Pulverulent, directly compressible polyvinyl alcohol grades

Abstract

The present invention relates to premixes for the production of active compound-containing tablets which comprise polyvinyl alcohols (PVAs). The invention also relates to active compound-containing tablets which comprise a corresponding premix.

Claims

1. A premix, consisting of a co-mixture of polyvinyl alcohols (PVAs) which have average particle sizes <100 μm, and microcrystalline celluloses (MCCs) which have an average particle size of ≤150 μm, wherein the co-mixture contains only said polyvinyl alcohols (PVAs) and said microcrystalline celluloses (MCCs); which co-mixture is of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grades 18-88 and/or 26-88 which are suitable for active compound retardation in accordance with the requirements of the pharmacopoeias Ph. Eur., USP/NF and JPE, and/or of grade 20-99 in accordance with the requirements of JPE and Ph. Eur.; and wherein the premix is suitable for the production of a directly compressible delayed release active compound-containing tablet, but wherein the premix does not contain an active compound.

2. The premix according to claim 1, wherein the microcrystalline celluloses have an average particle size in the range from 100 μm to 140 μm.

3. The premix according to claim 1, wherein the polyvinyl alcohols have an average particle size in the range from 80 μm to 90 μm.

4. The premix according to claim 1, wherein the polyvinyl alcohols to microcrystalline celluloses have a ratio of 2:1 to 1:2 by weight.

5. The premix according to claim 1, which is a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grade 20-99 in accordance with the requirements of JPE and Ph. Eur.

6. The premix according to claim 1, which is a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grades 18-88 and/or 26-88 which are suitable for active compound retardation in accordance with the requirements of the pharmacopoeias Ph. Eur., USP/NF and JPE.

7. The premix according to claim 1, which is a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grade PVA 26-88 which are suitable for active compound retardation.

8. The premix according to claim 1, which is capable of being shaped by compression at a pressing force of 20 kN to give tablets having hardnesses of >380 N, and which have a friability ≤0.1% by weight.

9. The premix according to claim 1, which is capable of being shaped by compression at a pressing force of 10 kN to give tablets having hardnesses of >178 N, and which have a friability ≤0.1% by weight.

10. The premix according to claim 1, wherein the PVA has been milled or ground at a temperature in the range of 0 to minus 30° C.

11. The premix according to claim 10, wherein the microcrystalline celluloses have an average particle size in the range from 100 μm to 140 μm.

12. The premix according to claim 10, wherein the polyvinyl alcohols have an average particle size in the range from 80 μm to 90 μm.

13. The premix according to claim 10, wherein the polyvinyl alcohols to microcrystalline celluloses have a ratio of 2:1 to 1:2 by weight.

14. The premix according to claim 10, which is a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grade 20-99 in accordance with the requirements of JPE and Ph. Eur.

15. The premix according to claim 10, which is a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grades 18-88 and/or 26-88 which are suitable for active compound retardation in accordance with the requirements of the pharmacopoeias Ph. Eur., USP/NF and JPE.

16. The premix according to claim 10, which is a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs) of grade PVA 26-88 which are suitable for active compound retardation.

17. The premix according to claim 10, which is capable of being shaped by compression at a pressing force of 20 kN to give tablets having hardnesses of >380 N, and which have a friability 0.1% by weight.

18. The premix according to claim 10, which is capable of being shaped by compression at a pressing force of 10 kN to give tablets having hardnesses of >178 N, and which have a friability 0.1% by weight.

19. The premix according to claim 1, wherein the polyvinyl alcohols (PVAs) have not undergone prior granulation.

Description

BRIEF DESCRIPTION OF DRAWINGS

(1) FIG. 1 and FIG. 2: FIG. 1 and FIG. 2 show characterisations of the various polyvinyl alcohols PVA 26-88 and 40-88 having different particle sizes mixed with MCC and Parteck LUB MST by plotting of pressing force against tablet hardness.

EXAMPLES

(2) The present description enables the person skilled in the art to apply the invention comprehensively. Even without further comments, it is therefore assumed that a person skilled in the art will be able to utilise the above description in the broadest scope.

(3) If anything is unclear, it goes without saying that cited publications and possibly cited patent literature should be consulted. Accordingly, these documents are regarded as part of the disclosure content of the present description.

(4) For better understanding of the invention and in order to illustrate it, examples are given below which are within the scope of protection of the present invention. These examples also serve to illustrate possible variants. Owing to the general validity of the inventive principle described, however, the examples are not suitable for reducing the scope of protection of the present application to these alone.

(5) Furthermore, it goes without saying to the person skilled in the art that, both in the examples given and also in the remainder of the description, the component amounts present in the compositions always only add up to 100% by weight or mol-%, based on the composition as a whole, and cannot exceed this, even if higher values could arise from the percent ranges indicated. Unless indicated otherwise, % data are thus regarded as % by weight or mol-%, with the exception of ratios, which are reproduced in volume figures.

(6) The temperatures given in the examples and the description as well as in the claims are in ° C.

(7) Equipment/Methods for Characterisation of the Substance Properties

(8) 1. Bulk density: in accordance with DIN EN ISO 60: 1999 (German version)—quoted in “g/ml” 2. Tapped density: in accordance with DIN EN ISO 787-11: 1995 (German version)—quoted in “g/ml” 3. Angle of repose: in accordance with DIN ISO 4324: 1983 (German version)—quoted in “degrees” 4. Surface area determined in accordance with BET: evaluation and procedure in accordance with the literature “BET Surface Area by Nitrogen Absorption” by S. Brunauer et al. (Journal of American Chemical Society, 60, 9, 1983) instrument: ASAP 2420 Micromeritics Instrument Corporation (USA); nitrogen; sample weight: about 3.0000 g; heating: 50° C. (5 h); heating rate 3 K/min; quoting of the arithmetic mean from three determinations 5. Particle size determination by laser diffraction with dry dispersal: Master-sizer 2000 with Scirocco 2000 dispersion unit (Malvern Instruments Ltd. UK), determinations at a counterpressure of 1 and 2 bar; Fraunhofer evaluation; dispersant RI: 1.000, obscuration limits: 0.0-10.0%, tray type: general purpose, background time: 7500 msec, measurement time: 7500 msec, procedure in accordance with ISO 13320-1 and the information in the technical manual and specifications from the instrument manufacturer; result given in % by vol. 6. Particle size determination by laser diffraction with wet dispersal: Master-sizer 2000 with Hydro 2000SM wet-dispersion unit (Malvern Instruments Ltd., UK); dispersion medium low-viscosity silicone oil (manufacturer: Evonik Goldschmidt GmbH, Germany; manufacturer's name: Tegiloxan3, manufacturer's article no.: 9000305); dispersant RI: 1.403; stirrer speed: 2500 rpm; tray type: general purpose; background time: 7500 msec; measurement time: 7500 msec; obscuration limits: 7.0-13.0%; procedure in accordance with ISO 13320-1 and the information in the technical manual and specifications from the instrument manufacturer; result given in % by vol. Procedure: the suspension cell is filled with the low-viscosity silicone oil, the sample is added in portions until the target obscuration range (7.0-13.0%) has been reached, and the measurement is started after a waiting time of 2 minutes. Particle Size Determination: by dry sieving via a sieve tower: Retsch AS 200 control, Retsch (Germany); amount of substance: about 110.00 g; sieving time: 30 minutes; amplitude intensity: 1 mm; interval: 5 seconds; analytical sieve with metal-wire fabric in accordance with DIN ISO 3310; mesh widths (in μm): 710, 600, 500, 400, 355, 300, 250, 200, 150, 100, 75, 50, 32; amount distribution per sieve fraction indicated in the tables as “% by weight of the sample weight”: 7. The tableting tests are carried out as follows: The mixtures in accordance with the compositions indicated in the experimental part are mixed for 5 minutes in a sealed stainless-steel container (capacity: about 2 I, height: about 19.5 cm, diameter: about 12 cm outside dimension) in a laboratory tumble mixer (Turbula T2A, Willy A. Bachofen, Switzerland). The magnesium stearate employed is Parteck LUB MST (vegetable magnesium stearate) EMPROVE exp Ph. Eur., BP, JP, NF, FCC Article No. 1.00663 (Merck KGaA, Germany) which has been passed through a 250 μm sieve. The compression to give 500 mg tablets (11 mm punch, round, flat, with bevel edge) is carried out in a Korsch EK 0-DMS instrumented eccentric tableting machine (Korsch, Germany) with the Catman 5.0 evaluation system (Hottinger Baldwin Messtechnik—HBM, Germany). Depending on the pressing force tested (nominal settings: ˜5, ˜10, ˜20 and ˜30 kN; the effectively measured actual pressing forces are indicated in the examples), at least 100 tablets are produced for evaluation of the pressing data and the pharmaceutical formulation characteristic numbers. Tablet hardnesses, diameters and heights: Erweka Multicheck 5.1 (Erweka, Germany); average data (arithmetic means) from in each case 20 tablet measurements per pressing force. The measurements are carried out one day after the tablet production. Tablet abrasion: TA420 friability tester (Erweka, Germany); instrument parameters and performance of the measurements in accordance with Ph. Eur. 7th Edition “Friability of Uncoated Tablets”. The measurements are carried out one day after tablet production. Tablet weight: Multicheck 5.1 (Erweka, Germany) with Sartorius CPA 64 balance (Sartorius, Germany). Quoting of the average value (arithmetic mean) from the weighing of 20 tablets per pressing force. The measurements are carried out one day after tablet production.
Characterisation of the Materials Used
1. PVA Grades Used and their Properties:
1.1 Raw Materials for Grinding 1.1.1. PVA 26-88: Polyvinyl Alcohol 26-88, Suitable for Use as Excipient EMPROVE® exp Ph. Eur., USP, JPE, Article No. 1.41352, Merck KGaA, Darmstadt, Germany 1.1.2. PVA 40-88: polyvinyl alcohol 40-88, suitable for use as excipient EMPROVE® exp Ph. Eur., USP, JPE, Article No. 1.41353, Merck KGaA, Darmstadt, Germany These PVA grades are in the form of coarse particles with a size of several millimetres which cannot be employed in this form as a directly compressible tableting matrix. The coarse particles do not allow reproducible filling of the dies and thus also do not allow a constant tablet weight at the high rotational speeds of the (rotary) tableting machines. In addition, only fine-grained PVAs are able to ensure homogeneous distribution of the active compound in the tablet—without the occurrence of separation effects; this is absolutely necessary for ensuring individual dosage accuracy of the active compound (content uniformity) in each tablet produced. In addition, only a fine-grained PVA can also ensure the homogeneous gel formation throughout the tablet body that is necessary for reproducible retardation. For these reasons, the above-mentioned coarse-grained PVA grades must be comminuted, i.e. ground, before use as directly compressible retardation matrices. In order to determine the optimum particle size or particle-size distribution of the two PVA grades with respect to their compressibility, in each case 3 particle fractions of different particle size were produced by cold grinding.
1.2 Ground PVA Grades 1.2.1. Ground PVA 26-88, from Polyvinyl Alcohol 26-88 Article No. 1.41352 having the average particle-size fractions Dv50 (laser diffraction; dry dispersal) Fraction 1: Dv50 84.88-87.60 μm Fraction 2: Dv50 120.28-123.16 μm Fraction 3: Dv50 206.86-224.48 μm 1.2.2. Ground PVA 40-88, from polyvinyl alcohol 40-88 Article No. 1.41353 having the average particle-size fractions Dv50 (laser diffraction; dry dispersal) Fraction 1: Dv50 85.84-87.37 μm Fraction 2: Dv50 115.97-120.52 μm Fraction 3: Dv50 206.83-211.55 μm
Grinding:

(9) The grinding of the PVA grades is carried out in an Aeroplex 200 AS spiral jet mill from Hosokawa Alpine, Augsburg, Germany, under liquid nitrogen as cold grinding in a temperature range from 0° C. to minus 30° C. The different particle fractions are produced empirically, in particular by variation of the grinding temperature, i.e. the grinding conditions are varied by on-going in-process controls of the particle size until the desired particle size fraction is obtained.

(10) The resultant product properties of the ground PVA grades, in particular the powder characteristics, such as bulk density, tapped density, angle of repose, BET surface area, BET pore volume and the particle size distributions, are evident from the following tables:

(11) Bulk Density, Tapped Density, Angle of Repose, BET Surface Area, BET Pore Volume:

(12) (details on the measurement methods, see under Methods)

(13) TABLE-US-00001 Bulk density Tapped density Angle of repose Sample (g/ml) (g/ml) (°) PVA 26-88* 0.51 0.70 36.7 1st fraction PVA 26-88* 0.54 0.72 34.2 2nd fraction PVA 26-88* 0.57 0.74 35.2 3rd fraction PVA 40-88* 0.51 0.70 34.0 1st fraction PVA 40-88* 0.53 0.71 35.0 2nd fraction PVA 40-88* 0.56 0.72 33.8 3rd fraction *ground PVA

(14) TABLE-US-00002 BET surface area BET pore volume Sample (m.sup.2/g) (cm.sup.3/g) PVA 26-88* 0.35 0.0019 1st fraction PVA 26-88* 0.26 0.0015 2nd fraction PVA 26-88* 0.20 0.0011 3rd fraction PVA 40-88* 0.33 0.0018 1st fraction PVA 40-88* 0.22 0.0016 2nd fraction PVA 40-88* 0.19 0.0011 3rd fraction *ground PVA
Particle Distribution Determined by Laser Diffraction with Dry Dispersal (1 Bar Counterpressure):

(15) Figures in μm (details on the measurement method, see under Methods)

(16) TABLE-US-00003 Sample Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Dv95 PVA 26-88* 17.39 24.78 38.52 45.59 52.97 87.60 161.70 285.80 526.73 1st fraction PVA 26-88* 22.81 33.47 53.87 64.26 74.92 123.16 213.12 320.40 394.31 2nd fraction PVA 26-88* 34.27 51.46 85.84 104.56 124.33 210.80 350.73 499.99 593.56 3rd fraction PVA 40-88* 16.33 23.54 37.10 44.13 51.49 85.96 156.09 245.33 304.05 1st fraction PVA 40-88* 21.56 31.96 51.45 61.20 71.15 115.97 200.37 299.76 364.57 2nd fraction PVA 40-88* 37.50 56.52 92.13 110.24 128.68 206.83 334.62 472.78 559.87 2nd fraction *ground PVA
Particle Distribution Determined by Laser Diffraction with Dry Dispersal (2 Bar Counterpressure):

(17) Figures in μm (details on the measurement method, see under Methods)

(18) TABLE-US-00004 Sample Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Dv95 PVA 26-88* 16.15 23.53 37.22 44.26 51.56 85.05 151.30 240.02 305.79 1st fraction PVA 26-88* 21.04 31.58 52.06 62.54 73.32 122.08 213.33 320.49 390.77 2nd fraction PVA 26-88* 31.97 48.56 81.95 100.26 119.78 206.86 350.52 508.72 613.02 3rd fraction PVA 40-88* 15.46 22.54 36.12 43.27 50.77 85.84 156.51 247.86 309.84 1st fraction PVA 40-88* 20.84 31.22 51.29 61.57 72.13 120.52 215.62 344.29 457.95 2nd fraction PVA 40-88* 36.99 55.90 92.07 110.69 129.66 209.09 336.49 472.11 556.60 3rd fraction *ground PVA
Particle Distribution Determined by Laser Diffraction with Dry Dispersal (3 Bar Counterpressure):

(19) Figures in μm (details on the measurement method, see under Methods)

(20) TABLE-US-00005 Sample Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Dv95 PVA 26-88* 15.99 23.44 37.29 44.35 51.65 84.88 150.53 237.38 299.34 1st fraction PVA 26-88* 20.77 31.28 51.54 61.82 72.37 120.28 210.97 317.50 386.93 2nd fraction PVA 26-88* 33.68 52.28 90.41 111.23 132.97 224.48 367.96 518.55 611.79 3rd fraction PVA 40-88* 15.50 22.86 36.99 44.35 52.00 87.37 158.92 250.34 310.78 1st fraction PVA 40-88* 20.62 31.15 51.23 61.23 71.61 117.75 203.67 303.91 368.85 2nd fraction PVA 40-88* 37.26 56.18 92.22 110.98 130.24 211.55 340.76 475.48 558.34 3rd fraction *ground PVA
Particle Distribution Determined by Tower Sieving:

(21) Figures in percent by weight (details on the measurement method, see under Methods)

(22) TABLE-US-00006 <32 32-50 50-75 75-100 100-150 150-200 200-250 Sample μm μm μm μm μm μm μm PVA 26-88* 1.8 15.2 16.1 18.2 23.1 12.0 5.7 1st fraction PVA 26-88* 3.8 7.7 13.2 14.6 20.8 16.9 10.1 2nd fraction PVA 26-88* 0.5 5.2 7.4 10.0 15.7 12.8 14.1 3rd fraction PVA 40-88* 2.2 14.9 16.9 17.6 20.0 13.6 6.5 1st fraction PVA 40-88* 1.0 12.8 14.6 15.9 21.9 14.5 8.6 2nd fraction PVA 40-88* 0.8 2.3 6.4 9.7 15.2 14.2 15.5 3rd fraction 250-300 300-355 355-400 400-500 500-600 600-710 >710 Sample μm μm μm μm μm μm μm PVA 26-88* 2.5 1.7 1.1 1.0 0.6 0.6 0.4 1st fraction PVA 26-88* 4.9 3.1 1.8 2.0 0.4 0.4 0.3 2nd fraction PVA 26-88* 9.7 8.3 5.0 8.9 1.8 0.4 0.2 3rd fraction PVA 40-88* 3.0 2.0 1.1 1.1 0.8 0.2 0.1 1st fraction PVA 40-88* 4.1 2.5 1.4 1.6 0.4 0.5 0.2 2nd fraction PVA 40-88* 11.8 9.5 5.0 7.9 1.4 0.2 0.1 3rd fraction *ground PVA
2. Microcrystalline Celluloses (MCCs) 2.1 Vivapur® Type 200, microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, Rosenberg, Germany 2.2 Vivapur® Type 102 Premium, microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, Rosenberg, Germany
Particle Distribution Determined by Laser Diffraction with Dry Dispersal (1 Bar Counterpressure):

(23) Figures in μm (details on the measurement method, see under Methods)

(24) TABLE-US-00007 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur ® 102 31.56 53.04 66.00 79.89 135.87 215.53 293.94 Vivapur ® 200 49.25 97.09 125.64 152.47 245.21 375.17 507.15
Particle Distribution Determined by Laser Diffraction with Dry Dispersal (2 Bar Counterpressure):

(25) Figures in μm (details on the measurement method, see under Methods)

(26) TABLE-US-00008 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur ® 102 27.55 45.97 57.41 70.40 127.29 208.92 288.93 Vivapur ® 200 44.08 86.21 113.63 140.90 235.62 365.86 497.34
Particle Distribution Determined by Laser Diffraction with Dry Dispersal (3 Bar Counterpressure):

(27) Figures in μm (details on the measurement method, see under Methods)

(28) TABLE-US-00009 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur ® 102 23.61 38.84 48.19 59.22 114.76 198.37 278.99 Vivapur ® 200 38.43 73.36 97.85 124.94 223.50 356.46 490.73
Particle Distribution Determined by Laser Diffraction with Wet Dispersal (in Low-Viscosity Silicone Oil):

(29) Figures in μm (details on the measurement method, see under Methods)

(30) TABLE-US-00010 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur ® 102 28.28 47.27 58.07 69.46 119.03 200.35 285.42 Vivapur ® 200 33.53 59.12 74.18 90.77 171.42 302.56 434.89
3. Other Materials 3.1 Parteck LUB MST (vegetable magnesium stearate) EMPROVE exp Ph. Eur., BP, JP, NF, FCC Article No. 1.00663 (Merck KGaA, Germany) 3.2 Colloidal silicon dioxide, highly disperse suitable for use as excipient EMPROVE exp Ph. Eur., NF, JP, E 551 Article No. 1.13126 (Merck KGaA, Germany)

Experimental Results

(31) The following experiments have shown that the particle size of the PVA used has a considerable influence on the pressing behaviour (pressing force/tablet hardness ratio).

(32) A) Result:

(33) It was found that co-mixtures based on ground polyvinyl alcohols having a Dv50 of 70-90 μm have particularly good compressibility compared with coarser PVA particle-size fractions in combination with microcrystalline celluloses (MCCs). Thus, in Example A1, tablet hardnesses of >400 N are obtained at a pressing force of 20 kN and even harnesses of >500 N are obtained at a pressing force of 30 kN. In Example A3 too, tablet hardnesses of >350 N (at a pressing force of 20 kN) or >450 N (at a pressing force of 30 kN) are achieved.

(34) These specific PVA/MCC co-mixtures are thus particularly suitable in direct tableting as matrices for the formulation of retard tablets in combination with active compounds which are poorly compressible per se.

(35) B) Procedure:

(36) 1. Preparation of the blends consisting of the two commercial microcrystalline celluloses with the respective PVA particle-size fractions in the mixing ratio 1:1.

(37) 2. After mixing for 5 minutes in a Turbula mixer, 0.25% by weight of highly disperse silicon dioxide are added, and the mixture is mixed again for 5 minutes. The mixture is then passed through an 800 μm hand sieve.

(38) 3. After addition of 0.25% by weight of Parteck® LUB MST, the mixture is mixed again for 5 minutes and subsequently compressed.

(39) 4. The tablet characterisation is carried out with respect to the parameters tablet hardness, tablet weight, tablet height, tablet abrasion and requisite ejection force.

(40) C) Experimental Results:

(41) 1a. Preparation of the Blends of the Microcrystalline Cellulose Vivapur® 102 Premium with the 3 Particle-Size Fractions of PVA 26-88 and PVA 40-88

(42) General description: the respective particle-size fractions of PVA 26-88 and PVA 40-88 are passed through an 800 μm hand sieve in order to remove any coarse components and agglomerates. 300 g of this sieved product are weighed out into a 2 I Turbula mixing vessel, 300 g of the microcrystalline cellulose Vivapur® 102 Premium are added, and the mixture is mixed for 5 min. in a T2A Turbula mixer.

(43) TABLE-US-00011 TABLE 1a Composition of the co-mixtures of the ground PVA fractions with the microcrystalline cellulose Vivapur 102 Premium Composition 50% by weight of PVA 50% by weight of MCC Example A1 PVA 26-88* 1st fraction Vivapur ® 102 Premium Comparison B1 PVA 26-88* 2nd fraction Vivapur ® 102 Premium Comparison C1 PVA 26-88* 3rd fraction Vivapur ® 102 Premium Example A2 PVA 40-88* 1st fraction Vivapur ® 102 Premium Comparison B2 PVA 40-88* 2nd fraction Vivapur ® 102 Premium Comparison C2 PVA 40-88* 3rd fraction Vivapur ® 102 Premium *ground PVA
1b. Blends with Highly Disperse Silicon Dioxide

(44) In order to improve the flowability, 0.25% by weight of highly disperse silicon dioxide are added to each of the examples and comparisons and mixed again for 5 minutes.

(45) 1 c. Compression of these Blends and Tablet Characterisation

(46) Gen. description: 1.25 g of magnesium stearate are added to in each case 498.75 g of the co-mixtures from Examples A1 and A2 and Comparisons B1, C1, B2 and C2 prepared above in a Turbula mixing vessel, the mixture is mixed again for 5 minutes in a T2A Turbula mixer and tableted in a Korsch EK 0-DMS eccentric press.

(47) TABLE-US-00012 TABLE 1b Tableting data of the co-mixtures of the ground PVA fractions with the microcrystalline cellulose Vivapur ® 102 Premium A Sample Nominal Actual B C D E F Example A1 5 5.3 104.8 501.4 5.6 0.05 113.8 10 9.8 226.8 503.8 4.9 0 114.0 20 19.9 465.2 506.1 4.5 0 66.1 30 29.7 593.5 505.2 4.4 0 50.0 Comparison B1 5 5.0 75.6 496.1 5.6 0.13 104.4 10 9.9 177.9 495.3 4.9 0 109.3 20 20.9 372.6 496.8 4.5 0 67.3 30 29.8 459.6 497.6 4.4 0 55.4 Comparison C1 5 4.9 55.6 499.6 5.5 0.25 108.7 10 10.6 144.6 500.8 4.8 0 116.2 20 19.8 278.0 500.2 4.5 0 84.3 30 30.7 388.5 498.2 4.3 0 68.0 Example A2 5 5.0 92.4 497.7 5.5 0.05 111.9 10 9.5 207.2 496.7 4.8 0 118.6 20 20.9 447.7 498.7 4.3 0 68.4 30 28.0 544.4 500.3 4.3 0 55.3 Comparison B2 5 5.2 80.3 497.8 5.7 0.04 117.9 10 9.3 171.7 499.6 5.1 0 126.4 20 18.7 360.7 502.1 4.6 0 85.6 30 28.4 495.4 507.0 4.6 0 63.9 Comparison C2 5 5.4 53.7 502.5 5.7 0.28 104.1 10 9.9 119.2 502.6 5.1 0 114.4 20 19.6 255.4 497.3 4.6 0 84.4 30 27.1 326.8 496.7 4.5 0 71.5 Key: A: Pressing force [kN] B: Tablet hardness after 1 day [N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F: Ejection force (N)

(48) FIG. 1 shows a graph of the very different pressing force/tablet hardness profiles for better illustration.

(49) 2a. Preparation of the Blends of the Microcrystalline Cellulose Vivapur® 200 with the 3 Particle-Size Fractions of PVA 26-88 and PVA 40-88

(50) General description: the respective particle-size fractions of PVA 26-88 and PVA 40-88 are passed through an 800 μm hand sieve in order to remove any coarse components and agglomerates. 300 g of this sieved product are weighed out into a 2 I Turbula mixing vessel, 300 g of the microcrystalline cellulose Vivapur® 200 are added, and the mixture is mixed for 5 min. in a T2A Turbula mixer.

(51) TABLE-US-00013 TABLE 2a Composition of the co-mixtures of the around PVA fractions with the microcrystalline cellulose Vivapur ® 200 Composition 50% by weight of PVA 50% by weight of MCC Example A3 PVA 26-88* 1st fraction Vivapur ® 200 Comparison B3 PVA 26-88* 2nd fraction Vivapur ® 200 Comparison C3 PVA 26-88* 3rd fraction Vivapur ® 200 Example A4 PVA 40-88* 1st fraction Vivapur ® 200 Comparison B4 PVA 40-88* 2nd fraction Vivapur ® 200 Comparison C4 PVA 40-88* 3rd fraction Vivapur ® 200 *ground PVA
2b. Blends with Highly Disperse Silicon Dioxide

(52) In order to improve the flowability, 0.25% by weight of highly disperse silicon dioxide are added to each of the examples and comparisons and mixed again for 5 minutes.

(53) 2c. Compression of these Blends and Tablet Characterisation

(54) Gen. description: 1.25 g of magnesium stearate are added to in each case 498.75 g of the co-mixtures from Examples A3 and A4 and Comparisons B3, C3, B4 and C4 prepared above in a Turbula mixing vessel, the mixture is mixed again for 5 minutes in a T2A Turbula mixer and tableted in a Korsch EK 0-DMS eccentric press.

(55) TABLE-US-00014 TABLE 2b Tableting data of the co-mixtures of the ground PVA fractions with the microcrystalline cellulose Vivapur ® 200 A Sample Nominal Actual B C D E F Example A3 5 5.1 72.7 494.3 5.6 0.19 108.1 10 10.0 183.5 493.5 4.9 0 115.7 20 19.9 387.8 495.8 4.5 0 74.4 30 29.6 507.8 494.2 4.3 0 59.1 Comparison B3 5 5.0 58.0 500.4 5.6 0.27 102.2 10 9.9 145.0 500.2 5.0 0 109.6 20 20.2 309.1 501.4 4.5 0 72.7 30 29.7 416.6 502.5 4.5 0 60.6 Comparison C3 5 5.0 39.7 495.6 5.5 1.53 98.6 10 10.1 100.3 495.6 4.9 0.01 109.2 20 20.9 211.4 497.8 4.5 0 79.0 30 30.1 295.4 497.6 4.4 0 68.2 Example A4 5 5.0 70.1 498.9 5.5 0.27 108.7 10 9.8 179.6 499.8 4.8 0 119.3 20 20.9 391.4 501.6 4.4 0 75.8 30 29.5 491.6 503.1 4.3 0 62.9 Comparison B4 5 5.1 53.2 497.0 5.7 0.42 105.8 10 10.0 138.7 498.0 5.0 0.01 118.6 20 18.8 281.7 493.6 4.6 0 82.4 30 29.1 389.4 491.1 4.5 0 64.9 Comparison C4 5 5.3 35.5 498.7 5.7 1.96 92.3 10 10.2 87.8 501.1 5.1 0 103.0 20 19.3 176.7 502.6 4.7 0 80.7 30 28.5 242.2 502.9 4.6 0 67.4 Key: A: Pressing force [kN] B: Tablet hardness after 1 day [N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F: Ejection force (N)

(56) FIG. 2 shows a graph of the very different pressing force/tablet hardness profiles for better illustration.