Method for the production of a dosage form

Abstract

A method is described for producing a dosage form and granules including surface-reacted calcium carbonate. Also described, are tablets and/or capsules obtained by the method. Methods using such a surface-reacted calcium carbonate, and a dosage form comprising the granules are also described. Further, methods of using the granules, or the tablets and/or capsules, or the dosage form in a pharmaceutical product, a nutraceutical product, an agricultural product, a cosmetic product, a home product, a food product, a packaging product and a personal care product are also described. A pharmaceutical product, a nutraceutical product, an agricultural product, a cosmetic product, a home product, a food product, a packaging product and a personal care product including the granules, or the tablets and/or capsules, or the dosage form are also described.

Claims

1. A method of producing granules comprising surface-reacted calcium carbonate, the method comprising the steps of: a) providing the surface-reacted calcium carbonate, wherein the surface-reacted calcium carbonate is a reaction product of: (1) natural ground or precipitated calcium carbonate with (2) carbon dioxide and (3) one or more H.sub.3O.sup.+ ion donors in an aqueous medium, wherein the carbon dioxide is formed in-situ by the H.sub.3O.sup.+ ion donor treatment and/or is supplied from an external source; b) compacting the surface-reacted calcium carbonate of step a) by means of a roller compactor at a compaction pressure in the range from 1 kN/cm to 30 kN/cm into a compacted form; c) milling the compacted form of step b) into granules; and d) optionally, sieving the granules of step c) with at least one mesh size to obtain granules having a median grain size of from 180 μm to 710 μm; wherein the method further comprises loading the compacted form obtained in step b) or the granules obtained in step c) with at least one active ingredient and/or inactive precursor thereof, to obtain loaded granules, wherein the loading is carried out by spraying or dropping the at least one active ingredient and/or inactive precursor thereof onto the compacted form obtained in step b) or the granules obtained in step c), and mixing in a device selected from the group consisting of a fluidized bed dryer/granulator, a ploughshare mixer, a vertical mixer, a horizontal mixer, a high shear mixer, a low shear mixer and a high speed blender, wherein the at least one active ingredient and/or inactive precursor thereof is in liquid form; wherein the compacted form obtained in step b) comprises the surface-reacted calcium carbonate of step a); and wherein the method further comprises mixing the granules with at least one formulating aid selected from the group consisting of a lubricant, an impact modifier, a plasticizer, a wax, a stabilizer, a pigment, a coloring agent, a scenting agent, a taste masking agent, a flavoring agent, a sweetener, a mouth-feel improver, a diluent, a film forming agent, an adhesive, a buffer, an adsorbent, an odor-masking agent and mixtures thereof.

2. The method according to claim 1, wherein the natural ground calcium carbonate comprises a calcium carbonate containing mineral selected from the group consisting of marble, chalk, dolomite, limestone and mixtures thereof; and wherein the precipitated calcium carbonate comprises a precipitated calcium carbonate having aragonitic, vateritic or calcitic mineralogical crystal forms and mixtures thereof.

3. The method according to claim 1, wherein the surface-reacted calcium carbonate i) has a BET specific surface area of from 20 m.sup.2/g to 450 m.sup.2/g measured using the nitrogen and BET method according to ISO 9277; and/or ii) comprises particles having a volume median grain diameter d.sub.50 of from 1 μm to 50 μm; and/or iii) has an intra-particle intruded specific pore volume within the range of 0.15 cm.sup.3/g to 1.35 cm.sup.3/g calculated from a mercury intrusion porosimetry measurement.

4. The method according to claim 1, wherein roller compacting step b) is carried out at a roller compaction pressure in the range from 1 kN/cm to 28 kN/cm.

5. The method according to claim 1, wherein sieving step d) is carried out by sieving with a mesh having a size selected from the group consisting of 180 μm, 250 μm, 355 μm, 500 μm and 710 μm.

6. The method according to claim 1, wherein the granules are mixed with a disintegrant.

7. The method according to claim 1, wherein the at least one active ingredient and/or inactive precursor thereof is selected from the group consisting of a fragrance, a flavour, a herbal extract a fruit extract, a nutrient, a trace mineral, a repellent, food, a cosmetic, a flame retardant, an enzyme, a macromolecule, a pesticide, a fertilizer, a preserving agent, an antioxidant, a reactive chemical, a pharmaceutically active agent, a pharmaceutically inactive precursor of synthetic origin, a pharmaceutically inactive precursor of semi-synthetic origin, a pharmaceutically inactive precursor of natural origin thereof, and mixtures thereof.

8. The method according to claim 1, further comprising a final step of tableting or filling the loaded granules into capsules.

9. The method according to claim 1, wherein the at least one active ingredient and/or inactive precursor thereof is provided in a solvent selected from the group consisting of water, methanol, ethanol, n-butanol, isopropanol, n-propanol, n-octanol, acetone, dimethylsulphoxide, dimethylformamide, tetrahydrofurane, a vegetable oil, a derivative of a vegetable oil, an animal oil, a derivative of an animal oil, a molten fat, a wax, and mixtures thereof.

10. The method of claim 1, wherein the compacted form obtained in step b) consists essentially of the surface-reacted calcium carbonate of step a).

11. The method according to claim 1, wherein sieving step d) is carried out.

12. The method according to claim 1, wherein the compacted form obtained in step b) does not comprise a formulating aid.

13. The method according to claim 1, wherein the compacted form obtained in step b) does not comprise a binder or disintegrant.

14. The method according to claim 1, wherein the compacted form obtained in step b) does not comprise an active ingredient and/or inactive precursor thereof.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) FIG. 1 shows a SEM picture of FCC consisting granules.

(2) FIG. 2 shows a SEM picture of FCC consisting granules loaded with 10% eugenol.

(3) FIG. 3 shows a SEM picture of FCC consisting granules loaded with 25% eugenol.

(4) FIG. 4 shows a SEM picture of FCC consisting granules loaded with 40% eugenol.

(5) FIG. 5 shows a SEM picture of FCC consisting granules loaded with 10% ibuprofen.

(6) FIG. 6 shows a SEM picture of FCC consisting granules loaded with 40% ibuprofen.

(7) FIG. 7 depicts calculation of the angle of repose (β) in a flowability tester using the equation tan β=h/r.

(8) The following examples and tests will illustrate the present invention, but are not intended to limit the invention in any way.

EXAMPLES

(9) Materials and Methods

(10) 1. Measurement Methods

(11) The following measurement methods were used to evaluate the parameters given in the examples and claims.

(12) BET Specific Surface Area (SSA) of a Material

(13) The BET specific surface area was measured via the BET process according to ISO 9277 using nitrogen, following conditioning of the sample by heating at 250° C. for a period of 30 minutes. Prior to such measurements, the sample was filtered, rinsed and dried at 110° C. in an oven for at least 12 hours.

(14) Particle Size Distribution (Volume % Particles with a Diameter <X), d.sub.50 Value (Volume Median Grain Diameter) and d.sub.98 Value of a Particulate Material:

(15) Volume median grain diameter d.sub.50 was evaluated using a Malvern Mastersizer 2000 Laser Diffraction System. The d.sub.50 or d.sub.98 value, measured using a Malvern Mastersizer 2000 Laser Diffraction System, indicates a diameter value such that 50% or 98% by volume, respectively, of the particles have a diameter of less than this value. The raw data obtained by the measurement is analysed using the Mie theory, with a particle refractive index of 1.57 and an absorption index of 0.005.

(16) The weight median grain diameter is determined by the sedimentation method, which is an analysis of sedimentation behaviour in a gravimetric field. The measurement is made with a Sedigraph™ 5100 of Micromeritics Instrument Corporation. The method and the instrument are known to the skilled person and are commonly used to determine grain size of fillers and pigments. The measurement is carried out in an aqueous solution of 0.1 wt.-% Na.sub.4P.sub.2O.sub.7. The samples were dispersed using a high speed stirrer and sonicated.

(17) A vibrating sieve tower was used to analyze the particle size distribution of the granules. Aliquots of 120 g of granules were put on steel wire screens (Retsch, Germany) with mesh sizes of 90 μm, 180 μm, 250 μm, 355 μm, 500 μm, 710 μm and 1 mm. The sieving tower was shaken for 3 minutes with 10 seconds interval at a shaking displacement of 1 mm.

(18) The processes and instruments are known to the skilled person and are commonly used to determine grain size of fillers and pigments.

(19) Intra-Particle Intruded Specific Pore Volume (in Cm.sup.3/g) of Surface Reacted Calcium Carbonate

(20) 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 (˜nm). The equilibration time used at each pressure step is 20 seconds. The sample material is sealed in a 5 cm.sup.3 chamber powder penetrometer for analysis. The data are corrected for mercury compression, penetrometer expansion and sample material 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, 35(5), 1996, p 1753-1764.).

(21) The total pore volume seen in the cumulative intrusion data can be separated into two regions with the intrusion data from 214 μm down to about 1-4 μm showing the coarse packing of the sample between any agglomerate structures contributing strongly. Below these diameters lies the fine inter-particle packing of the particles themselves. If they also have intra-particle pores, then this region appears bi modal, and by taking the specific pore volume intruded by mercury into pores finer than the modal turning point, i.e. finer than the bi-modal point of inflection, we thus define the specific intra-particle 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.

(22) 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 inter-particle pore region and the intra-particle pore region, if present. Knowing the intra-particle pore diameter range it is possible to subtract the remainder inter-particle and inter-agglomerate 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.

(23) Intra-Particle Intruded Specific Pore Volume (in Cm.sup.3/g) of Surface Reacted Calcium Carbonate Granules Loaded with Active

(24) 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 (˜nm). The equilibration time used at each pressure step is 20 seconds. The sample material is sealed in a 3 cm3 chamber powder penetrometer for analysis. The data are corrected for mercury compression, penetrometer expansion and sample material 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, 35(5), 1996, p 1753-1764).

(25) The first derivative of the cumulative intrusion curve showed the intra and inter-particle pore volume regions are not independent and separable in all cases. Thus, in order to show the pore volume difference for the loaded samples compared to the empty granules, the pore volume for each sample was obtained by taking the cumulative intrusion curve for pore diameters below 5 μm, representing the intrusion volume from the sum of the intra and inter particle pore volumes of the granulated materials.

(26) Loose Bulk Density

(27) 120 g of the granules of selected granular fraction (from 180 μm to 710 μm) were sieved through a 0.5 mm screen by means of a brush. 100±0.5 g of this sample were carefully filled through a powder funnel into the 250 mL measuring cylinder and the volume was read off to the nearest 1 mL. The loose bulk density was the calculated according the formula:
Loose bulk density [g/mL]=bulk volume [mL]/weighed sample [g]
and the result was recorded to the nearest 0.01 g/mL.
Tapped Density

(28) 120 g of the granules of selected granular fraction (from 180 μm to 710 μm) were sieved through a 0.5 mm screen by means of a brush. 100±0.5 g of this sample were carefully filled through a powder funnel into the 250 mL measuring cylinder. The graduated cylinder is connected to a support provided with a settling apparatus capable of producing taps. The cylinder is secured in this support and the volume after 1250 taps is read. A subsequent second tapping step consisting of 1250 taps is performed and the value of the volume is read. When this second tapped volume value does not differ in more than 2 mL from this first tapped volume value, this is the tapped volume. When this value differs in more than 2 mL, the tapping step of 1250 taps is repeated until no differences of more than 2 mL in subsequent steps is observed.

(29) Angle of Repose

(30) The angle of repose is measured in a flowability tester. The hopper equipped with the 10 mm nozzle is filled with approximately 150 ml of granulate. After emptying the hopper, the granulate bevel is measured by means of a laser beam and the angle of repose is calculated. The angle of repose B is the angle of the bevel flank opposite the horizontal line that is calculated as shown in FIG. 7.

(31) Compressibility Index

(32) The compressibility index is calculated as follows:
Compressibility Index=(Tapped density−Bulk density)/Tapped density*100
Thermo Gravimetric Analysis (TGA)

(33) The TGA is basically used to determine the loss ignition of mineral samples and filled organic materials. The equipment used to measure the TGA was the Mettler-Toledo TGA/DSC1 (TGA 1 STARe System) and the crucibles used were aluminium oxide 900 μl. The method consists of two heating steps the first between 30-130° C. for 10 minutes at a heating rate of 20° C./minute and the second one between 130-570° C. for 20 minutes at a heating rate of 20° C./minute.

(34) 2. Material

(35) Surface-reacted calcium carbonate (FCC), (from Omya International AG, Switzerland) was compared to microcrystalline cellulose (Avicel® PH 102, FMC BioPolymer, Ireland). Further details of the surface-reacted calcium carbonate are summarized in the following table 1:

(36) TABLE-US-00001 TABLE 1 Intra- Mean particle weight BET Stratum/ intruded Apparent median Top cut Specific and specific true particle particle surface Core interparticle pore density size size d.sub.98 area voids voids volume [g/cm.sup.3] [μm] [μm] [m.sup.2/g] [%, v/v] [%, v/v] [cm.sup.3/g] 2.7259 6.15 15 55.52 11 89 0.97
Eugenol (≥98%, FCC, FG, Sigma Aldrich, W246700, CAS No. 97-53-0,
EC No. 202-589-1) and ibuprofen (Shashun Pharmaceuticals Limited, BP/Ph.Eur., Cas #15687-27-1) were chosen as active ingredients.
3. Granulation Experiments
Granulation of FCC by Roller Compaction

(37) The granulation was performed using the Fitzpatrick CCS220. A bar mill and a rasped 1 mm screen were used for granulation. The parameters set were:

(38) TABLE-US-00002 Roll gap 0.7 mm (actual value during process 0.9 rpm) Roll force 5 kN/cm Roll speed 8 rpm Horizontal screw 25 rpm (actual value during process 13 rpm) speed Vertical screw speed 250 rpm Mill speed 500 rpm

(39) The granule fraction between 250-710 μm was produced using a Retsch tower sieve shaker AS300 with 90, 180, 250, 355, 500, 710 and 1000 μm.

(40) The particle size distribution and further parameters are outlined in tables 2, 3 and 4.

(41) TABLE-US-00003 TABLE 2 Particle size distribution of manufactured empty granules Mean PSD Granules manufactured with Granule size FCC (Mass fraction %) range (μm) 0.01  0-90 3.32  90-180 18.37 180-250 17.90 250-355 18.34 355-500 36.18 500-710 5.85   710-1 000 0.01 <1 000

(42) TABLE-US-00004 TABLE 3 Parameters measured in the 250-710 μm range Parameters Empty granules Specific surface area 52 (m.sup.2/g) Particle median diameter 500 (sieve) (d.sub.50, μm) Bulk density (g/mL) 0.48 Tapped density (g/mL) 0.61 Compressibility Index 21.31 Angle of repose (°) 47

(43) TABLE-US-00005 TABLE 4 Pore Volume Parameters Empty granules Truncated volume cm.sup.3/g - 0.897 diameter range 0.004-4.9 μm
Tableting with Granules Obtained from FCC Granules Loaded with Eugenol

(44) The granules obtained from eugenol loaded FCC were further mixed with 0.5 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas #557-04-0, Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes. The mix was further used to prepare tablets in a Fette 1200i using EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mm punches and a tableting speed of 15000 tablets/hour. The fill depth was adjusted to obtain compression forces of 2, 4 and 6 kN and the table weight was fixed at 175 mg. The tableting parameters are outlined in table 5.

(45) TABLE-US-00006 TABLE 5 Tableting parameters Tablet hardness empty granules Parameters (N) Compression 2 35 force (kN) 4 83 6 119

(46) A SEM picture of FCC consisting granules is shown in FIG. 1.

(47) Loading FCC Granules with Eugenol

(48) 150 g of FCC granules (250-710 μm) were placed on a 3 L plastic beaker. The granules were loaded with 16.7 g (10 wt.-%), 50 g (25 wt.-%) and 100 g of eugenol (40 wt.-%) of Eugenol (Sigma Aldrich W246700). The eugenol was loaded by dropping at a rate of 1-2 drops/second by means of a peristaltic pump Ismatec IPC 8 with a two-stop tubing 1.52 mm wide. While loading, the granules were permanently mixed with an overhead stirrer IKA RW20 at a speed ranging between 80 and 120 rpm using an open blade paddle mixer. After the total amount of liquid was loaded onto the FCC granules the loaded granules were left to mix 10 minutes longer.

(49) The results obtained from eugenol loaded FCC granules are outlined in tables 6, 7 and 8.

(50) TABLE-US-00007 TABLE 6 Particle size distribution of manufactured granules FCC granules FCC granules loaded with loaded with FCC granules 40 wt.-% 10 wt.-% loaded with eugenol eugenol. 25 wt.-% eugenol Mass fraction Granule size Mass fraction (%) Mass fraction (%) (%) range (μm) 0.13 1.06 0.13  0-90 3.56 4.18 1.82  90-180 7.49 5.31 3.47 180-250 14.41 11.41 9.11 250-355 26.35 25.40 21.30 355-500 47.43 50.27 44.52 500-710 0.57 1.86 14.23   710-1 000 0.06 0.53 5.42 >1 000

(51) TABLE-US-00008 TABLE 7 Parameters measured in the 250-710 μm range FCC granules FCC granules FCC granules loaded with loaded with loaded with 40 wt.-% Parameters 10 wt.-% eugenol 25 wt.-% eugenol eugenol Particle median 499 510 568 diameter (sieve) (d.sub.50, μm) Bulk density 0.56 0.69 1.1 (g/mL) Tapped density 0.67 0.76 0.93 (g/mL) Compressibility 16.42 9.21 15.45 Index Angle of repose (°) 50 45 64 Loading % (TGA) 8.21 23.80 39.53

(52) TABLE-US-00009 TABLE 8 Pore Volume Tablet hardness Tablet hardness Tablet hardness granules granules FCC granules manufactured manufactured loaded with with 25 wt.-% with 40 wt.-% 10 wt.-% eugenol. eugenol loaded eugenol loaded Parameters (N) FCC (N) FCC (N) Truncated volume 0.701 0.409 0.105 cm.sup.3/g - diameter range 0.004-4.9 μm
Tableting with Granules Obtained from FCC Granules Loaded with Eugenol

(53) The granules obtained from eugenol loaded FCC were further mixed with 0.5 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas #557-04-0, Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes. The mix was further used to prepare tablets in a Fette 1200i using EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mm punches and a tableting speed of 15 000 tablets/hour. The fill depth was adjusted to obtain compression forces of 2, 4 and 6 kN and the table weight was fixed at 175 mg. The tableting parameters are outlined in table 9.

(54) TABLE-US-00010 TABLE 9 Tableting parameters Tablet hardness FCC granules Tablet hardness Tablet hardness loaded FCC granules FCC granules with loaded with loaded with 40 wt.-% 10 wt.-% 25 wt.-% eugenol. Parameters eugenol. (N) eugenol. (N) (N) Compression 2 33 20 N/A force (kN) 4 59 20 N/A 6 85 16 N/A

(55) SEM pictures of granules loaded with 10% or 25% or 40% eugenol are shown in FIGS. 2, 3 and 4.

(56) Loading FCC Granules with Ibuprofen

(57) 150 g of FCC granules (250-710 μm) were placed on a 3 L plastic beaker. The powder was loaded with 16.7 g (10 wt.-%) and 100 g (40% w/w) of Ibuprofen (BASF). The ibuprofen was first dissolved in acetone 75 g and 150 g for the 10 wt.-% and 40 wt.-% loadings, respectively. The ibuprofen acetone solution was loaded by spraying at a rate of 5 hits every 15 seconds by means of a spray bottle. While loading, the granules were permanently mixed with an overhead stirrer IKA RW20 at a speed ranging between 80 and 120 rpm using an open blade paddle mixer. After the total amount of solution was loaded onto the FCC granules the loaded granules were left to mix 10 minutes longer. The loaded granules were dried at a vacuum oven ThermoScientific VT 6130 until no more solvent could be collected.

(58) The results obtained from ibuprofen loaded FCC granules are outlined in tables 10, 11 and 12.

(59) TABLE-US-00011 TABLE 10 Particle size distribution of manufactured granules FCC granules FCC granules loaded with loaded with Granule size range 10 wt.-% Ibuprofen 40 wt.-% Ibuprofen (μm) 0.74 1.33  0-90 2.54 2.51  90-180 5.02 3.93 180-250 11.44 10.23 250-355 25.75 20.01 355-500 50.30 43.46 500-710 3.75 14.45   710-1 000 0.47 4.08 >1 000

(60) TABLE-US-00012 TABLE 11 Parameters measured in the 250-710 μm range FCC granules FCC granules loaded with loaded with Parameters 10 wt.-% Ibuprofen 40 wt.-% Ibuprofen Particle median 520 555 diameter (sieve) (d.sub.50, μm) Bulk density (g/mL) 0.65 0.65 Tapped density 0.65 0.69 (g/mL) Compressibility 0 5.80 Index Angle of repose (°) 36.20 36.40 Loading % (TGA) 7.39 33.63

(61) TABLE-US-00013 TABLE 12 Pore Volume Tablet hardness Tablet hardness FCC granules FCC granules loaded with loaded with 10 wt.-% 40 wt.-% Parameters Ibuprofen (N) Ibuprofen (N) Truncated volume 0.629 0.420 cm.sup.3/g - diameter range 0.004-4.9 μm
Tableting with Granules Obtained from FCC Granules Loaded with Ibuprofen

(62) The granules obtained from eugenol loaded FCC were further mixed with 0.5 wt.-% lubricant (Magnesium stearate, Ligamed MF-2-V, Cas #557-04-0, Peter Greven) in a Turbula Mixer (Willy A. Bachofen, Turbula T10B) for 5 minutes. The mix was further used to prepare tablets in a Fette 1200i using EU1″ tooling, a 10 mm fill cam, 8 standard convex round 10 mm punches and a tableting speed of 15 000 tablets/hour. The fill depth was adjusted to obtain compression forces of 2, 4 and 6 kN and the table weight was fixed at 175 mg. The tableting parameters are outlined in table 13.

(63) TABLE-US-00014 TABLE 13 Tableting parameters Tablet hardness Tablet hardness FCC granules FCC granules loaded with loaded with 10 wt.-% 40 wt.-% Parameters Ibuprofen (N) Ibuprofen (N) Compression 2 21 36 force (kN) 4 45 67 6 67 64

(64) SEM pictures of granules loaded with 10% or 40% ibuprofen are shown in FIGS. 5 and 6.