DIRECTLY COMPRESSIBLE POLYVINYL ALCOHOLS

Abstract

The present invention relates to directly compressible co-mixtures for the production of tablets having delayed release of active compound which comprise polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs). The invention also relates to a process for the preparation of corresponding directly compressible co-mixture

Claims

1. Directly compressible composition having extended release of active compound, comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs).

2. Directly compressible composition according to claim 1, comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs), where the latter meet the requirements of the pharmacopoeias (PhEur, USP or JPE.

3. Directly compressible composition according to claim 1, comprising polyvinyl alcohols (PVAs) of grades 18-88, 26-88 and 40-88 and all grades in between in accordance with the requirements of the pharmacopoeias PhEur, USP or JPE, including grade 28-99 in accordance with the requirements of JPE or PhEur.

4. Directly compressible composition according to claim 1, comprising polyvinyl alcohols (PVAs) which conform to PhEur and which have been obtained by polymerisation of vinyl acetate and by subsequent partial or virtually complete hydrolysis of the polyvinyl acetate.

5. Directly compressible composition according to claim 1, comprising polyvinyl alcohols (PVAs) which have been obtained by 85%-89% hydrolysis.

6. Directly compressible composition according to claim 1, comprising polyvinyl alcohols (PVAs) having an average relative molecular weight in the range between 20,000 and 150,000 g/mol which have a viscosity in accordance with PhEur in the range 3-70 mPa.Math.s, (measured in a 4% solution at 20° C.).

7. Directly compressible composition according to claim 1, comprising polyvinyl alcohols (PVAs) which have an ester value of not greater than 280 mg of KOH/g (degree of hydrolysis >72.2 mol %).

8. Directly compressible composition according to claim 1, which comprises polyvinyl alcohols (PVAs) as water-soluble resin, which is characterised in accordance with USP by the formula
(C.sub.2H.sub.4O).sub.n, in which n denotes an integer in the range from 500 to 5,000.

9. Directly compressible composition according to claim 1, comprising PVA and MCC in a co-mixture in a ratio in the range 2:1 to 1:2, preferably in a ratio in the range 2:1 to 1:1.

10. Directly compressible composition according to claim 1, characterised in that the co-mixture of PVA with MCCs have bulk densities in the range 0.40-0.48 g/ml with tapped densities in the range 0.55-0.63 g/ml.

11. Tablet comprising a composition according to claim 1 which result in tablets having a tablet hardness of 295.7 N, even on use of a pressing force of 19.5 kN, and require an ejection force of about 66.7 N.

12. Active compound-containing tablet having extended release of active compound over several hours, comprising a co-mixture of polyvinyl alcohols (PVAs) and microcrystalline celluloses (MCCs) in accordance with claim 1.

13. Active compound-containing tablet having extended release of active compound over several hours, comprising a directly compressible composition in the form of a co-mixture in accordance with claim 1 an amount of 1-99% by weight, preferably in an amount of 5-95% by weight, very particularly preferably in an amount of 10-90% by weight, based on the total weight of the tablet.

14. Active compound-containing tablet according to claim 12, which have particularly high tablet hardnesses, even on use of low pressing forces, and require low ejection forces.

15. Active compound-containing tablet according to claim 12, which exhibit low friabilities of less than 1% by weight, preferably of less than 0.5% by weight, in particular of less than 0.1% by weight.

16. Active compound-containing tablet according to claim 11 having delayed release of active compound of at least 2 hours, preferably over at least 6 hours, particularly preferably of at least 8 hours, especially preferably of at least 10 hours, and very particularly preferably of at least 12 hours.

17. Active compound-containing tablet according to claim 11 having delayed release of active compound, comprising active compounds in BCS class I, either alone or in combination with other active compounds.

18. Process for the preparation of directly compressible compositions according to claim 1 having extended release of active compound, comprising a co-mixture of microcrystalline celluloses (MCCs) and polyvinyl alcohols (PVAs), characterised in that polyvinyl alcohol is ground to give a fine-grained powder and sieved through an 800 μm sieve, and mixed intensively with microcrystalline cellulose (MCCs) having an average particle size D.sub.v50 in the range from 60 to 250 μm, and a bulk density in the range from 0.22 to 0.38 g/cm.sup.3.

Description

LIST OF FIGURES

[0068] FIG. 1: FIG. 1 shows a graph of the pressing force/hardness profiles according to the data from Table 1.

[0069] FIG. 2: FIG. 2 shows a graph of the pressing force/abrasion profiles according to the data from Table 1.

[0070] FIG. 3: FIG. 3 shows the pressing force/hardness profiles of the data of the compositions from Table 4.

[0071] FIG. 4: FIG. 4 shows a graph of the pressing force/abrasion profiles using the data from Table 4.

[0072] FIG. 5: FIG. 5 shows a graph of the release of ascorbic acid from retard tablets according to sample 1, characterised by data from Table 9.

[0073] FIG. 6: FIG. 6 shows a graph of the release of ascorbic acid from retard tablets (sample 2) characterised by data from Table 9.

EXAMPLES

[0074] 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.

[0075] If anything is unclear, it goes without saying that the publications and patent literature cited should be consulted. Accordingly, these documents are regarded as part of the disclosure content of the present description.

[0076] 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.

[0077] 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.

[0078] The temperatures given in the examples and the description as well as in the claims are in ° C.

[0079] Equipment/Methods for Characterisation of the Substance Properties

[0080] 1. Bulk density: in accordance with DIN EN ISO 60: 1999 (German version) [0081] quoted in “g/ml”

[0082] 2. Tapped density: in accordance with DIN EN ISO 787-11: 1995 (German version) [0083] quoted in “g/ml”

[0084] 3. Angle of repose: in accordance with DIN ISO 4324: 1983 (German version) [0085] quoted in “degrees”

[0086] 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

[0087] 5. Particle size determination by laser diffraction with dry dispersal: Mastersizer 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.

[0088] 6. Particle size determination by laser diffraction with wet dispersal: Mastersizer 2000 with Hydro 2000SM wet-dispersion unit (Malvern Instruments Ltd., UK); dispersion medium low-viscority 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.

[0089] 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.

[0090] 7. 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”:

[0091] 8. The tableting tests are carried out as follows:

[0092] 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 l, height: about 19.5 cm, diameter: about 12 cm outside dimension) in a laboratory tumble mixer (Turbula T2A, Willy A. Bachofen, Switzerland).

[0093] 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.

[0094] 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).

[0095] 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.

[0096] Tablet Hardnesses, Diameters and Heights:

[0097] 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.

[0098] Tablet Abrasion:

[0099] 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.

[0100] Tablet Weight:

[0101] 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.

[0102] 9. Ascorbic acid release test: The ascorbic acid-containing compressed tablets (from the compressions with a pressing force of 20 kN) are measured in a SOTAX (Allschwil, Switzerland) in-vitro release apparatus using the “Apparatus 2 (Paddle Apparatus)” described in USP 36 under <711> and under the conditions described therein for “Extended-release dosage forms” (USP=United States Pharmacopoeia). The sampling is carried out automatically via a hose pump system with subsequent measurement in an 8453 spectrometer (Agilent Technologies, USA) and a flow cell.

[0103] The averaged values are obtained from the release tests of in each case 6 ascorbic acid-containing tablets pressed with a pressing force of 20 kN.

[0104] Ascorbic acid used for tableting: L(+)-ascorbic acid, Ph Eur, USP, NF, Product 83568.290 (VW R, Germany)

[0105] Measurement Apparatuses and Measurement Parameters:

[0106] 1. —Sotax AT7s release apparatus fitted with Apparatus 2 (Paddle Apparatus in accordance with USP 36) [0107] Temperature: 37° C.+/−0.5° C. [0108] Paddle speed: 100 rpm [0109] Volume of release medium per measurement vessel: 900 ml [0110] Tablet weight: 500 mg [0111] Total run time of the measurement: 720 min. (with sampling after 15, 30, 45, 60, 120, 180, 240, 300, 360, 420, 480, 540, 600, 660, 720 min.)

[0112] 2. —Hose pump for sampling: Sotax CY 7-50 (SOTAX, Switzerland)

[0113] 3. —8453 spectrometer (Agilent Technologies, USA) [0114] Measurement at 244 nm in a 2 mm flow measurement cell [0115] Evaluation via Excel [0116] Medium preparation: Dosa Prep X8 (DOSATEC GmbH, Germany)

[0117] Composition (in % by Weight) of the Release Medium:

TABLE-US-00001 Potassium dihydrogenphosphate 0.68% (Article No. 1.04873, Merck KGaA Darmstadt, Germany) Titriplex III 0.02% (Article No. 1.08418, Merck KGaA, Darmstadt, Germany) 85% phosphoric acid 0.20% (Article No. 1.00573, Merck KGaA Darmstadt, Germany) demineralised water 99.10%

Characterisation of the Materials Used

[0118] 1. PVA Grades Used and their Properties:

[0119] 1.1 Raw Materials for Grinding

[0120] 1.1.1. PVA 4-88: polyvinyl alcohol 4-88, suitable for use as excipient EMPROVE® exp Ph Eur, USP, JPE, Article No. 1.41350, Merck KGaA, Darmstadt, Germany

[0121] 1.1.2. PVA 18-88: polyvinyl alcohol 18-88, suitable for use as excipient EMPROVE® exp Ph Eur, USP, JPE, Article No. 1.41355, Merck KGaA, Darmstadt, Germany

[0122] 1.1.3. 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

[0123] 1.1.4. 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

[0124] 1.1.5. PVA 28-99: polyvinyl alcohol 28-99, suitable for use as excipient EMPROVE® exp JPE, Article No. 1.41356, Merck KGaA, Darmstadt, Germany

[0125] 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.

[0126] 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.

[0127] For these reasons, the above-mentioned coarse-grained PVA grades must be comminuted, i.e. ground, before use as directly compressible retardation matrices.

[0128] 1.2 Ground PVA Grades 1.2.1. Ground PVA 4-88, from polyvinyl alcohol 4-88 Article No. 1.41350, Merck KGaA, Darmstadt, Germany

[0129] 1.2.2. Ground PVA 18-88, from polyvinyl alcohol 18-88 Article No. 1.41355, Merck KGaA, Darmstadt, Germany

[0130] 1.2.3. Ground PVA 26-88, from polyvinyl alcohol 26-88 Article No. 1.41352, Merck KGaA, Darmstadt, Germany

[0131] 1.2.4. Ground PVA 40-88, from polyvinyl alcohol 40-88 Article No. 1.41353, Merck KGaA, Darmstadt, Germany

[0132] 1.2.5. Ground PVA 28-99, from polyvinyl alcohol 28-99 Article No. 1.41356, Merck KGaA, Darmstadt, Germany

[0133] Grinding:

[0134] 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.,

[0135] 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:

[0136] Bulk Density, Tapped Density, Angle of Repose, BET Surface Area, BET Pore Volume:

[0137] (details on the measurement method, see under Methods)

TABLE-US-00002 Angle BET Bulk Tapped of BET pore density density repose surface area volume Sample (g/ml) (g/ml) (°) (m.sup.2/g) (cm.sup.3/g) PVA 0.61 0.82 35.1 0.1308 0.0008 4-88* PVA 0.57 0.76 35.5 0.1831 0.0011 18-88* PVA 0.56 0.74 35.5 0.2045 0.0013 26-88* PVA 0.59 0.77 36.9 0.1123 0.0009 40-88* PVA 0.58 0.76 37.7 0.2210 0.0016 28-99* *ground PVA

[0138] Particle Distribution Determined by Laser Diffraction with Dry Dispersal (1 Bar Counterpressure):

[0139] Figures in μm (details on the measurement method, see under Methods)

TABLE-US-00003 Sample PVA Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90  4-88* 21.36 33.93 60.39 75.25 91.61 177.74 380.57 790.37 18-88* 29.67 44.93 73.95 89.11 105.22 185.49 375.88 755.84 26-88* 27.76 42.32 73.01 90.14 108.67 198.51 382.65 676.96 40-88* 31.84 50.64 89.13 109.77 131.45 230.52 413.71 634.59 28-99* 24.87 39.81 72.81 90.72 109.31 191.42 343.54 561.23 *ground PVA

[0140] Particle Distribution Determined by Laser Diffraction with Dry Dispersal (2 Bar Counterpressure):

[0141] Figures in μm (details on the measurement method, see under Methods)

TABLE-US-00004 Sample PVA Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90  4-88* 19.09 30.21 52.69 64.83 77.87 143.83 279.64 451.94 18-88* 26.90 40.38 65.30 78.08 91.55 159.10 321.46 607.64 26-88* 24.59 36.93 61.67 75.05 89.33 157.79 286.17 434.23 40-88* 31.03 49.47 88.54 110.06 132.79 235.87 430.35 686.10 28-99* 24.27 39.63 74.31 93.13 112.51 196.45 350.21 570.12 *ground PVA

[0142] Particle Distribution Determined by Laser Diffraction with Dry Dispersal (3 Bar Counterpressure):

[0143] Figures in μm (details on the measurement method, see under Methods)

TABLE-US-00005 Sample PVA Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90  4-88* 18.35 29.27 51.25 63.09 75.77 139.46 269.80 425.62 18-88* 24.55 36.60 57.91 68.48 79.45 132.37 246.56 393.59 26-88* 25.17 38.18 64.35 78.47 93.57 167.41 317.16 514.18 40-88* 32.81 53.33 96.27 119.61 144.21 256.31 463.67 717.76 28-99* 22.33 35.92 65.94 82.31 99.37 174.84 305.50 454.03 *ground PVA

[0144] Particle Distribution Determined by Laser Diffraction with Wet Dispersal (in Low-viscosity Silicone Oil):

[0145] Figures in μm (details on the measurement method, see under Methods)

TABLE-US-00006 Sample PVA Dv5 Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90  4-88* 10.03 20.10 38.02 47.82 58.31 110.91 231.64 390.95 18-88* 17.19 30.25 50.06 59.22 68.47 111.89 212.70 357.70 26-88* 15.42 26.76 45.50 54.83 64.47 110.50 212.91 353.68 40-88* 20.41 34.80 60.35 73.32 86.96 154.96 299.57 490.08 28-99* 14.68 25.96 47.49 58.88 70.80 127.68 240.70 376.70 *ground PVA

[0146] Particle Distribution Determined Via Tower Sieving:

[0147] Figures in % by weight (details on the measurement method, see under Methods)

TABLE-US-00007 Sample PVA <32 μm 32-50 μm 50-75 μm 75-100 μm 100-150 μm 150-200 μm 200-250 μm 250-300 μm  4-88* 3.3 7.9 12.6 12.2 19.6 12.9 10.5 6.5 18-88* 0.5 8.1 12.8 13.6 20.4 15.0 9.4 5.8 26-88* 5.3 8.4 12.3 13.6 21.8 13.1 9.0 5.0 40-88* 2.6 5.5 8.1 8.8 17.8 14.0 10.7 7.5 28-99* 5.0 7.1 9.1 9.8 20.4 13.2 11.7 7.9 *ground PVA

TABLE-US-00008 Sample PVA 300-355 μm 355-400 μm 400-500 μm 500-600 μm 600-710 μm >710 μm  4-88* 4.5 2.8 3.5 2.0 0.9 0.8 18-88* 4.2 2.6 3.5 2.1 1.0 1.0 26-88* 3.7 2.2 2.7 1.8 0.6 0.5 40-88* 6.6 3.9 5.9 4.1 1.9 2.6 28-99* 5.3 3.2 3.7 2.0 0.8 0.8 *ground PVA

[0148] 2. Directly Compressible Excipients for the Preparation of the Blends with Polyvinyl Alcohols (Ground)

[0149] 2.1 Parteck® SI 150 (sorbitol), suitable for use as excipient EMPROVE® exp Ph Eur, BP, JP, JSFA, NF, E 420, Article No. 1.03583, Merck KGaA, Darmstadt, Germany

[0150] 2.2 Parteck® M 200 (mannitol), suitable for use as excipient EMPROVE® exp Ph Eur, BP, JP, USP, E 421, Article No. 1.00419, Merck KGaA, Darmstadt, Germany

[0151] 2.3 Parteck® Mg DC (magnesium hydroxide carbonate), heavy, suitable for use as excipient EMPROVE® exp Ph Eur, BP, USP, E 504, Article No. 1.02440, Merck KGaA, Darmstadt, Germany

[0152] 2.4 Fujicalin®, calcium hydrogen phosphate, anhydrous, DCPA, USP/NF, EP, JP (Fuji Chemical Industry Co, Ltd, Japan, purchased via SEPPIC GmbH, Cologne, Germany)

[0153] 2.5 Lactose monohydrate (milk sugar), special product for tableting, suitable for use as excipient EMPROVE® exp Ph Eur, BP, NF, JP, Article No. 1.08195, Merck KGaA, Darmstadt, Germany

[0154] 2.6 Starch 1500® (pregelatinised maize starch) USP/NF, Ph Eur, JPE, IN 516247, Colorcon Limited, UK

[0155] 2.7 Vivapur® 102 Premium, MCC (microcrystalline cellulose) Ph Eur, NF, JP, JRS Pharma, Rosenberg, Germany

[0156] 2.8 Avicel® PH 102, MCC (microcrystalline cellulose) Ph Eur, NF, JP, FMC BioPolymer, USA

[0157] 2.9 Emcocel® 90 M, MCC (microcrystalline cellulose) Ph Eur, NF, JP, JRS Pharma, Rosenberg, Germany

[0158] 3. Pulverulent Ascorbic Acid (Used as Model Active Compound)

[0159] L(+)-Ascorbic acid, Ph Eur, USP, NF, Prod, 83568.290, batch: 11D180012, VWR, Germany

[0160] Particle Distribution Determined by Laser Diffraction with Dry Dispersal with 1 Bar Counterpressure:

[0161] Figures μm (details on the measurement method, see under Methods)

TABLE-US-00009 Sample Dv5 Dv10 Dv20 Dv25 Dv30 Ascorbic 27.63 57.03 103.64 123.02 141.50 acid Sample Dv50 Dv75 Dv90 Dv95 Ascorbic 215.48 335.67 467.13 552.17 acid

[0162] Particle Distribution Determined Via Laser Diffraction with Dry Dispersal with 2 Bar Counterpressure:

[0163] Figures μm (details on the measurement method, see under Methods)

TABLE-US-00010 Sample Dv5 Dv10 Dv20 Dv25 Dv30 Ascorbic 24.74 52.40 100.25 120.64 140.02 acid Sample Dv50 Dv75 Dv90 Dv95 Ascorbic 217.41 346.52 505.33 634.51 acid

[0164] Particle Distribution Determined Via Laser Diffraction with Dry Dispersal with 3 Bar Counterpressure:

[0165] Figures μm (details on the measurement method, see under Methods)

TABLE-US-00011 Sample Dv5 Dv10 Dv20 Dv25 Dv30 Ascorbic 11.85 24.55 62.66 82.02 100.81 acid Sample Dv50 Dv75 Dv90 Dv95 Ascorbic 177.57 304.33 451.03 558.34 acid

[0166] Procedure:

[0167] 1. Compression of the ground polyvinyl alcohols without any additives

[0168] 2. Preparation of the blends consisting of the various commercial directly compressible excipients with the ground PVA grade 26-88

[0169] 3. Compression of these blends and tablet characterisation

[0170] 4. Preparation descriptions of the co-mixtures of ground PVA 26-88 or 40-88 with the microcrystalline cellulose Vivapur® 102

[0171] 5. Preparation description of the blends of the two co-mixtures obtained under 4. with pulverulent ascorbic acid

[0172] 6. Compression of these blends and tablet characterisation

[0173] 7. Testing of the delayed in-vitro release of ascorbic acid from pressed tablets obtained in this way

[0174] A) Experimental Results:

[0175] 1. Compression of the Ground PVAs without any Additives

[0176] The ground PVA grades 4-88, 18-88, 26-88, 40-88 and 28-99 are compressed without further additives (also no lubricant) in a Korsch EK 0-DMS tableting machine. Before the compression, the ground PVA grades are passed through an 800 μm hand sieve (diameter 20 cm; Retsch, Haan, Germany) in order to eliminate any agglomerated PVA particles.

[0177] Parteck® M200 blended with 1% of Parteck® LUB MST serves as comparison. Note: compression of Parteck® M200 without any lubricant is not possible owing to the resultant very high ejection forces.

TABLE-US-00012 TABLE 1 Tableting data of ground PVAs without additives A Sample Nominal Actual B C D E F PVA 4-88* 5 5.0 17.0 470.3 5.9 59.94 237.0 10 10.1 40.8 491.8 5.6 8.94 383.5 20 20.7 137.2 503.2 5.1 0.35 378.3 30 30.3 194.1 504.5 5.0 0.05 322.5 PVA 18-88* 5 5.6 <10 409.7 5.9 100 246.4 10 10.1 23.0 493.7 5.7 18.90 354.4 20 19.9 89.1 499.9 5.2 1.03 382.7 30 29.9 151.1 504.0 5.0 0.14 355.7 PVA 26-88* 5 7.3 23.9 444.7 5.6 23.37 318.2 10 10.7 51.1 488.8 5.4 4.98 345.7 20 19.2 129.5 492.9 5.0 0.46 327.7 30 30.7 191.8 490.9 4.8 0.06 275.7 PVA 40-88* 5 7.6 20.5 443.1 5.7 39.93 296.7 10 10.1 33.0 490.3 5.6 9.67 321.7 20 18.8 150.8 506.6 5.0 0.65 317.7 30 28.5 151.4 504.6 5.0 0.12 282.9 PVA 28-99* 5 4.7 <10 450.6 5.9 100 169.0 10 9.7 25.5 483.9 5.5 14.22 279.5 20 19.5 102.0 471.3 4.8 0.83 292.3 30 30.3 178.0 472.1 4.6 0.10 263.2 Parteck ® 5 5.2 84.1 497.8 5.1 0.21 155.8 M200 10 10.7 196.5 500.6 4.6 0.17 306.0 20 20.3 340.0 499.4 4.2 0.15 513.6 30 30.0 396.7 498.3 4.0 0.16 647.6 *ground PVA 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)

[0178] FIG. 1 shows a graph of the pressing force/hardness profiles in accordance with the data from Table 1.

[0179] FIG. 2 shows a graph of the pressing force/abrasion profiles in accordance with the data from Table 1.

[0180] Result:

[0181] a) direct compression of the ground PVA grades is not possible, since tablets of inadequate hardnesses which do not allow safe handling (inadequate pressing force/hardness profiles) are obtained.

[0182] b) the tablet abrasion, in particular on use of low pressing forces, is very high.

[0183] c) relatively low ejection forces (“self-lubrication effect”) of the ground PVAs; theoretical advantage: stronger interparticular binding forces in the tablet; in the case of the PVAs tested, however, this effect is not sufficient to obtain tablets having adequate hardnesses and low abrasion.

[0184] 2. Preparation of the Blends of the Directly Compressible Excipients with the Ground PVA Grade 26-88

[0185] General description: ground PVA 26-88 is passed through an 800 μm hand sieve. 300 g of this sieved product are weighed out into a 2 l Turbula mixing vessel, 300 g of the corresponding excipient from A to I (see Table 2) are added, and the mixture is mixed for 5 min. in a T2A Turbula mixer.

TABLE-US-00013 TABLE 2 Composition of Examples A-C and Comparisons D-I 50% by weight of Composition 50% by weight of PVA excipient Example A PVA 26-88* Vivapur.sup. ®102 Example B PVA 26-88* Avicel.sup. ® PH 102 Example C PVA 26-88* Emcocel.sup. ® 90 M Comparison D PVA 26-88* Parteck.sup. ® SI 150 Comparison E PVA 26-88* Parteck.sup. ® M 200 Comparison F PVA 26-88* Parteck.sup. ® Mg DC Comparison G PVA 26-88* Fujicalin.sup. ® Comparison H PVA 26-88* Lactose Comparison I PVA 26-88* Starch.sup. ® 1500 *ground PVA

TABLE-US-00014 TABLE 3 Bulk density, tapped density and angle of repose of Examples A-C Angle of Bulk density Tapped density repose Example A 0.43 g/ml 0.58 g/ml 36.4° Example B 0.44 g/ml 0.60 g/ml 35.3° Example C 0.45 g/ml 0.59 g/ml 35.6°

[0186] 3. Compression of these Blends and Tablet Characterisation

[0187] General description: 1.25 g of magnesium stearate are added to in each case 498.75 g of the co-mixtures from Examples A-C or Comparisons D-I prepared above in a Turbula mixing vessel, the mixture is mixed again for 5 min. in a T2A Turbula mixer and tableted in a Korsch EK 0-DMS eccentric press.

TABLE-US-00015 TABLE 4 Tableting data of the co-mixtures of ground PVA 26-88 with excipients A Sample Nominal Actual B C D E F Example A 5 5.1 76.8 498.4 5.4 0.26 91.3 10 10.2 171.4 502.1 4.8 0.05 91.8 20 19.5 295.7 503.4 4.5 0 66.7 30 30.0 354.5 502.5 4.4 0 58.6 Example B 5 4.9 70.2 501.8 5.4 0.49 85.9 10 9.6 153.1 506.1 4.9 0.16 87.3 20 18.4 267.3 506.6 4.5 0.07 61.1 30 28.6 325.1 506.8 4.4 0.04 52.1 Example C 5 4.9 71.0 494.2 5.5 0.39 90.9 10 10.2 159.6 497.0 4.9 0.06 92.3 20 20.0 273.6 496.8 4.5 0 64.8 30 30.4 318.0 498.2 4.4 0 57.3 Comparison D 5 5.0 31.0 498.2 5.4 3.86 66.6 10 9.9 86.0 502.8 4.9 0.37 94.1 20 20.5 170.0 503.6 4.5 0.08 78.6 30 30.8 188.5 503.4 4.5 0.06 64.8 Comparison E 5 5.0 17.1 493.0 5.6 17.05 84.2 10 10.0 51.5 499.8 5.1 1.12 138.8 20 20.3 137.6 501.3 4.7 0.21 162.9 30 29.7 178.0 500.1 4.6 0.16 150.9 Comparison F 5 6.1 22.1 482.7 5.6 7.30 107.7 10 10.2 50.1 501.4 5.2 1.28 133.2 20 20.9 137.4 505.0 4.7 0.13 149.0 30 31.2 224.3 501.6 4.5 0.01 144.0 Comparison G 5 5.0 22.7 492.7 4.9 9.55 121.0 10 10.3 48.6 495.0 4.5 1.42 148.5 20 20.6 115.2 494.5 4.1 0.27 126.2 30 29.6 161.6 492.1 3.9 0.10 102.0 Comparison H 5 4.9 <10 374.7 5.1 n.b. 57.3 10 10.2 16.7 488.2 5.0 100 98.4 20 19.9 50.2 495.3 4.6 2.00 127.3 30 29.0 77.4 497.3 4.5 0.50 135.1 Comparison I 5 5.0 <10 468.2 5.5 100 54.8 10 9.8 28.9 492.3 5.1 10.49 69.1 20 19.6 77.3 494.1 4.7 0.78 57.2 30 30.0 98.7 494.3 4.6 0.30 50.6 Parteck ® 5 5.2 84.1 497.8 5.1 0.21 155.8 M200 10 10.7 196.5 500.6 4.6 0.17 306.0 20 20.3 340.0 499.4 4.2 0.15 513.6 30 30.3 396.7 498.3 4.0 0.16 647.6 Key: A: Pressing force [kN] B: Tablet hardness after 1 day [N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F: Injection force (N)

[0188] FIG. 3 shows the pressing force/hardness profiles of the data for the compositions from Table 4.

[0189] FIG. 4 shows a graph of the pressing force/abrasion profiles with reference to the data from Table 4.

[0190] Result:

[0191] a) only the co-mixtures based on ground PVA 26-88 with the three MCC grades tested (Examples A-C) give tablets having adequate hardnesses at all 4 pressing forces tested and come very close in their compressibilities to the internal standard Parteck® M 200; all other co-mixtures exhibit significantly lower tablet hardnesses at the same pressing forces

[0192] b) tablets based on Examples A-C exhibit a reduced friability compared with the other matrices, in particular at low pressing forces.

[0193] 4. Preparation Description of the Co-Mixtures of Ground PVA 26-88 and Ground PVA 40-88 with Vivapur® 102

Example A

[0194] Ground PVA 26-88 is passed through an 800 μm hand sieve. 300 g of the sieved product are weighed out into a 2 l Turbula mixing vessel, 300 g of Vivapur® Type 102 are added, and the mixture is mixed for 5 min. in a T2A Turbula mixer.

Example D

[0195] Ground PVA 40-88 is passed through an 800 μm hand sieve. 300 g of the sieved product is weighed out into a 2 l Turbula mixing vessel, 300 g of Vivapur® Type 102 are added, and the mixture is mixed for 5 min. in a T2A Tubula mixer.

TABLE-US-00016 TABLE 5 Composition of Examples A and D 50% by weight of Composition 50% by weight of PVA excipient Example A PVA 26-88* Vivapur.sup. ®102 Example D PVA 40-88* Vivapur.sup. ®102 *ground PVA

TABLE-US-00017 TABLE 6 Bulk density, tapped density and angle of repose of Examples A and D Angle of Bulk density Tapped density repose Example A 0.43 g/ml 0.58 g/ml 36.4° Example D 0.43 g/ml 0.59 g/ml 36.3°

TABLE-US-00018 TABLE 7 Tableting data of Example A and Example D A Sample Nominal Actual B C D E F Example A 5 5.1 76.8 498.4 5.4 0.26 91.3 10 10.2 171.4 502.1 4.8 0.05 91.8 20 19.5 295.7 503.4 4.5 0 66.7 30 30.0 354.5 502.5 4.4 0 58.6 Example D 5 5.0 64.2 500.4 5.4 0.49 76 10 10.3 146.9 505.7 4.9 0.15 90 20 20.1 247.4 506.0 4.5 0.08 62 30 32.0 296.6 506.0 4.5 0.07 91 Key: A: Pressing force [kN] B: Tablet hardness after 1 day [N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F: Injection force (N)

[0196] 5. Preparation Description of the Blends of the Two Co-Mixtures Obtained Under 4. with Pulverulent Ascorbic Acid

[0197] Sample 1: 150 g of ascorbic acid are added to 450 g of co-mixture Example A and mixed for 5 min. in a T2A Turbula mixer. 1.25 g of magnesium stearate are sieved into 498.75 g of this mixture via a 250 μm sieve, and the mixture is mixed for 5 minutes in a T2A Turbula mixer.

[0198] Sample 2: 150 g of ascorbic acid are added to 450 g of co-mixture Example D and mixed for 5 min. in a T2A Turbula mixer. 1.25 g of magnesium stearate are sieved into 498.75 g of this mixture via a 250 μm sieve, and the mixture is mixed for 5 minutes in a T2A Turbula mixer.

[0199] 6. Compression of Samples 1 and 2 and Tablet Characterisation

TABLE-US-00019 TABLE 8 Tableting derivative of samples 1 and 2 A Sample Nominal Actual B C D E F Sample 1 5 5.3 34.8 501.6 5.1 3.19 73.4 10 10.0 74.4 504.6 4.7 0.61 88.2 20 20.0 140.0 504.5 4.3 0.21 88.0 30 30.5 173.7 505.2 4.2 0.14 87.6 Sample 2 5 5.1 25.5 498.0 5.1 7.15 73.6 10 11.2 61.9 501.1 4.6 0.75 95.6 20 20.8 125.8 503.5 4.4 0.12 96.0 30 31.1 157.6 506.3 4.2 0.08 95.7 Key: A: Pressing force [kN] B: Tablet hardness after 1 day [N] C: Tablet weight [mg] D: Tablet height [mm] E: Abrasion [%] F: Injection force (N)

[0200] Result:

[0201] 1. Even in combination with a pulverulent ascorbic acid which is regarded as poorly directly compressible, tablets of adequate hardness and low friability which can be handled without problems are obtained using co-mixtures Example A and D according to the invention; the use of directly compressible ascorbic acid grades which are otherwise usual can thus be omitted.

[0202] 2. The ejection forces of the mixtures with Example A and Example D are unusually low—even in the case of the only very small amount of added magnesium stearate; this causes lower wear of the punch tools and tableting machines.

[0203] 3. The relatively small amount of added magnesium stearate means that the target retarded release of active compound is essentially determined only by the amounts and properties of the PVA used; the known interfering influence of the hydrophobic magnesium stearate on the active compound release behaviour is minimised.

[0204] 7. Testing of the Delayed In-Vitro Release of Ascorbic Acid from Pressed Tablets Obtained in this Way

TABLE-US-00020 TABLE 9 Results of the release of ascorbic acid from retard tablets of sample 1 and sample 2 (pressed at a pressing force of 20 kN) (Figures in % by weight of the amount of ascorbic acid released, based on the expected total amount of ascorbic acid/tablet, measurement of 6 tablets per sample) Sample 1 Sample 2 (tablets pressed (tablets pressed at a pressing at a pressing Time force of 20 kN) force of 20 kN) (min.) Min Max Average Min Max Average 0 0 0 0 0 0 0 15 14 20 17 15 18 16 30 21 28 24 22 25 24 45 26 34 30 27 32 30 60 31 40 35 32 37 35 120 46 57 51 46 53 50 180 60 72 65 58 66 63 240 71 84 77 67 77 73 300 81 91 86 72 82 78 360 89 98 93 78 89 85 420 94 101 97 86 93 90 480 97 103 100 90 96 94 540 98 104 101 96 102 99 600 98 104 101 98 103 101 660 98 104 101 99 103 101 720 98 104 101 100 103 102

[0205] FIG. 5 shows a graph of the release of ascorbic acid from retard tablets in accordance with sample 1, characterised by data from Table 9.

[0206] FIG. 6 shows a graph of the release of ascorbic acid from retard tablets in accordance with sample 2 with reference to the data from Table 9.

[0207] Result:

[0208] retarded in-vitro release of the model active compound ascorbic acid is possible over several hours

[0209] B) Conclusion

[0210] 1. The co-mixtures of ground PVA with MCC result in very readily directly tabletable tablet matrices. Even at relatively low pressing forces, tablets having adequate hardness and mechanical stability can be produced.

[0211] 2. With these matrices, even active compounds which are per se regarded as poorly tabletable can be converted into tablets having good pharmaceutical formulation properties, in particular with respect to hardness and mechanical stability, in a direct tableting process.

[0212] 3. With the aid of these matrices, retard tablets having release of active compound lasting over several hours can be produced rapidly and unproblematically by direct tableting.