Pharmaceutical compositions containing dexketoprofen and tramadol

Abstract

A pharmaceutical composition as a solid oral dosage form is described, comprising: i) a combination of two pharmacological active principles, dexketoprofen salt with an organic or inorganic base and tramadol salt with an organic or inorganic acid, wherein: the organic or inorganic base is selected in the group: trometamol, trimethylamine, dimethylamine, ethylamine, triethylamine, diethylamine, L-lysine, L-arginine, diethanolamine, sodium hydroxide, calcium hydroxide the organic or inorganic acid is selected in the group: hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, propionic, malic, maleic, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic; ii) microcrystalline cellulose as a filler; iii) a binder selected in the group: maize starch, pre-gelatinized maize starch, hypromellose or their mixtures; iv) pharmaceutically acceptable excipients.

Claims

1. A pharmaceutical composition in a solid oral dosage form, comprising: i) a combination of the two active pharmaceutical ingredients, dexketoprofen as a salt with organic or inorganic bases and tramadol as a salt with organic or inorganic acids, wherein: the organic or inorganic base is selected from the group consisting of trometamol, trimethylamine, dimethylamine, ethylamine, trimethylamine, diethylamine, L-lysine, L-arginine, diethanolamine, sodium hydroxide, the organic or inorganic acid is selected from the group consisting of hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, propionic, malic, maleic, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic; ii) a filler which is microcrystalline cellulose; iii) a binder selected from the group consisting of maize starch, maize starch pregelatinized and hypromellose, or mixtures thereof; iv) a pharmaceutically acceptable excipient, wherein the two active ingredients form a homogeneous mixture in which said active ingredients are intimately mixed.

2. A pharmaceutical composition according to claim 1, wherein the organic base is trometamol and the inorganic acid is hydrochloric acid.

3. A pharmaceutical composition according to claim 1, wherein said pharmaceutical excipient is selected from disintegrant, lubricant and glidant.

4. A pharmaceutical composition according to claim 1, containing a mixture of the two active ingredients in a weight ratio of dexketoprofen to tramadol from 2:1 to 1:10, equivalent to a weight ratio of dexketoprofen trometamol to tramadol hydrochloride from 2.59:1 to 1:7.7.

5. A pharmaceutical composition according to claim 4, containing a mixture of the two active ingredients in a weight ratio of dexketoprofen to tramadol from 1:1 to 1:6, equivalent to a weight ratio of dexketoprofen trometamol to tramadol hydrochloride from 1.3:1 to 1:4.63.

6. A pharmaceutical composition according to claim 1 containing the two active ingredients, dexketoprofen and tramadol or salts thereof, in the following amounts for each oral dosage unit: dexketoprofen from 8 to 50 mg, equivalent to dexketoprofen trometamol from 11.8 to 73.8 mg; tramadol from 17.6 to 105.4 mg, equivalent to tramadol hydrochloride from 20 to 120 mg.

7. A pharmaceutical composition according to claim 6, containing the two active ingredients, dexketoprofen and tramadol or salts thereof, in the following amounts, for each oral dosage unit: dexketoprofen from 10 to 30 mg, equivalent to dexketoprofen trometamol from 14.8 to 44.29 mg; tramadol from 26.3 to 87.8 mg, equivalent to tramadol hydrochloride from 30 to 100 mg.

8. A pharmaceutical composition according to claim 1, containing the two active ingredients, dexketoprofen and tramadol or salts thereof, in the following specific amounts for each oral dosage unit: dexketoprofen 12.5 mg or 25 mg, equivalent to dexketoprofen trometamol 18.45 mg or 36.95 mg; tramadol 32.9 mg or 65.9 mg, equivalent to tramadol hydrochloride 37.5 mg or 75 mg.

9. A pharmaceutical composition according to claim 1, wherein microcrystalline cellulose is in a concentration range from 45 to 75% by weight of the total amount.

10. A pharmaceutical composition according to claim 1, wherein the binder is selected from the group consisting of maize starch, maize starch pregelatinized and hypromellose or mixtures thereof, in amounts from 7% to 12% by the total weight of the composition.

11. A pharmaceutical composition according to claim 1, further comprising a disintegrant which is selected from croscarmellose sodium and sodium starch glycolate or mixtures thereof, in amounts from 4% to 14% by the total composition weight.

12. A pharmaceutical composition according to claim 1, wherein the dissolution of the two active ingredients, dexketoprofen and tramadol, occurs in a time range between 3 and 11 minutes.

13. A pharmaceutical composition according to claim 1, wherein the dissolution rate and the purity profile of the components remain unchanged during shelf-life of 18 months at (252 C. and (605)% relative humidity in aluminium-aluminium and PVC/PVDC packages.

14. A pharmaceutical composition according to claim 1, which is in the form of tablet for immediate release of the active principles.

15. A pharmaceutical composition according to claim 14, wherein said tablet comprises a hypromellose based outer film coating.

16. A pharmaceutical composition according to claim 14, comprising a polyvinyl alcohol based outer film coating.

17. A pharmaceutical composition according to claim 1, which is in the form of a capsule for the immediate-release of both active principles.

18. A method of treating acute pain related to the following conditions: headache, toothache, inflammations and migraine, the method comprising administering to a patient in need thereof the pharmaceutical composition according to claim 1.

19. A method of manufacturing a pharmaceutical composition in accordance with claim 1, said method comprising fluid bed granulation and fluid bed drying of a mixture of active principles and excipients.

20. A pharmaceutical composition in a solid oral dosage form, comprising: i) a combination of the two active pharmaceutical ingredients, dexketoprofen as a salt with organic or inorganic bases and tramadol as a salt with organic or inorganic acids, wherein: the organic or inorganic base is selected from the group consisting of trometamol, trimethylamine, dimethylamine, ethylamine, trimethylamine, diethylamine, L-lysine, L-arginine, diethanolamine, sodium hydroxide, the organic or inorganic acid is selected from the group consisting of hydrochloric, hydrobromic, phosphoric, sulfuric, methanesulfonic, benzenesulfonic, toluenesulfonic, acetic, propionic, malic, maleic, succinic, citric, L-tartaric, lactic, malonic, aspartic, glutamic; ii) a filler which is microcrystalline cellulose; iii) a binder selected from the group consisting of maize starch, maize starch pregelatinized and hypromellose, or mixtures thereof; iv) a pharmaceutically acceptable excipient, wherein the two active ingredients form a homogeneous and physico-chemical interaction-free mixture in which said active ingredients are intimately mixed.

21. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a disintegration time of below 15 minutes when stored for two weeks at 60 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIGS. 1, 2 and 3 are graphs showing the dissolution behaviour of both active ingredients, dexketoprofen TRIS and tramadol hydrochloride, respectively at the initial conditions and after accelerated stability tests (1 and 4 weeks at 60 C.). The dissolution tests were performed, according to USP, in pH 6.8 R1 buffer, using a paddle apparatus, at a speed of 50 rpm and in a volume of 1000 ml.

(2) FIG. 4: shows the dissolution profile of the film-coated tablets of dexketoprofen TRIS and tramadol hydrochloride derived from a pilot batch production, at the initial conditions.

(3) FIG. 5: shows the dissolution profile of the film-coated tablets of dexketoprofen trometamol and tramadol hydrochloride originated from the first manufactured sub-batch of 100 Kg at the initial conditions.

(4) FIG. 1: Dissolution profile of active ingredients, initial conditions.

(5) FIG. 2: Dissolution profile of active ingredients after 1 week at 60 C.

(6) FIG. 3: Dissolution profile of active ingredients after 4 weeks at 60 C.

(7) FIG. 4: Dissolution profile of film-coated tablets (pilot batch), initial conditions.

(8) FIG. 5: Dissolution profile of film-coated tablets (100 kg manufactured sub-batch), initial conditions.

EXAMPLES

(9) The examples comprise solid oral dosage forms in several combinations. However, the dosage strengths which can be prepared with the present invention are not limited to these combinations only.

(10) The detailed description of the examples is intended to illustrate the invention, but not to limit its scope.

Example 1: Manufacturing of Dexketoprofen Trometamol+Tramadol Hydrochloride Tablet or Film-Coated Tablets, with Maize Starch

(11) Batch size: 4 kg

(12) The composition and batch formulas of the (film-coated) tablets with the combination dosage strengths DKP TRIS 18.4 mg+TRA-HCl 37.5 mg (1), DKP TRIS 18.4 mg+TRA-HCl 75 mg (2), DKP TRIS 36.9 mg+TRA-HCl 37.5 mg (3) and DKP TRIS 36.9 mg+TRA-HCl 75 mg (4) are given in table 1 and table 2, respectively.

(13) TABLE-US-00008 TABLE 1 Composition of the tablets and film-coated tablets, respectively: Quantity, mg per tablet Ingredient Reference Function 1 2 3 4 Tablet core Dexketoprofen Manufacturers Active 18.45 18.45 36.90 36.90 trometamol specification ingredient (12.5) (12.5) (25.0) (25.0) (equivalent to dexketoprofen) Tramadol Ph. Eur. Active 37.50 75.00 37.50 75.00 hydrochloride ingredient Microcrystalline Ph. Eur. Filler 378.85 341.35 360.40 322.90 cellulose Maize starch Ph. Eur. Binder 49.60 49.60 49.60 49.60 Sodium starch Ph. Eur. Disintegrant 27.10 27.10 27.10 27.10 glycolate Glycerol Ph. Eur. Lubricant 5.20 5.20 5.20 5.20 distearate Silica colloidal, Ph. Eur. Glidant 3.30 3.30 3.30 3.30 anhydrous Purified water* Ph. Eur. Solvent for q.s. q.s. q.s. q.s. granulation Total tablet core weight 520.00 520.00 520.00 520.00 Film-coating (optional) Hypromellose Ph. Eur. Film former 4.95 4.95 4.95 4.95 Titanium dioxide Ph. Eur. Pigment 3.24 3.24 3.24 3.24 Povidone K 30 Ph. Eur. Dispersant 0.87 0.87 0.87 0.87 Macrogol 4000 Ph. Eur. Polishing 0.95 0.95 0.95 0.95 agent Purified water* Ph. Eur. Solvent for q.s. q.s. q.s. q.s. film-coating Total weight of film coated tablet 530.01 530.01 530.01 530.01 *not part of the final drug product

(14) TABLE-US-00009 TABLE 2 Batch formulas of the tablets and film-coated tablets, respectively: Quantity, g per batch Ingredient Reference 1 2 3 4 Tablet core Dexketoprofen Manufacturers 141.923 141.923 283.846 283.846 trometamol specification Tramadol Ph. Eur. 288.462 576.923 288.462 576.923 hydrochloride Microcrystalline Ph. Eur. 2914.231 2625.769 2772.308 2483.846 cellulose Maize starch Ph. Eur. 381.538 381.538 381.538 381.538 Sodium starch Ph. Eur. 208.462 208.462 208.462 208.462 glycolate Glycerol Ph. Eur. 40.000 40.000 40.000 40.000 distearate Silica colloidal, Ph. Eur. 25.385 25.385 25.385 25.385 anhydrous Purified water Ph. Eur. q.s. q.s. q.s. q.s. (solvent for granulation) * Film coating (optional) Hypromellose Ph. Eur. 38.077 38.077 38.077 38.077 Titanium dioxide Ph. Eur. 24.923 24.923 24.923 24.923 Povidone K 30 Ph. Eur. 6.692 6.692 6.692 6.692 Macrogol 4000 Ph. Eur. 7.308 7.308 7.308 7.308 Purified water Ph. Eur. q.s. q.s. q.s. q.s. (solvent for film coating)*

(15) Dexketoprofen trometamol and tramadol hydrochloride are sieved together with microcrystalline cellulose and about of maize starch through 1.0 mm mesh size. The compounds are mixed for 20 min. With the remaining amount of maize starch the granulation fluid is prepared: approximately of water is mixed with the second half of maize starch. The remaining water is heated to near the boiling point and then added to the maize starch slurry. For the wet granulation the binder fluid is stirred to 72-80 C. The granulation is performed applying standard procedures using a fluid bed granulator. It is dried to a loss on drying of 2.5-3.5%. Afterwards, the granules are sieved (1.0 mm mesh size) and subsequently mixed with sodium starch glycolate, glycerol distearate and silica colloidal anhydrous for 10 min. The obtained compactable mixture is compressed on a standard rotary die press to tablet cores with the following properties: Oblong with dimensions of 178 mm Tablet mass: 5203% Height: 5.50 2 mm Resistance to crushing: 90 N Disintegration time: 5 min. Friability: 1.0%

(16) The resulting tablet cores can be coated with the hypromellose film. The hypromellose is added to purified water heated to near the boiling point. Afterwards, povidone K 30 and macrogol 4000 are added and the mixture is stirred until a clear solution is obtained. Directly before the film-coating, titanium dioxide is added and dispersed with a high frequency stirrer. The film-coating is performed in a standard film-coater.

(17) The obtained film-coated tablets show the following properties:

(18) Tablet mass: 5305% Height: 5.60 3 mm Resistance to crushing: 90 N Disintegration time: 7.5 min.

(19) Sample batches with different dexketoprofen/tramadol ratios were produced and tested under ICH conditions for 18 months at (252) C. and (605)% relative humidity. Results of these tests are presented in tables 3 to 6.

(20) The obtained results indicate excellent chemical and physical stability of the produced batches (regarding disintegration, dissolution and other tablet parameters).

(21) TABLE-US-00010 TABLE 3 Stability data of the film-coated tablets DKP TRIS 18.4 mg + TRA-HCl 37.5 mg at (25 2) C. and (60 5)% RH in AlAl blisters: Shelf-life specifi- Results (after months) Test parameters cation 0 3 6 9 12 18 General and specific characteristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 75) 101 98 99 100 101 101 TRIS [%] Tramadol (Q = 75) 102 102 101 102 102 102 hydrochloride [%] Disintegration nmt 15 3 4 5 4 3 4 time [min] Assay Dexketoprofen 90.0 to 99.4 102.1 100.2 100.7 100.4 102.2 TRIS [%] 105.0 Tramadol 90.0 to 99.7 101.8 102.9 102.0 101.6 105.0 hydrochloride [%] 105.0 Additional parameter Resistance to crushing mean t: 90N 203 252 198 189 189 199 nmt = not more than

(22) TABLE-US-00011 TABLE 4 Stability data of the film-coated tablets DKP TRIS 18.4 mg + TRA-HCl 75 mg at (25 2) C. and (60 5)% RH in AlAl blisters: Shelf-life specifi- Results (after months) Test parameters cation 0 3 6 9 12 18 General and specific characteristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 75) 102 100 101 101 98 102 TRIS[%] Tramadol (Q = 75) 103 100 102 100 100 102 hydrochloride [%] Disintegration nmt 15 6 7 9 9 11 8 time [min] Assay Dexketoprofen 90.0 to 99.1 101.7 101.3 103.3 100.9 101.6 TRIS [%] 105.0 Tramadol 90.0 to 99.2 101.8 101.3 103.1 101.1 101.2 hydrochloride [%] 105.0 Additional parameter Resistance to crushing mean t: 90N 200 224 189 194 183 192 nmt = not more than

(23) TABLE-US-00012 TABLE 5 Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl 37.5 mg at (25 2) C. and (60 5)% RH in AlAl blisters: Shelf-life specifi- Results (after months) Test parameters cation 0 3 6 9 12 18 General and specific characteristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 75) 102 101 102 100 101 102 TRIS [%] Tramadol (Q = 75) 101 100 100 100 100 101 hydrochloride [%] Disintegration nmt 15 3 5 6 3 1 3 time [min] Assay Dexketoprofen 90.0 to 98.2 102.3 101.6 102.2 101.1 102.4 TRIS [%] 105.0 Tramadol 90.0 to 96.8 100.5 101.4 100.8 98.7 101.4 hydrochloride [%] 105.0 Additional parameter Resistance to crushing mean t: 90N 207 257 190 205 203 204 nmt = not more than

(24) TABLE-US-00013 TABLE 6 Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl 75 mg at (25 2) C. and (60 5)% RH in AlAl blisters: Shelf-life specifi- Results (after months) Test parameters cation 0 3 6 9 12 18 General and specific characteristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 104 103 103 n.t. 101 99 TRIS [%] 75) Tramadol (Q = 104 101 102 n.t. 103 99 hydrochloride [%] 75) .sup.(1) Disintegration nmt 15 3 8 9 8 7 8 time [min] Assay Dexketoprofen 90.0 to 100.5 103.1 103.0 103.2 104.9 104.1 TRIS [%] 105.0 Tramadol 90.0 to 100.6 102.4 103.1 103.4 102.7 102.6 hydrochloride [%] 105.0 Additional parameter Resistance to crushing mean t: 90N 152 184 170 167 174 183 nmt = not more than

Example 2: Manufacturing of Dexketoprofen Trometamol+Tramadol Hydrochloride Film-Coated Tablets with Pregelatinised Maize Starch

(25) Batch size: 550 g

(26) Composition of the film-coated tablets:

(27) TABLE-US-00014 Amount per single Amount per Active substances dose unit [mg] batch [g] Dexketoprofen trometamol 36.90 57.99 Tramadol hydrochloride 75.00 117.86 Other ingredients Tablet core: Microcrystalline cellulose 179.70 282.39 Maize starch pregelatinised 29.20 45.89 Croscarmellose sodium 21.90 34.41 Sodium stearyl fumarate 3.65 5.74 Silica, colloidal anhydrous 3.65 5.74 Purified water* q.s. q.s. Film coating: polyvinyl alcohol based coating 7.30 11.47 Purified water* q.s. q.s. *not part of the final product

(28) Dexketoprofen trometamol and tramadol hydrochloride are sieved together with microcrystalline cellulose and of croscarmellose sodium through 1.0 mm mesh size. The compounds are transferred to the fluid bed granulator. For the preparation of the binder fluid pregelatinised maize starch is added to purified water and stirred for about 60 min. in order to obtain homogenous binder slurry. The granulation is performed applying standard procedures in a fluid bed granulator. It is dried to a loss on drying of 2.5-3.5%. Afterwards, the granules are sieved (1.0 mm mesh size) and subsequently mixed with croscarmellose-sodium, silica, colloidal anhydrous for 10 min. After the mixture with sodium stearyl fumarate for 5 min., the obtained compactable mixture is compressed on a standard rotary tablet press to tablet cores with the following properties: Oblong with dimensions of 167 mm Tablet mass: 350 mg5% Height: 4.50 2 mm Resistance to crushing: 90 N Disintegration time: 4 min. Friability: 1.0%

(29) The resulting tablet cores are subsequently coated with an aqueous film coating system based on a polyvinyl alcohol motif, which is prepared according to the manufacturer's recommendation. The film-coating is performed in a standard film-coater. The resulting film-coated tablets show the following properties: Tablet mass: 357 mg5% Height: 4.60 2 mm Resistance to crushing: 90 N Disintegration time: 6 min.

(30) The dissolution profiles of the film-coated tablets in Ph. Eur. buffer pH 6.8 R1 with paddle apparatus, at 50 rpm of stirring speed and 1000 ml of buffer volume are shown in FIGS. 1, 2 and 3. FIG. 1 presents the dissolution profiles of both active ingredients at the initial value, whereas FIGS. 2 and 3 displays the dissolution profiles after accelerated stability testing for 1 and 4 weeks, respectively, at 60 C. in a dry oven. No significant difference between the dissolution profiles was detectable, so that a physico-chemical interaction of both compounds can be excluded.

Example 3: Manufacturing of Dexketoprofen+Tramadol Film-Coated Tablets with Pregelatinised Maize Starch as Binder and Croscarmellose Sodium as Disintegrant in Pilot Batch Scale (12.7 kg)

(31) The identical formulation as presented in EXAMPLE 2 was upscaled to 12.7 kg (pilot scale). The characteristics for the tablet cores are presented below: Oblong with dimensions of 146 mm Tablet mass: 350 mg5% Height: 5.10 5 mm Resistance to crushing: 13015 N Disintegration time: 6 min. Friability: 0.5%

(32) The properties of the film-coated tablets are as follows: Tablet mass: 357 mg5% Height: 5.20 5 mm Resistance to crushing: 90 N Disintegration time: 15 min.

(33) The film-coated tablets were tested for the dissolution profile and for stability under accelerated conditions at 40 C./75% relative humidity. The results are presented in FIG. 4 and table 7.

(34) TABLE-US-00015 TABLE 7 Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl 75 mg at (25 2) C. and (60 5)% RH in A1-A1 blisters Shelf-life Results (after months) Test parameters specification 0 3 6 General and specific charac- teristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 75) .sup.(1) 98 101 98 TRIS [%] Tramadol hydro- (Q = 75) .sup.(1) 99 102 99 chloride [%] Disintegration time nmt 15 6 7 6 [min] Assay Dexketoprofen 90.0 to 105.0 101.3 99.6 99.2 TRIS [%] Tramadol hydro- 90.0 to 105.0 102.7 101.4 100.8 chloride [%] Additional parameter Resistance to t: 90 191 228 233 crushing [N] .sup.(7)

Example 4: Manufacturing of Dexketoprofen+Tramadol Film-Coated Tablets with Pregelatinised Maize Starch as Binder and Croscarmellose Sodium as Disintegrant in the Large Scale of 223 kg

(35) The formulation from EXAMPLES 2 and 3 was slightly modified and upscaled to the large-scale batch size of 223 kg. The granulation was performed in two sub-batches.

(36) Composition of the Film-Coated Tablets:

(37) TABLE-US-00016 Amount per Amount per Amount per single dose granulation batch Active substances unit [mg] sub-batch [kg] [kg] Dexketoprofen 36.90 11.121 22.241 trometamol Tramadol 75.00 22.603 45.206 hydrochloride Other ingredients Tablet core: Microcrystalline 179.70 54.157 108.314 cellulose Maize starch 29.20 8.800 17.600 pregelatinised Croscarmellose 11.02 3.321 6.642 sodium (inner phase) Croscarmellose 22.04 13.292 sodium (outer phase) Sodium stearyl 1.83 4.442 fumarate Silica, colloidal 7.37 1.103 anhydrous Purified water* q.s. Film coating: polyvinyl alcohol 7.30 4.400 based coating Purified water* q.s. q.s.

(38) For the first sub-batch of 100 kg, dexketoprofen trometamol, tramadol hydrochloride, microcrystalline cellulose and croscarmellose-sodium for the inner phase mixed and sieved together through 1.0 mm mesh size. The compounds are transferred to the fluid bed granulator. For the preparation of the binder fluid pregelatinised maize starch is added to purified water and stirred for about 60 min. in order to obtain a homogenous binder slurry. The granulation is performed applying standard procedures in a fluid bed granulator. It is dried to a loss on drying of 2.5-3.5%. Afterwards, the granules are sieved (1.0 mm mesh size) and subsequently mixed with croscarmellose-sodium and silica, colloidal anhydrous for 10 min. The second sub-batch is prepared following identical procedures and then added to the first sub-batch. Sodium stearyl fumarate is sieved and added to the mixture of both sub-batches. The obtained compactable mixture is compressed on a standard rotary tablet press to tablet cores with the following properties: Oblong with dimensions of 146 mm Tablet mass: 363 mg2% Height: 5.10 2 mm Resistance to crushing: 115-150 N Disintegration time: <5 min. Friability: 0.05%

(39) The properties of the film-coated tablets are as follows: Tablet mass: 370 mg5% Height: 5.20.2 mm Resistance to crushing: >90 N Disintegration time: 6 min.

(40) TABLE-US-00017 TABLE 8 Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl 75mg at (40 2) C. and (75 5)% RH in A1-A1 blisters Shelf-life Results (after months) Test parameters specification 0 3 6 General and specific charac- teristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 75) 100 98 98 TRIS [%] Tramadol hydro- (Q = 75) 100 98 100 chloride [%] Disintegration time nmt 15 8 8 9 [min] Assay Dexketoprofen 90.0 to 105.0 98.7 99.5 98.8 TRIS [%] Tramadol hydro- 90.0 to 105.0 100.5 100.1 100.0 chloride [%] Additional parameter Resistance to t: 90 221 255 266 crushing [N]

(41) TABLE-US-00018 TABLE 9 Stability data of the film-coated tablets DKP TRIS 36.9 mg + TRA-HCl 75 mg at (30 2) C. and (75 5)% RH in A1-A1 blisters Shelf-life Results (after months) Test parameters specification 0 3 6 General and specific charac- teristics of the dosage form Dissolution (after 30 min) Dexketoprofen (Q = 75) 100 94 96 TRIS [%] Tramadol hydro- (Q = 75) 100 95 95 chloride [%] Disintegration time nmt 15 8 8 8 [min] Assay Dexketoprofen 90.0 to 105.0 98.7 100.1 97.6 TRIS [%] Tramadol hydro- 90.0 to 105.0 100.5 100.8 99.9 chloride [%] Additional parameter Resistance to t: 90 221 232 245 crushing [N] .sup.(7)

(42) The dissolution profile of the obtained film-coated tablets is shown in FIG. 5 and is comparable to that of the sample and pilot size batches.