USE OF FUNCTIONALIZED CALCIUM CARBONATE AS ACTIVE INGREDIENT

Abstract

The present invention relates to a dosage form comprising functionalized calcium carbonate serving as active ingredient. The invention further relates to the use of the dosage form as nutritional supplement or as a medicament and to the use of functionalized calcium carbonate as active ingredient, preferably in the field of calcium fortification and in the treatment of calcium deficiency.

Claims

1. A dosage form comprising functionalized calcium carbonate, characterized in that the functionalized calcium carbonate serves as active ingredient.

2. The dosage form according to claim 1, characterized in that the functionalized calcium carbonate serves as nutritionally active ingredient.

3. The dosage form according to claim 2, characterized in that: (a) the dosage form further comprises a second nutritionally active ingredient; or (b) the functionalized calcium carbonate is the only nutritionally active ingredient.

4. The dosage form according to claim 1, characterized in that the functionalized calcium carbonate serves as therapeutically active ingredient.

5. The dosage form according to claim 4, characterized in that: (a) the dosage form further comprises a second therapeutically active ingredient; or (b) the functionalized calcium carbonate is the only therapeutically active ingredient.

6. The dosage form according to claim 1, characterized in that the functionalized calcium carbonate is a reaction product of ground natural calcium carbonate (GNCC) or precipitated calcium carbonate (PCC) treated with carbon dioxide and one or more H.sub.3O.sup.+ ion donors, wherein the carbon dioxide is formed in situ by the H.sub.3O.sup.+ ion donors treatment and/or is supplied from an external source.

7. The dosage form according to claim 6, characterized in that the H.sub.3O.sup.+ ion donor is selected from strong acids, medium-strong acids, weak acids, acidic salts thereof or mixtures thereof.

8. The dosage form according to claim 1, characterized in that the functionalized calcium carbonate is obtainable by a process comprising the steps of: (8a) providing a suspension of ground natural calcium carbonate (GNCC) or precipitated calcium carbonate (PCC); (8b) adding at least one acid having a pK.sub.a value of 0 or less at 20° C. or having a pK.sub.a value from 0 to 2.5 at 20° C. to the suspension of step (8a); and (8c) treating the suspension of step (8a) with carbon dioxide before, during or after step (8b).

9. The dosage form according to claim 8, characterized in that the acid having a pK.sub.a value of 0 or less at 20° C. is selected from sulphuric acid, hydrochloric acid or mixtures thereof.

10. The dosage form according to claim 8, characterized in that the acid having a pK.sub.a value from 0 to 2.5 at 20° C. is selected from sulphurous acid, phosphoric acid, oxalic acid or mixtures thereof.

11. The dosage form according to claim 1, characterized in that the functionalized calcium carbonate is obtainable by a process comprising the steps of: (11a) providing a suspension of ground natural calcium carbonate (GNCC) or precipitated calcium carbonate (PCC); (11b) providing at least one acid; (11c) providing gaseous carbon dioxide; and (11d) contacting the suspension provided in step (11a), the at least one acid provided in step (11b) and the gaseous carbon dioxide provided in step (11c); wherein (i) the at least one acid provided in step (11b) has a pK.sub.a of greater than 2.5 and less than or equal to 7 at 20° C., associated with the ionisation of its first available hydrogen, and a corresponding anion is formed on loss of this first available hydrogen capable of forming a water-soluble calcium salt; and (ii) following contacting the suspension provided in step (11a) and the at least one water-soluble acid provided in step (11b), at least one water-soluble salt, which in the case of a hydrogen-containing salt has a pK.sub.a of greater than 7 at 20° C., associated with the ionisation of the first available hydrogen, and the salt anion of which is capable of forming water-insoluble calcium salts, is additionally provided.

12. The dosage form according to claim 11, characterized in that the acid added in step (11b) is selected from acetic acid, formic acid, propanoic acid or mixtures thereof.

13. The dosage form according to claim 1, characterized in that the functionalized calcium carbonate has: (i) a specific surface area of from 10 to 250 m.sup.2/g, measured using nitrogen and the BET method according to ISO 9277:2010; and/or (ii) a volume-based particle size d.sub.50(vol) of from 0.8 to 75 μm; and/or (iii) a volume-based particle size d.sub.98(vol) of from 2 to 150 μm; and/or (iv) an intra-particle intruded specific pore volume in the range from 0.1 to 2.3 cm.sup.3/g, calculated from mercury porosimetry measurement.

14. The dosage form according to claim 1, characterized in that the dosage form is an oral dosage form.

15. The dosage form according to claim 1, characterized in that the dosage form further comprises one or more formulation aids.

16.-24. (canceled)

25. A nutritional supplement comprising functionalized calcium carbonate or the dosage form of claim 1.

26. A method for administering the nutritional supplement of claim 25, comprising orally administering to a patient the nutritional supplement of claim 25.

27. A method for the treatment of calcium deficiency comprising administering to a patient the nutritional supplement of claim 25.

28. A method for calcium fortification comprising administering to a patient the nutritional supplement of claim 25.

29. An active ingredient comprising functionalized calcium carbonate.

30. The active ingredient of claim 29, wherein the active ingredient is a nutritionally active ingredient or a therapeutically active ingredient.

31. The active ingredient of claim 29, wherein the active ingredient releases calcium.

32. A nutrient supplement comprising functionalized calcium carbonate.

33. A method for calcium fortification comprising administering to a human or an animal the nutrient supplement of claim 32.

Description

EXAMPLES

[0166] The scope and interest of the invention may be better understood on basis of the following examples which are intended to illustrate embodiments of the present invention.

[0167] (A) Analytical Methods

[0168] All parameters defined throughout the present document and mentioned in the following examples are based on the following measuring methods:

[0169] Specific Surface Area (SSA)

[0170] The specific surface area (in m.sup.2/g) is determined using the BET method (using nitrogen as adsorbing gas), which is well known to the skilled man (ISO 9277:2010). The total surface area (in m.sup.2) of the filler material is then obtained by multiplication of the specific surface area and the mass (in g) of the corresponding sample.

[0171] Particle Size Distribution

[0172] All particle sizes described herein, with the exception of the particle sizes of the ground calcium carbonate that was used for the production of the functionalized calcium carbonate and that of precipitated calcium carbonate, refer to the volume-based particle size distribution d.sub.x(vol). The volume-based median particle size d.sub.50(vol) and top cut d.sub.98(vol) are evaluated using a Malvern Mastersizer 3000 Laser Diffraction System (Malvern Instruments Plc., Great Britain). The raw data obtained by the measurement is analyzed using the Fraunhofer theory. The methods and instruments are known to the skilled person and are commonly used to determine particle size distributions. Measurements were carried out on the dry products.

[0173] The particle size of the ground calcium carbonate that was used for the production of the functionalized calcium carbonate is described herein as weight-based particle size distribution d.sub.x(wt). The same applies to precipitated calcium carbonate. The weight-based median particle size d.sub.50 (wt) and top cut d.sub.98 (wt) are measured by the sedimentation method, which is an analysis of sedimentation behaviour in a gravimetric field. The measurement is made with a Sedigraph™ 5120 of Micromeritics Instrument Corporation, USA. The method and the instrument are known to the skilled person and are commonly used to determine particle size distributions. The measurement is carried out in an aqueous solution of 0.1 wt % Na.sub.4P.sub.2O.sub.7. The samples are dispersed using a high speed stirrer and sonication.

[0174] Specific Pore Volume

[0175] The specific pore volume is measured using a mercury intrusion porosimetry measurement using a Micromeritics Autopore V 9620 mercury porosimeter having a maximum applied pressure of mercury 414 MPa (60 000 psi), equivalent to a Laplace throat diameter of 0.004 μm. The equilibration time used at each pressure step is 20 s. The sample material is sealed in a 3 cm.sup.3 chamber powder penetrometer for analysis. The data are corrected for mercury compression, penetrometer expansion and sample material elastic compression using the software Pore-Comp (Gane, P. A. C., Kettle, J. P., Matthews, G. P. and Ridgway, C. J., “Void Space Structure of Compressible Polymer Spheres and Consolidated Calcium Carbonate Paper-Coating Formulations”, Industrial and Engineering Chemistry Research, 1996, 35(5), 1753-1764).

[0176] The total pore volume seen in the cumulative intrusion data is separated into two regions with the intrusion data from 214 μm down to about 1 to 4 μm showing the coarse packing of the sample between any agglomerate structures contributing strongly. Below these diameters lies the fine interparticle packing of the particles themselves. If they also have intraparticle pores, then this region appears bimodal, and by taking the specific pore volume intruded by mercury into pores finer than the modal turning point, i.e. finer than the bimodal point of inflection, we thus define the specific intraparticle pore volume. The sum of these three regions gives the total overall pore volume of the powder, but depends strongly on the original sample compaction/settling of the powder at the coarse pore end of the distribution.

[0177] By taking the first derivative of the cumulative intrusion curve, the pore size distributions based on equivalent Laplace diameter, inevitably including pore-shielding, are revealed. The differential curves clearly show the coarse agglomerate pore structure region, the interparticle pore region and the intraparticle pore region, if present. Knowing the intraparticle pore diameter range it is possible to subtract the remainder interparticle and interagglomerate pore volume from the total pore volume to deliver the desired pore volume of the internal pores alone in terms of the pore volume per unit mass (specific pore volume). The same principle of subtraction, of course, applies for isolating any of the other pore size regions of interest.

[0178] (B) Examples

[0179] The following examples are not to be construed to limit the scope of the claims in any manner whatsoever.

Preparation of Functionalized Calcium Carbonates

[0180] Example 1A—FCC 1

[0181] FCC 1 has a d.sub.50=4.44 μm, a d.sub.98=11.0 μm, a SSA=54.7 m.sup.2g.sup.−1 and an intra-particle intruded specific pore volume of 0.807 cm.sup.3/g (for the pore diameter range of 0.004 to 0.47 μm).

[0182] FCC 1 was obtained by preparing 350 litres of an aqueous suspension of ground calcium carbonate in a mixing vessel by adjusting the solids content of a ground limestone calcium carbonate from Omya SAS, Orgon having a weight-based median particle size of 1.3 μm, as determined by sedimentation, such that a solids content of 10 wt %, based on the total weight of the aqueous suspension, is obtained.

[0183] Whilst mixing the slurry at a speed of 6.2 m/s, 11.2 kg phosphoric acid was added in form of an aqueous solution containing 30 wt % phosphoric acid to said suspension over a period of 20 minutes at a temperature of 70° C. After the addition of the acid, the slurry was stirred for additional 5 minutes, before removing it from the vessel and drying using a jet-dryer.

[0184] Example 1B—FCC 2

[0185] FCC 2 has a d.sub.50=5.58 μm, d.sub.98=15.0 μm, a SSA=90.6 m.sup.2/g and an intra-particle intruded specific pore volume of 1.71 cm.sup.3/g (for the pore diameter range of 0.004 to 0.47 μm).

[0186] FCC 2 was obtained by preparing 1500 liters of an aqueous suspension of ground calcium carbonate in a mixing vessel by adjusting the solids content of a ground limestone calcium carbonate from Omya SAS, Orgon, having a weight-based median particle size of 0.6 μm, as determined by sedimentation, such that a solids content of 10.0 wt %, based on the total weight of the aqueous suspension, is obtained.

[0187] Whilst mixing the slurry rapidly, 80 kg phosphoric acid was added in form of an aqueous solution containing 20 wt % phosphoric acid to said suspension over a period of 60 minutes at a temperature of 62° C. After the addition of the acid, the slurry was stirred for additional 5 minutes, before removing it from the vessel and drying using a jet-dryer.

[0188] Calcium Release Testings

[0189] The functionalized calcium carbonates prepared according to the above protocols were tested in terms of their calcium release rate:

TABLE-US-00001 d.sub.50 d.sub.98 SSA Pore volume Materials* [μm] [μm] [cm.sup.2/g] [cm.sup.3/g] FCC 1 4.44 11.0 54.7 0.807 FCC 2 5.58 15.0 90.6 1.711

[0190] The following materials were used for comparative purposes:

TABLE-US-00002 d.sub.50 d.sub.98 SSA Pore volume Materials* [μm] [μm] [cm.sup.2/g] [cm.sup.3/g] Calcium citrate tetrahydrate 6.83 80 TCP 1 (nano) 4.57 33 52.9 0.519 TCP 2 (non-nano) 4 30 7.6 0.157 NCC 1 1.83 9 4.1 *FCC = functionalized calcium carbonate TCP = tricalcium phosphate NCC = natural calcium carbonate

[0191] Example 2—Calcium Ion Potential in Solution

[0192] In this example, the calcium ion concentration at pH 3 was analysed to investigate the release of calcium ions in an acidic environment.

[0193] One litre of distilled water was provided in a beaker and adjusted to pH 3 by addition of 1 M HCl (Sigma-Aldrich) under continuous stirring to obtain an acidified medium.

[0194] For each calcium ion source (FCC 1, TCP 1 and NCC 1) 80 mL of the acidified medium was used. To these 80 mL of acidified medium, the calcium ion source FCC 1, TCP 1 or NCC 1 was added in an amount to provide a calcium ion concentration that is equal to 20 mg/L.

[0195] The release of calcium ions over time was investigated by measuring the electrical potential using a calcium-selective ion probe (Mettler-Toledo DX240) and a reference electrode (Mettler-Toledo DX200). The voltage developed across the membrane is directly linked to the amount of calcium ions in the solution. Before every measurement, the electrodes were cleaned with distilled water. In addition, the calcium-selective ion probe (Mettler-Toledo DX240) was dried with a tissue.

[0196] The measurements are illustrated in FIG. 1. It was shown that the calcium ion release rate is higher in case of functionalized calcium carbonate (FCC 1) compared to conventional calcium carbonate (NCC 1) and nano-scale tricalcium phosphate (TCP 1).

[0197] Example 3—Normalized Calcium Ion Concentration in Solution

[0198] In these trials, an ionic strength adjuster was used in addition in order to keep the ionic strength at a constant level and to exclude any impact of variable ionic strengths on the measured calcium ion activity.

[0199] Ionic strength adjuster solution: 53.49 g of NH.sub.4Cl were dissolved in a 1 L volumetric flask with distilled water.

[0200] Reaction solution: 14.6 g of 25% HCl were diluted in a 1 L volumetric flask with distilled water. 10 mL of this solution and 100 mL of the ionic strength adjuster solution were added and then diluted in a 1 L volumetric flask with distilled water.

[0201] Calcium standard solution: 5 mL of a 1000 ppm calcium standard for ion-selective electrodes (ISE) were added in a 100 mL volumetric flask and diluted with distilled water.

[0202] Calibration solutions: 10 mL of ionic strength adjuster were added in 5 volumetric flasks and a calculated volume of calcium standard solution was added to each one.

[0203] Measurement: The release of calcium ions over time was investigated by measuring the electrical potential. All solutions (calibration solutions and sample solutions) were measured by using a calcium-selective ion probe (Mettler-Toledo DX240) and a reference electrode (Mettler-Toledo DX200). Before every measurement, the electrodes were cleaned with distilled water. In addition, the calcium-selective ion probe (Mettler-Toledo DX240) was dried with a tissue. All samples were stirred at the same stirring rate with a magnetic stirrer. A calibration curve was measured before every sample series. Potentials were converted into concentrations based on the calibration measurement.

[0204] Calibration measurement: Calibration solutions were measured in 100 mL memo beakers and stirred with a magnetic stirrer. The potential had to be constant before it was noted.

[0205] Sample measurement: Each 1 L of reaction solution as described above were provided in a 1 L beaker and the calcium ion source (FCC 1, FCC 2, TCP 1, TCP 2, calcium citrate tetrahydrate) was added in an amount to provide a calcium ion concentration that is equal to 20 mg/L after the measured potential of the reaction solution reached a constant level. Measurements were stopped after 20 min.

[0206] The measurements are illustrated in FIG. 2. It was shown that the calcium ion release rate is higher in case of functionalized calcium carbonate (FCC 1 and FCC 2) compared to conventional calcium sources (TCP 1, TCP 2, calcium citrate tetrahydrate). The concentrations were normalized for each sample based on the final concentration of calcium ions so that a normalized concentration of 1 means that the final concentration level is reached.