42 (380) 10 60 (250) 16 83 (187) 25 100 (145) 16 140 (105) 24 200 (74) 5

[0047] The dried granules have an elemental silicon concentration between 0.75% and 1.5% (w/w) as measured by graphite furnace atomic absorption spectrometry. Surprisingly, the analysis of a dissolution medium containing 500 mg granules in 500 ml dissolution medium, shows an identical profile when analyzed with GFAAS or the molybdenum blue colorimetric method (see FIG. 1). The latter is only reactive for monomeric silicic acid. This indicates that the granulation process does not result in polycondensation of stabilized silicic acid and that it is rapidly released in an aqueous environment from the starch carrier.

[0048] The granules show excellent stability as the concentration of silicon measured by the colorimetric molybdenum blue method does not change significantly when incubated in a sealed container at 40° C. and 75% relative humidity for 6 months (see table 2).

TABLE-US-00002 TABLE 2 Stability of choline stabilized silicic acid granules incubated at 40° C. and 75 RH in a sealed container. Silicon concentration measured with Incubation time at colorimetric molybdenum blue 40° C./75% relative method humidity % (w/w) 0 months 1.03 1 months 1.07 2 months 1.07 3 months 1.04 4 months 1.09 5 months 1.09 6 months 1.05

Example 2

[0049] The silicic acid granules prepared according to example 1 are mixed with sweeteners, salt and flavors using the following formula:

TABLE-US-00003 TABLE 3 Stability of a blend of choline stabilized silicic acid granules with sweeteners and flavors, incubated at 40° C. and 75 RH in a stick pack. INGREDIENT AMOUNT Maltitol .sup. 64% Stabilized silicic acid granules .sup. 25% Sodium chloride 0.50% Citric acid 5.25% Grapefruit flavor  3.5% Lemon flavor   1% Mix of: 24% sucralose, 18% acesulfame K 0.75%

[0050] The blend has excellent flow properties and can be packed easily in uni-dose stick packs (4 g per stick pack). The filled stick packs were incubated at 40° C. during 6 months to test the stability of the flavored granulate. As shown in table 3, excellent stability was found and no interaction occurred between the stabilized silicic acid and the added compounds.

TABLE-US-00004 Incubation time at Silicon concentration Silicon concentration 40° C./75% relative GFAAS molybdenum blue method humidity % (w/w) % (w/w) 0 months 0.27 0.27 1 months 0.25 0.24 3 months 0.26 0.26 6 months 0.26 0.25

Example 3

[0051] Choline chloride is treated with dry hydrochloric acid. Silicon (IV) tetrachloride is added to the formed choline solution (ratio SiCl4 versus choline chloride: 1 mol per 1 to 5 mol). The resulting solution is hydrolyzed by adding water (ice/ice water) while cooling within a temperature range of −10 to −30° C. The solution is neutralized by adding sodium hydroxide and maintaining the temperature below 0° C. The final pH is between 1-1.5. The pH was measured with a pH analyser commercially available from Stratos, type MS A405, Knick, equipped with a Memosens pH electrode with a Ag/AgCl2 reference system and liquid KCl electrolyte. Following purification by active carbon, the precipitate is removed by filtration together with the active carbon. The water concentration is reduced by distillation under vacuum until a preparation is obtained containing 2.0-4% silicon by volume and 60-80% choline chloride by weight and 15-30% water by weight.

[0052] Precipitation which is formed during distillation is removed by filtration.

[0053] Modified starches, i.e. Octyl-succinate starch commercially available as Capsul HS (Ingredion) and dextrin (Crystal Tex 626, Ingredion), and combinations thereof are used as carriers for liquid choline-stabilized silicic acid (ch-OSA) in a laboratory scale fluid bed apparatus type GPCG 1.1 (Glatt). The formula is given in table 4. The dry starch and dextrin are fluidized with a hot inlet air stream of 80-100° C., leading to a maximum product temperature in the range of 60−70° C. Choline-stabilized silicic acid is sprayed with a top nozzle on the carrier resulting in the formation of granules which are dried in the same apparatus until a loss on drying of less than 3.5% is obtained. Depending on the formula the density of the dried granules is between 330 and 360 g/l. Sieving analysis shows that more than 90% of particles are smaller than 600 μm (see table 5). The use of dextrin results in less dust (i.e. particles below 100 μm) which improves the processability and flowability of the obtained granulate.

TABLE-US-00005 TABLE 4 Formula of preparations made in the fluid bed apparatus type GPCG 1.1 (Glatt). ch-OSA Capsul HS Preparation (g) (g) Crystal tex 626 (g) A47-01 500 1000 — A47-03 750 1500 — A47-04 750 1000 500

TABLE-US-00006 Table 5Sieve analysis of preparations made in the fluid bed apparatus type GPCG 1.1 (Glatt). Particle size A47-01 A47-03 A47-04  .sup. % > 800 μm 0 0 2 %600-800 μm 0 0 2 %400-600 μm 4 0 6 %200-400 μm 14 18 56 %100-200 μm 48 70 34   .sup. <100 μm 34 12 0

Example 4

[0054] Example 3 is repeated with a mixture of 8 kg Capsul HS and 4 kg Crystal Tex 626 which is used as a carrier for 6 kg choline-stabilized silicic acid in a larger pilot scale GPCG15 system (Glatt), but using an inlet air stream of only 65° C., which results in a maximum product temperature of 53° C. Again, at these conditions the fluid bed process on a pilot scale results in a granulate with more than 90% of the particles having a size smaller than 600 μm (see table 6). Due to the use of a higher spray rate in experiment A47-06 than in experiment A47-05 within the range of 500-2000 g/mol, the granules become more coarse and very fine particles (dust, <100 μm) are eliminated.

TABLE-US-00007 TABLE 6 Sieve analysis of preparations made in the pilot scale fluid bed apparatus type GPCG 15 (Glatt) Particle size A47-05 A47-06  .sup. % > 800 μm 1 3 %600-800 μm 1 4 %400-600 μm 5 16 %200-400 μm 48 49 %100-200 μm 42 28   .sup. <100 μm 3 0

[0055] The silicon concentration of all the preparations both for labscale and pilot scale, is between 0.99 and 1.05% (w/w). The water content of the preparations is between 2 and 3% (w/w).

Example 5

[0056] Example 4 was repeated on an industrial level: 140.8 kg Capsul HS and 70.4 kg Crystal Tex 626 was used as a carrier for 105.6 kg choline-stabilized silicic acid in a GPCG 300 fluid bed system equipped with a top spray nozzle. The solid materials were heated up to 53° C. using an inlet air temperature of 65° C., followed by spraying choline-stabilized silicic acid into the fluidized bed at a spraying rate of 540-1800 g/min and 2 bar pressure. For drying a similar temperature of the inlet air was used resulting in a moisture content of the final granulate of 3-4%.

[0057] The bulk density of the resulting granules was 0.356 g/cm.sup.3 and 93% of the particles had a size below 600 μm, and 94% a size of at least 125 μm. The particle size distribution is shown in Table 7, which demonstrates that the particle size distribution obtained in the experiment on industrial scale is not significantly different from the labscale experiments. The total output of the process was 293 kg granules.

[0058] Samples were taken randomly to check the homogeneity. The results which are summarized in Table 8, demonstrate formation of a homogenous product. This confirms that the industrial granulation process does not result in polycondensation of stabilized silicic acid, since GFAAS and molybdenum analysis revealed no differences in silicon concentration.

TABLE-US-00008 TABLE 7 Sieve analysis of granulate made on an industrial level with a fluid bed apparatus type GPCG 300 (Glatt). Particle size Lot 18G26 .sup. % > 1180 μm 0.61 %600-1180 μm  6.3 %400-600 μm 18.1 %200-400 μm 62.3 %125-200 μm 7.1   .sup. <125 μm 5.5

TABLE-US-00009 TABLE 8 Chemical analysis of randomly chosen samples of granulate made in an fluid bed apparatus type GPCG 300 (Glatt). Silicon Silicon concentration concentration molybdenum blue Choline Sample GFAAS method chloride Moisture Lot 18G26 % (w/w) % (w/w) % (w/w) % (w/w) 1 1.06 0.96 25.0 3.54 2 0.99 1.00 24.9 3.81 3 1.00 0.99 25.2 3.92

Example 6

[0059] Granulate obtained in example 1, was compressed into tablets, using the following formula: [0060] 200 mg choline-stabilized silicic acid granulate [0061] 90.01 mg microcrystalline cellulose [0062] 6 mg calcium stearate [0063] 3.99 mg tricalciumphosphate [0064] 3 mg Shellac

[0065] The tablet was found to be stable when packed in alu/alu foil and incubated at 40° C. and 75% relative humidity for 3 months since GFAAS and molybdenum analysis revealed no differences in silicon concentration and disintegration time remained similar over time (table 9).

TABLE-US-00010 TABLE 9 Stability of tablets packed in sealed alu/alu bags and incubated at 40° C. and 75% relative humidity. baseline 1 month 3 months Silicon concentration 2.06 2.03 1.94 GFAAS mg/tablet Silicon concentration 1.90 1.95 1.94 molybdenum blue method mg/tablet Desintegration time 47′0″ 52′30″ 48′55″

Example 7

[0066] Granulate obtained in example 1, was compressed into chewable tablets, using the following formula: [0067] 500 mg choline-stabilized silicic acid granulate [0068] 1.25 g microcrystalline cellulose [0069] 650 mg advantose [0070] 10 mg sucralose [0071] 300 mg maltodextrin [0072] 100 mg magnesiumstearate [0073] 30 mg ginger-lemon flavor [0074] 30 mg banana flavor [0075] 45 mg ascorbic acid

[0076] The tablet was found to be stable when packed in alu/alu foil and incubated at 40° C. and 75% relative humidity for 3 months since GFAAS and molybdenum analysis revealed no differences in silicon concentration which also remained unchanged over time (table 10).

TABLE-US-00011 TABLE 10 Stability of chewable tablets packed in sealed alu/alu bags and incubated at 40° C. and 75% relative humidity. baseline 1 month 3 months Silicon concentration 5.05 4.99 5.00 GFAAS mg/tablet Silicon concentration 4.98 4.89 4.90 molybdenum blue method mg/tablet Desintegration time 47′30″ 52′30″ 48′55″