Formulation having controlled, delayed release of active ingredient

Abstract

The present invention relates to novel pharmaceutical formulations which have controlled, delayed release of active ingredient, and to a process for the preparation of such formulations. The invention additionally relates to the use of these novel pharmaceutical administration forms as medicaments for the treatment of diseases which require delayed release of the active ingredient, such as hypertension, or asthmatic diseases.

Claims

1. A process for preparing a pharmaceutical administration form of a composition having extended release of active ingredient in the form of a tablet, comprising a) grinding a polyvinyl alcohol at a temperature of minus 30 C. to 0 C. to give a finely divided powder having an average particle size Dv50 of 50-100 m, and sieving through an 800 m sieve, b) mixing with microcrystalline cellulose having an average particle size Dv50 of 100 to 150 m, c) mixing the resultant mixture from b) with an active ingredient, d) optionally adding additives, and e) tabletting by compression.

2. The process according to claim 1, wherein extended release tablets are produced, which tablets' release of active ingredient is independent of the compression force applied during the preparation process and remains unchanged over a hardness in the range of 50 to 290 N.

3. A process for preparing a pharmaceutical administration form of a composition having extended release of active ingredient in the form of a tablet, comprising a) grinding a polyvinyl alcohol at a temperature of minus 30 C. to 0 C. to give a finely divided powder having an average particle size Dv50 of 50-100 m, and sieving through an 800 m sieve, b) mixing with microcrystalline cellulose having an average particle size Dv50 of 100 to 150 m, wherein polyvinyl alcohol and microcrystalline cellulose are mixed with one another in a ratio 2:1 to 1:2 w/w, c) mixing the resultant mixture from b) with an active ingredient, d) optionally adding additives, and e) tabletting by compression.

4. The process according to claim 1, wherein the active ingredient is propranolol or a pharmaceutically acceptable salt, hydrate or solvate of propranolol or theophylline, which is anhydrous or is the monohydrate of theophylline.

5. The process according to claim 1, wherein one or more additives are added, which is silicon dioxide or magnesium stearate.

6. The process according to claim 1, wherein resultant tablets have a hardness of 50 to 290 N and have an average release rate of 80% of the active ingredient in a time of at least 9 to 12 hours.

7. The process according to claim 1, wherein the active ingredient is propranolol, and where tablets are formed that contain said propranolol by a compression force of 10 to 30 kN to give tablets having a hardness of 100 to 260 N and have an average release rate of 80% of the propranolol in a time of at least 9 to 12 hours.

8. The process according to claim 1, wherein the finely divided powder has an average particle size Dv50 of 60-95 m.

9. The process according to claim 1, wherein polyvinyl alcohol and microcrystalline cellulose are mixed with one another in a ratio of 1.5:1 to 1:1.5 w/w.

10. The process according to claim 1, wherein polyvinyl alcohol and microcrystalline cellulose are mixed with one another in a ratio of 1:1 w/w.

11. The process according to claim 1, wherein the active ingredient is propranolol in the form of the hydrochloride or succinate.

12. The process according to claim 1, wherein the polyvinyl alcohol is of grade 26-88 and/or 40-88, and have, before compression, average particle-size fractions in the range Dv50 of 60-95 m.

13. The process according to claim 1, wherein the polyvinyl alcohol, before compression, has a bulk density of 0.40 to 0.65 g/ml, and a tapped density of 0.50 to 0.80 g/ml.

14. The process according to claim 1, wherein the polyvinyl alcohol, before compression, has a bulk density of 0.45 to 0.60 g/ml, and a tapped density of 0.55 to 0.75 g/ml.

15. The process according to claim 1, wherein the active ingredient is theophylline, and where tablets are formed that contain said theophylline by a compression force of 10 to 30 kN to give tablets having a hardness of 100 to 260 N and have an average release rate of 80% of the theophylline in a time of at least 9 to 12 hours.

16. The process according to claim 1, wherein the active ingredient is in a matrix that has been formed from the compression of the polyvinyl alcohol and microcrystalline cellulose, which matrix is capable of releasing the active ingredient by diffusion and/or gradual erosion of the matrix in the presence of liquid in the gastrointestinal system.

17. The process according to claim 1, wherein the active ingredient is propranolol, which is present in an amount of 10 to 140 mg per dose.

18. The process according to claim 1, wherein the active ingredient is theophylline, which is present in an amount of 100 to 600 mg per dose.

19. The process according to claim 1, wherein the active ingredient is propranolol hydrochloride in an amount of 80 or 160 mg per dose.

20. The process according to claim 1, wherein the active ingredient is anhydrous theophylline.

21. A process for preparing a pharmaceutical administration form of a composition having extended release of active ingredient in the form of a tablet, comprising a) grinding a polyvinyl alcohol which is selected from grades 18-88, 26-88, 40-88, 48-88 and all grades in between at a temperature of minus 30 C. to 0 C. to give a finely divided powder having an average particle size Dv50 of 50-100 m, and sieving through an 800 m sieve, b) mixing with microcrystalline cellulose having an average particle size Dv50 of 100 to 150 m, c) mixing the resultant mixture from b) with an active ingredient, d) optionally adding additives, and e) tabletting by compression.

22. The process according to claim 1, wherein the polyvinyl alcohol is selected from grade 28-99.

23. The process according to claim 1, wherein the mixing in step b) is done in a tumble mixer for at least 5 minutes.

24. The process according to claim 1, wherein the mixing in step b) is done in a tumble mixer for 5 minutes to 10 minutes.

25. The process according to claim 1, wherein the tabletting by compression is achieved by a compression force of 5 to 32 kN.

26. The process according to claim 1 for preparing a pharmaceutical administration form of a composition having extended release of active ingredient, comprising a) grinding a polyvinyl alcohol at a temperature of minus 30 C. to 0 C. to give a finely divided powder having an average particle size Dv50 of 50-100 m, and sieving through an 800 m sieve, b) mixing with microcrystalline cellulose having an average particle size Dv50 of 100 to 150 m in a tumble mixer for at least 5 minutes, c) mixing the resultant mixture from b) with an active ingredient, d) optionally adding additives, and e) tabletting by compression with a compression force of 5 to 32 kN.

Description

EXAMPLES

(1) Instruments and methods for the characterisation of the material properties 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. Anale of repose: in accordance with DIN ISO 4324:1983 (German version) quoted in degrees 4. Surface area determined by the BET method: 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; arithmetic mean from three determinations quoted 5. Particle size determination by laser diffraction with dry dispersal: Mastersizer 2000 with Scirocco 2000 dispersion unit (Malvem Instruments Ltd., UK), determinations at a counterpressure of 1, 2 and 3 bar; Fraunhofer evaluation; dispersant RI: 1.000, obscuration limits: 0.1-10.0%, 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; quoted in % by vol. 6. 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 l, 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 m 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 MesstechnikHBM, Germany). Depending on the compression force tested (nominal settings: 5, 10, 20 and 30 kN; the effectively measured actual values are indicated in the examples), at least 100 tablets are produced for evaluation of the compression data and determination of the pharmaceutical characteristics. Tablet hardnesses, diameters and heights: Erweka Multicheck 5.1 (Erweka, Germany); average data (arithmetic means) from in each case 20 tablet measurements per compression force. The measurements are carried out one day after 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: Average (arithmetic mean) from the weighing of 20 tablets per compression force: Multicheck 5.1 (Erweka, Germany) with Sartorius CPA 64 balance (Sartorius, Germany). The measurements are carried out one day after tablet production. 7. Active ingredient release testing: The compressed tablets containing propranolol HCl or anhydrous theophylline (compressed with a compression force of 5, 10, 20 or 30 kN) are measured in an in vitro release apparatus from ERWEKA (Heusenstamm, Germany) using the Apparatus 2 (Paddle Apparatus) described in Ph. Eur. 8.4 under 2.9.3. Dissolution test for solid dosage forms and under the conditions described therein (Ph. Eur.=European Pharmacopoeia). The sampling is carried out automatically via a hose pump system with subsequent measurement in a Lambdae 35 photometer (Perkin Elmer, USA) and a flow cell.

(2) Measurement Apparatuses and Measurement Parameters: ERWEKA DT70 release apparatus fitted with Apparatus 2 (Paddle Apparatus in accordance with Ph.Eur.) Temperature: 37 C.+/0.5 C. Speed of rotation of the paddle: 50 rpm Release medium: 900 ml of phosphate buffer pH 6.8 in accordance with Ph.Eur. Total running time of the measurements: 12 hours (with sampling after 15, 30, 45, 60 minutes or hourly thereafter up to a total running time of 12 hours (in the tables, the data for the 15, 30 and 45 minute samples are not shown) Hose pump with sampling: Ismatec IPC, model ISM 931; App. No. 12369-00031 Lambdae 35 photometer, Perkin Elmer Measurement at 214 nm for propranolol or 293 nm for theophylline in a 0.5 mm flow measurement cell Evaluation via Dissolution Lab Software Version 1.1, Perkin Elmer Inc. (USA)

(3) Commercial Comparative Preparation:

(4) Dociton 160 mg extended release; hard capsules, with extended release; active ingredient: propranolol hydrochloride, batch: 131203, use by: December 2018; Mibe GmbH Arzneimittel (Brehna, Germany);

(5) consisting of propranolol-containing pellets in hard capsules (containing 160 mg of propranolol hydrochloride per capsule); other constituents are: ethylcellulose, microcrystalline cellulose, hypromellose, gelatin, titanium dioxide (E171), sodium dodecylsulfate, iron(III) oxide (E172), shellac

(6) The release of active ingredient from Dociton 160 mg extended release were carried out using spider sinkers (Erweka, Germany) in order to prevent the capsules from floating in the release vessels.

(7) Characterisation of the Raw Materials Used

(8) 1. PVA 40-88 and PVA 26-88: 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 originally in the form of coarse particleswith a size of several millimetreswhich 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 ingredient. in the tabletwithout the occurrence of separation effects. This is vital for ensuring individual dosage accuracy of the active ingredient. (content uniformity) in each tablet produced. In addition, only a fine-grained PVA can ensure the homogeneous gel formation throughout the tablet body that is also 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. 1.2 Ground PVA grades 1.2.1 Ground PVA 26-88, from polyvinyl alcohol 26-88, Article No. 1.41352, batch F1862862 having the average particle-size fractions Dv50 (laser diffraction; dry dispersal): Dv50 80-90 m 1.2.2 Ground PVA 40-88, from polyvinyl alcohol 40-88 Article No. 1.41353, batch F1862963 having the average particle-size fractions Dv50 (laser diffraction; dry dispersal): Dv50 68-75 m

(9) Grinding:

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

(11) 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 as well as the particle size distributions, are evident from the following tables:

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

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

(14) TABLE-US-00001 Bulk Tapped Angle of BET BET density density repose surface area pore volume Sample (g/ml) (g/ml) () (m.sup.2/g) (cm.sup.3/g) PVA 26-88* 0.54 0.73 36.0 0.25 0.0016 PVA 40-88* 0.55 0.75 34.6 0.40 0.0027 *ground PVA

(15) Particle Distribution Determined by Laser Diffraction with Dry Dispersal (1 Bar Counterpressure):

(16) Figures in m (details on the measurement method, see under Methods)

(17) TABLE-US-00002 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 26-88* 27.31 42.18 49.4 56.74 89.95 158.92 289.97 PVA 40-88* 22.20 34.08 40.1 46.33 74.59 127.68 195.59 *ground PVA

(18) Particle Distribution Determined by Laser Diffraction with Dry Dispersal (2 Bar Counterpressure):

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

(20) TABLE-US-00003 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 26-88* 25.77 39.82 46.59 53.41 83.47 139.91 213.11 PVA 40-88* 20.55 31.37 36.88 42.61 69.13 119.47 181.24 *ground PVA

(21) Particle Distribution Determined by Laser Diffraction with Dry Dispersal (3 Bar Counterpressure):

(22) Figures in m (details on the measurement method, see under Methods)

(23) TABLE-US-00004 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 PVA 26-88* 25.77 39.75 46.37 53.00 81.97 135.81 202.72 PVA 40-88* 19.60 30.70 36.29 42.06 68.61 120.34 183.38 *ground PVA

(24) 2. Microcrystalline Celluloses (MCCs)

(25) Vivapur Type 102 Premium, microcrystalline cellulose, Ph. Eur., NF, JP, JRS Pharma, Rosenberg, Germany

(26) Particle Distribution Determined by Laser Diffraction with Dry Dispersal (1 Bar Counterpressure):

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

(28) TABLE-US-00005 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur 102 31.56 53.04 66.00 79.89 135.87 215.53 293.94

(29) Particle Distribution Determined by Laser Diffraction with Dry Dispersal (2 Bar Counterpressure):

(30) Figures in m (details on the measurement method, see under Methods)

(31) TABLE-US-00006 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur 102 27.55 45.97 57.41 70.40 127.29 208.92 288.93

(32) Particle Distribution Determined by Laser Diffraction with Dry Dispersal (3 Bar Counterpressure):

(33) Figures in m (details on the measurement method, see under Methods)

(34) TABLE-US-00007 Sample Dv10 Dv20 Dv25 Dv30 Dv50 Dv75 Dv90 Vivapur 102 23.61 38.84 48.19 59.22 114.76 198.37 278.99

(35) 3. Other Materials 3.1 Propranolol HCl BP, EP, USP Batch No. M130302 (Changzhou Yabang Pharmaceutical Co., LTD., China) 3.2 Parteck LUB MST (vegetable grade magnesium stearate) EMPROVE exp Ph. Eur., BP, JP, NF, FCC Article No. 1.00663 (Merck KGaA, Germany) 3.3 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) 3.4 Anhydrous theophylline EP expiry Oct. 2016 Article No. 000983 (Selectchemie, Switzerland)

(36) Experimental Results

(37) A) Aim:

(38) Extended release oral active ingredient formulations frequently have a complex structure. It can surprisingly be shown below that propranolol and theophylline tablets having extended release of active ingredient (cumulative >80% release of active ingredient after 12 hours) can be produced in a simple manner by using hydrophilic PVA grades as release-delaying polymer matrices. The in-vitro release behaviour, in particular of the propranolol tablets according to the invention, comes very close to the release profile of a commercially available product used therapeutically.

(39) In the following examples, co-mixtures are employed as have been described in the patent applications PCT/EP2015/001355, PCT/EP2015/001356 and PCT/EP2015/001357. These are co-mixtures of ground polyvinyl alcohols (PVAs) with microcrystalline celluloses (MCCs) having specific particle sizes.

(40) B) Summary of the Experimental Results with Propranolol:

(41) With the following data, it can be shown that propranolol tablets having extended release of active ingredient can be produced particularly simply with the aid of the co-mixtures described, where it has surprisingly been found that 1. tablets having high hardnesses and low friability are obtained even at low compression forces; 2. the release of active ingredient from these tablets is virtually independent of the compression force applied; 3. the release of active ingredient remains unchanged over a very large tablet hardness range; and that 4. this simple production process enables the development of an extended release propranolol formulation whose in-vitro release behaviour is virtually identical to that of a commercial formulation of the same dose, but which has a significantly more complex structure.

(42) On account of to these advantages, it is possible to prepare the extended release formulations described in a simple manner. At the same time, the tablets according to the invention have improved medicament safety.

(43) Procedure: 1. Preparation of the two co-mixtures from PVA 26-88 and MCC and PVA 40-88 and MCC, and in each case the mixture with the active ingredient and further additives and subsequent compression at a compression force of 5, 10, 20 and 30 kN, and characterisation of the resultant pressed products in pharmaceutical formulation terms 2. Measurement of the in-vitro release of active ingredient in phosphate buffer pH 6.8 over 12 hours: testing of the pressed products obtained at a compression force of 10, 20 and 30 kN 3. Measurement of the in-vitro release of Dociton 160 mg extended release capsules in phosphate buffer pH 6.8 over 12 hours: comparison of the in-vitro release of propranolol from these capsules against the in-vitro release of propranolol from the PVA-based extended release tablets according to the invention

(44) Results:

(45) Re 1.: Production and Characterisation of the Propranolol Extended Release Tablets in Pharmaceutical Formulation Terms: a. Preparation of the co-mixtures of the two ground PVA grades 26-88 and 40-88 with microcrystalline cellulose (MCC) in the mixing ratio 1:1 (see patent applications PCT/EP2015/001355, PCT/EP2015/001356 and PCT/EP2015/001357). For the preparation of the co-mixtures, consisting of the two constituents, microcrystalline celluloses (standard commercial product) and PVA having the suitable particle-size fraction are mixed in the mixing ratio 1:1 in a Turbula mixer for 5 minutes. b. 337.5 g (Example A) or 335.0 g (Example B) of these co-mixtures are mixed with 160 g of propranolol HCL and 1.25 g of highly disperse silicon dioxide (Example A) and 2.5 g of highly disperse silicon dioxide (Example B) in a Turbula mixer for a further 5 minutes. The mixture obtained is then passed through an 800 m hand sieve. c. After addition of 1.25 g of Parteck LUB MST (Example A) or 2.5 g of Parteck LUB MST (Example B), the mixture is mixed again for 5 minutes and subsequently tabletted in a Korsch EK 0-DMS eccentric press to give tablets weighing 500 mg; this corresponds to 160 mg of propranolol HCL per tablet d. The tablet characterisation is carried out with respect to the parameters tablet hardness, tablet weight, tablet thickness, tablet abrasion (friability) and ejection force required

(46) Composition (in % by Weight) Example A: with PVA 26-88 as Retardation Matrix

(47) TABLE-US-00008 Propranolol Magnesium PVA 26-88* MCC HCl Silicon dioxide stearate 33.75% 33.75% 32.0% 0.25% 0.25% *ground PVA

(48) Composition (in % by Weight) Example B: with PVA 40-88 as Retardation Matrix

(49) TABLE-US-00009 Magnesium PVA 40-88* MCC Propranolol HCl Silicon dioxide stearate 33.5% 33.5% 32.0% 0.5% 0.5% *ground PVA

(50) Tablet Characterisation

(51) TABLE-US-00010 TABLE 1 Tableting data Example A and Example B A Nominal Actual B C D E F Example A 5 5.1 46.7 495.3 5.3 1.45 177.4 10 9.4 102.3 497.4 4.9 0.12 312.2 20 19.5 211.7 513.5 4.6 0.05 326.8 30 28.9 258.5 515.2 4.6 0.04 316.8 Example B 5 5.2 48.0 497.4 5.3 1.33 122.4 10 10.2 110.5 496.7 4.8 0.09 211.4 20 19.7 207.0 498.3 4.5 0.07 249.8 30 29.0 247.4 497.0 4.4 0.03 264.8 Key: A: Compression force [kN] B: Tablet hardness after 1 day [N] C: Tablet weight [mg] D: Tablet thickness [mm] E: Abrasion [%] F: Ejection force (N)

(52) FIG. 1 shows a graph of the compression force/tablet hardness profiles of the two examples for better illustration.

(53) All tablets exhibit unusually high tablet hardnesses at compression forces equal to/greater than 10 kN together with very low abrasion after mechanical loading (low friability) and relatively low ejection forces.

(54) There are virtually no differences in the tableting data between the tablets based on the matrices PVA 26-88 or PVA 40-88. In particular, the tablet hardnesses are virtually identical at the same compression forces.

(55) Re 2.: In-Vitro Release from the Propranolol Extended Release Tablets at pH 6.8

(56) TABLE-US-00011 TABLE 2a In-vitro release data of Example A at pH 6.8 The cumulative amounts of propranolol HCl (in %) released from the tablets obtained at a compression force of 10, 20 and 30 kN are shown. Compression Compression Compression force 10 kN force 20 kN force 30 kN Time Min Max Mean Min Max Mean Min Max Mean (hours) (%) (%) (%) (%) (%) (%) (%) (%) (%) 1 19 22 20 17 19 18 16 18 17 2 32 36 34 28 31 29 27 30 28 3 43 49 46 39 42 40 37 40 38 4 53 61 57 48 52 49 46 50 47 5 63 71 67 56 61 58 53 58 55 6 72 79 76 64 69 66 60 66 62 7 79 85 82 71 77 73 67 73 69 8 83 89 86 76 83 79 73 79 75 9 86 91 89 81 87 83 77 85 80 10 88 93 91 84 90 86 81 88 84 11 90 94 92 86 91 88 85 90 87 12 91 95 93 88 93 90 87 92 89

(57) FIG. 2a shows a graph of the release data of Example A at pH 6.8 for better illustration.

(58) Example A shows a virtually identical release behaviour for tablets produced with compression forces of 20 and 30 kN with resultant tablet hardnesses of 212 and 259 N respectively; the tablets produced at a compression force of 10 kN (with a tablet hardness of 102 N) have, in comparison, only slightly faster in-vitro release.

(59) TABLE-US-00012 TABLE 2b In-vitro release date of Example B at pH 6.8 The cumulative amounts of propranolol HCl (in %) released from the tablets obtained at a compression force of 10, 20 and 30 kN are shown. Compression Compression Compression force force force 10 kN 20 kN 30 kN Time Min Max Mean Min Max Mean Min Max Mean (hours) (%) (%) (%) (%) (%) (%) (%) (%) (%) 1 17 18 17 15 18 16 16 17 16 2 28 29 29 26 31 28 26 30 27 3 37 40 39 35 44 39 35 42 37 4 46 49 48 44 55 49 43 53 47 5 54 59 57 52 66 58 50 63 55 6 62 67 64 60 77 67 58 72 63 7 69 74 72 66 85 74 64 80 70 8 75 80 78 73 90 80 70 86 76 9 80 85 83 79 94 85 76 92 82 10 84 89 87 84 97 89 80 94 86 11 87 92 90 88 99 92 84 96 89 12 89 93 91 91 99 94 88 97 92
FIG. 2b shows a graph of the release data of Example B at pH 6.8 for better illustration.

(60) Surprisingly, Example B shows an identical release behaviour for tablets produced in the relevant compression force range from 10 to 30 kN. In relation to the tablet hardnesses (Table 1), this corresponds to an identical release behaviour over a very large hardness range from 110 to 247 N.

(61) Conclusion: both examples, but in particular Example B, exhibit unchanged in-vitro release of active ingredient over very broad compression force and tablet hardness ranges. This effect gives rise to great reliability in the industrial production of extended release tablets of this type, since variations occurring in the tableting compression force and also in the resultant changes in the tablet hardnesses over very broad ranges have no influence on the release of active ingredient. This is of considerable importance for medicament safety.

(62) Re 3.: In-Vitro Release from a Commercial Propranolol Extended Release Formulation at pH 6.8

(63) Dociton 160 mg extended release from mibe GmbH Arzneimittel (Brehna, Germany) was tested

(64) TABLE-US-00013 TABLE 3 In-vitro release data of Dociton at pH 6.8 The cumulative amounts of propranolol HCl (in %) released from the extended release capsules are shown. Time Min Max Mean (hours) (%) (%) (%) 1 18 22 20 2 31 37 35 3 41 48 46 4 50 58 55 5 57 65 62 6 63 71 68 7 68 76 73 8 72 80 76 9 76 83 80 10 79 85 82 11 82 88 85 12 84 89 87

(65) These release data are virtually congruent with the data from Example A (Table 2a), compressed at a compression force of 20 and 30 kN, and Example B (Table 2b), compressed at a compression force of 10, 20 and 30 kN.

(66) The release data of Dociton 160 mg extended release at pH 6.8 compared with the release data from Example A are shown in FIG. 3a and that compared with the release data from Example B are shown in FIG. 3b.

(67) Conclusion: A simple direct-compression process of a co-mixture consisting of PVA and MCC enables an extended release matrix tablet to be obtained which is equivalent in its in-vitro release behaviour to a pellet or capsule formulation which has a significantly more complex structure.

(68) C) Summary of the Experimental Results with Theophylline:

(69) With the following data, it can be shown that theophylline tablets having extended release of active ingredient can be produced particularly simply with the aid of PVA/MCC co-mixtures, where it has surprisingly been found that 1. tablets having high hardnesses and low friability are obtained even at low compression forces; 2. the release of active ingredient from these tablets is virtually independent of the compression force applied and 3. the release of active ingredient remains unchanged over a very large tablet hardness range.

(70) TABLE-US-00014 TABLE 4 Ingredients and amounts of theophylline-containing tablets Proportion [% Ingredient Amount [mg] by weight] Theophylline Anhydrous, 125.00 25.00 Selectchemie AG PVA 40-88 ground 185.00 37.00 Merck KGaA Vivapur 102 (MCC), 185.00 37.00 JRS Pharma GmbH&Co.KG Silicon dioxide colloidal, 2.50 0.50 highly disperse Merck KGaA Parteck LUB MST 2.50 0.50 (magnesium stearate), Merck KGaA

(71) 185 g of PVA 40-88 (ground) und 185 g of MCC are mixed intensively for 10 minutes in a Turbulaa mixer. 125 g of theophylline, anhydrous, and 2.5 g of silicon dioxide are subsequently added, and the mixture is homogenised for a further 10 minutes. The mixture obtained is passed through a sieve (800 m). 2.5 g of magnesium stearate are added to the mixture through a 250 m sieve, and all components are again mixed together for 5 minutes in a Turbula tumble mixer. The resultant powder material is compressed with compression forces of 5, 11, 21 and 32 kN to give tablets weighing 500 mg (diameter 11 mm, flat, facetted).

(72) TABLE-US-00015 TABLE 5 Physical data of the theophylline-containing tablets obtained (125 mg of anhydrous theophylline per tablet) Compression force (kN) 5 11 21 32 Tablet thickness (mm) 5.2 4.7 4.4 4.3 Tablet weight (mg) 499 500 502 503 Ejection force (N) 82 80 92 84 Tablet hardness (N, after 50 111 206 289 one day) Friability (%) 0.9 0.1 0.0 0.0

(73) Use of the PVA-containing mixture gives theophylline tablets having delayed release of active ingredient with high tablet hardness, where the injection forces required are extremely low.

(74) Table 6: In-vitro release data from theophylline extended release tablet at pH 6.8

(75) The cumulative amounts of theophylline released (in %) from the tablets obtained at a compression force of 5, 11, 21, 32 kN are shown.

(76) TABLE-US-00016 Compression Compression Compression Compression force 5 kN force 11 kN force 21 kN force 32 kN Time Mean Mean Mean Mean (hours) (%) (%) (%) (%) 1 20 18 17 17 2 30 30 28 29 3 38 39 38 39 4 45 46 47 48 5 51 52 54 56 6 57 57 61 62 7 63 62 67 68 8 68 66 72 72 9 72 71 77 77 10 77 75 82 80 11 81 78 86 84 12 85 81 89 87

(77) FIG. 4 shows a graph of the release data of theophylline for better illustration.

(78) Surprisingly, the theophylline extended release tablets produced in the compression force range from 5 to 32 kN exhibit an identical release behaviour. In relation to the tablet hardnesses (Table 5), this corresponds to an identical release behaviour over a very large hardness range from 50 to 289 N.

LIST OF FIGURES

(79) FIG. 1: Compression force/tablet hardness profile (from Table 1) of Examples A and B

(80) FIG. 2a: Release data of Example A at pH 6.8 (from Table 2a)

(81) FIG. 2b: Release data of Example B at pH 6.8 (from Table 2b)

(82) FIG. 3a: Release data of Dociton 160 extended release compared with Example A at pH 6.8

(83) FIG. 3b: Release data of Dociton 160 extended release compared with Example B at pH 6.8

(84) FIG. 4: Release of active ingredient from tablets produced on the basis of PVA-containing mixtures with theophylline, anhydrous