METHOD FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING AMPHIPHILIC ACTIVE INGREDIENTS

Abstract

The present invention relates to a method for granulating an amphiphilic active ingredient or a pharmaceutically acceptable salt thereof, comprising a step for coating the active ingredient in a polar aprotic solvent in the presence of a polymer binder to obtain a granule.

Claims

1. A method for granulating an amphiphilic active ingredient, or a pharmaceutically acceptable salt thereof, comprising a step for coating the active ingredient in a polar aprotic solvent in the presence of a polymer binder, so as to obtain a granule.

2. The method according to claim 1, wherein the amphiphilic active ingredient comprises at least one carboxylic acid group and at least one aryl group comprising from 6 to 50 carbon atoms.

3. The method according to claim 1, wherein the amphiphilic active ingredient is a nonsteroidal anti-inflammatory drug (NSAID).

4. The method according to claim 1, wherein the amphiphilic active ingredient is an arylacetic NSAID, an arylproprionic NSAID, or an anthranilic NSAID.

5. The method according to claim 1, wherein the amphiphilic active ingredient is selected from the group consisting of ibuprofen, ketoprofen, naproxen, flurbiprofen, oxaprozin, ibufenac, diclofenac, aceclofenac, sulindac, etodolac, ketorolac, indomethacin, mefenamic acid, and niflumic acid.

6. The method according to claim 1, wherein the pharmaceutically acceptable salt of the amphiphilic active ingredient is selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a calcium salt, an aluminum salt, a magnesium salt, a zinc salt, an arginine salt, a lysine salt, a histidine salt, a choline salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, an ethylenediamine salt, and a meglumine salt.

7. The method according to claim 1, wherein the amphiphilic active ingredient or the pharmaceutically acceptable salt thereof is the lysine salt or the sodium salt of ibuprofen.

8. The method according to claim 1, wherein the polymer binder is a polyvinylpyrrolidone (povidone) or a polyvinylpyrrolidone copolymer, in particular copovidone (a copolymer of polyvinylpyrrolidone and vinyl acetate), a polyethylene glycol (PEG), a polyoxypropylene copolymer, or a methacrylate copolymer.

9. The method according to claim 1, wherein the quantity of polymer binder is of at least 5% by weight relative to the weight of active ingredient.

10. The method according to claim 1, wherein the polar aprotic solvent is selected from the group consisting of acetone, ethyl acetate, acetonitrile, and N,N-dimethylformamide, or a mixture thereof.

11. The method according to claim 1, further comprising a step of drying and/or sieving the granule.

12. A granule that can be obtained by the method according to claim 1.

13. A granule comprising a polar active ingredient, or a pharmaceutically acceptable salt thereof, coated with a polymer binder and having a density of 0.5 to 0.7 g/mL and/or a flow rate of 3 to 15 g/sec.

14. The granule according to claim 13, wherein the amphiphilic active ingredient comprises at least one carboxylic acid group and at least one aryl group comprising from 6 to 50 carbon atoms.

15. The granule according to claim 13, wherein the amphiphilic active ingredient is a nonsteroidal anti-inflammatory drug (NSAID).

16. The granule according to claim 13, wherein the amphiphilic active ingredient is an arylacetic NSAID, an arylproprionic NSAID, or an anthranilic NSAID.

17. The granule according to claim 13, wherein the polar active ingredient is selected from the group consisting of ibuprofen, ketoprofen, naproxen, flurbiprofen, oxaprozin, ibufenac, diclofenac, aceclofenac, sulindac, etodolac, ketorolac, indomethacin, mefenamic acid, and niflumic acid.

18. The granule according to claim 13, wherein the pharmaceutically acceptable salt of the polar active ingredient is selected from the group consisting of a lithium salt, a sodium salt, a potassium salt, a calcium salt, an aluminum salt, a magnesium salt, a zinc salt, an arginine salt, a lysine salt, a histidine salt, a choline salt, an ethanolamine salt, a diethanolamine salt, a triethanolamine salt, an ethylenediamine salt, and a meglumine salt.

19. The granule according to claim 13, wherein the amphiphilic active ingredient or the pharmaceutically acceptable salt thereof is the lysine salt or the sodium salt of ibuprofen.

20. The granule according to claim 13, wherein the polymer binder is a polyvinylpyrrolidone (povidone) or a polyvinylpyrrolidone copolymer, in particular copovidone (a copolymer of polyvinylpyrrolidone and vinyl acetate), a polyethylene glycol (PEG), a polyoxypropylene copolymer, or a methacrylate copolymer.

21. The granule according to claim 13, wherein the quantity of polymer binder is of at least 5% by weight relative to the weight of active ingredient.

22. A pharmaceutical composition or medicine comprising a granule according to claim 12 and at least one pharmaceutically acceptable vehicle or excipient.

23. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. (canceled)

28. A method for the prevention or treatment of pain, fever, and/or inflammation in an in an individual in need thereof, comprising administering to the individual a therapeutically effective amount at least one granule according to claim 12.

Description

DESCRIPTION OF THE FIGURES

[0066] FIG. 1 is a flow chart for preparing a tablet according to the invention.

[0067] FIG. 2 represents the in vitro dissolution kinetics of tablets according to the invention (G17, G34-F42, G35-F46) and commercial tablets (NUROFEN® FLASH 512 mg batch BW538, NUROFEN® 400 mg batch DL365) (percentage of dissolution, y-axis) under the same conditions (pH=6.8) as a function of time (x-axis, in minutes).

[0068] FIG. 3 represents the percentage of dissolution of a tablet according to the invention (IBUNA 512 mg) and of the product NUROFEN® 400 mg batch DL 365 (y-axis, in μg/mL) as a function of time (x-axis, in minutes) in 900 mL of a solution at pH 6.8, under agitation at 50 rpm.

[0069] FIG. 4 represents the dissolution kinetics of a tablet according to the invention at pH=6.8 in vitro (percentage of dissolution) and in vivo (as a percentage of C.sub.max) (y-axis) as a function of time (x-axis, in minutes).

[0070] FIG. 5 represents images obtained by scanning electron microscopy (magnification 10 kV×100) of crystals of ibuprofen sodium salt dihydrate (on the left) and of granules according to the invention obtained from these crystals by coating in a polymer binder (on the right).

[0071] FIG. 6 represents, from top to bottom, the X-ray powder diffraction (XRPD) spectra of ibuprofen sodium salt dihydrate: [0072] (i) in crystalline form, [0073] (ii) of a film-coated tablet according to the invention, [0074] (iii) of a granule according to the invention obtained from copovidone (polymer binder) and acetone (polar aprotic solvent), [0075] (iv) of a granule according to the invention obtained from copovidone (polymer binder) and acetonitrile (polar aprotic solvent).

[0076] The x-axis represents the value of the 2-Theta angle in degrees and the y-axis represents the intensity of the diffracted rays.

EXAMPLES

[0077] The general flow chart of the method used in the following examples is given in FIG. 1.

[0078] The compression is performed in a rotary machine of the KYLLIAN LX20 type with conventional punches. The coating of the tablet is performed in a film-coating machine of the DRIACOATER type (DRIAM GmbH).

Examples 1, 2 and 3: Tablets of Ibuprofen Sodium Salt Obtained by Granulation in a Polar Aprotic Solvent

[0079]

TABLE-US-00003 TABLE 3 EXAMPLE 1 - G17 Ingredients mg/tablet Internal Phase Ibuprofen sodium salt dihydrate 512.00 (acetonitrile granulation) Povidone (PLASDONE K29/32) 55.00 Acetonitrile (intermediate solvent) External phase Mannitol (PEARLITOL ® SD200) 235.55 Croscarmellose sodium (VIVASOL ®) 45.00 Hydrated Silica (LEVILITE ®) 100.00 Magnesium stearate 14.45 Mixture before compression Flow time (Sec.) 12.62 Apparent volumes (mL) V10 269 V1250 257 Density (g/mL) 0.34 Compressibility index 13 Hausner ratio 1.15 Tablets Average mass (mg) 962 Hardness (N) 75.7 Disaggregation (min.) Dissolution % 15 min. 90 Friability % 0.49 Capping 0 Binding 0

TABLE-US-00004 TABLE 4 EXAMPLE 2 - G34-F42 Ingredients mg/tablet Internal Phase Ibuprofen sodium salt dihydrate 512.00 (acetone granulation) Povidone (PLASDONE K29/32) 80.00 Acetonitrile (intermediate solvent) External phase Mannitol (PEARLITOL ® SD200) 235.55 Croscarmellose sodium (VIVASOL ®) 45.00 Hydrated Silica (LEVILITE ®) 100.00 Magnesium stearate 14.45 Mixture before compression Flow time (g/sec.) 13.72 Apparent volumes (mL) V10 224 V1250 211 Density (g/mL) 0.42 Compressibility index 13 Hausner ratio 1.14 Tablets Average mass (mg) 987 Hardness (N) 82.4 Disaggregation (min.) 10.4 Dissolution % 15 min. 81 Friability % 0.76 Capping 0 Binding 0

TABLE-US-00005 TABLE 5 EXAMPLE 3 - G35-F46 Ingredients mg/tablet Internal Phase Ibuprofen sodium salt dihydrate 512.00 (ethyl acetate granulation) Povidone (PLASDONE K29/32) 80.00 Acetonitrile (intermediate solvent) External phase Mannitol (PEARLITOL ® SD200) 242.62 Croscarmellose sodium (VIVASOL ®) 46.35 Hydrated Silica (LEVILITE ®) 46.00 Magnesium stearate 17.00 Mixture before compression Flow time (g/sec.) 15.27 Apparent volumes (mL) V10 225 V1250 212 Density (g/L) 0.37 Compressibility index 13 Hausner ratio 1.14 Tablets Average mass (mg) 970 Hardness (N) 80 Disaggregation (min.) 12.36 Dissolution % 15 min. 76.4 Friability % 0.2 Capping 0 Binding 0

[0080] The three examples reported above use different polar aprotic solvents according to the invention: acetonitrile in Example 1, acetone in Example 2, ethyl acetate in Example 3. Granulation in all 3 examples is performed with Povidone (Ph. Eur.).

[0081] The tables below present exemplary characteristics of granules according to the invention obtained with acetone:

TABLE-US-00006 TABLE 6 Granule batch 729740 Ingredients mg Ibuprofen sodium salt dihydrate 512.00 Povidone (PLASDONE K29/32) 55.00 Acetone (intermediate solvent) Quantum satis Pharmacotechnical properties Flow time (Sec.) 10.3 Apparent volumes (mL) V10 182 V1250 161 Density before compaction (g/mL) 0.55 Density after compaction (g/mL) 0.62 Compressibility index 21 Hausner ratio 1.13

TABLE-US-00007 TABLE 7 Granule batch 729650 Ingredients mg Ibuprofen sodium salt dihydrate 512.00 Povidone (PLASDONE K29/32) 55.00 Acetone (intermediate solvent) Quantum satis Pharmacotechnical properties Flow time (Sec.) 12.1 Apparent volumes (mL) V10 185 V1250 149 Density before compaction (g/mL) 0.54 Density after compaction (g/mL) 0.67 Compressibility index 36 Hausner ratio 1.24
FIG. 5 shows scanning electron microscopy images of crystals of ibuprofen sodium salt dihydrate and of granules according to the invention obtained from these crystals by coating with a polymer binder. Due to the coating with the polymer binder, an increase in the size of the granules relative to the crystals, a reduction in the number of crystals of small size (less than 50 μm), and the maintenance of the crystalline form in the granules can be observed.

[0082] The external phases of the tablets comprise: [0083] two hydrophilic excipients: Mannitol and Hydrated Silica (Ph. Eur.), the latter of which, depending on the type (LEVILITE® or SYLOID®), can have a more or less pronounced hydrophilic character; [0084] a disintegrating agent: croscarmellose sodium, and [0085] a lubricant: magnesium stearate.

[0086] These formulations make it possible to obtain a grain, composed of the active ingredient granule and of the external phase, that has good flowability, and suitable compressibility (HAUSNER ratio of 1.14-1.15) as evidenced by tablets which hardness is between and 76 and 83 N, and that shows no capping, no trace of sticking, and no binding, with a friability of less than 1%.

[0087] Moreover, the test of their dissolution in accordance with the European Pharmacopoeia at 37° C. in 900 mL of buffer at pH 6.8 reveals a fast dissolution of the ibuprofen sodium salt, since the following are dissolved within 15 minutes: [0088] 90% of Example 1 (acetonitrile granulation) [0089] 80% of Example 2 (acetone granulation) [0090] 76% of Example 3 (ethyl acetate granulation).

[0091] These results are confirmed by comparing the dissolution rates, expressed as a percentage dissolved per minute of these three formulations according to the invention as a function of time relative to that of tablets of reference products formulated either with ibuprofen sodium salt, i.e. NUROFEN® MAX STRENGTH 512 mg batch BW 538, or with ibuprofen in acid form, i.e. NUROFEN® 400 mg batch DL365.

[0092] The results of FIG. 2 show that, advantageously, the formulations according to the invention reach their maximum rate from the 5th minute, unlike the two reference products, which dissolution does not start until after 5 minutes (NUROFEN® MAX STRENGTH 512 mg) and 10 minutes (NUROFEN® 400 mg), their maximum rates not being reached until after 12 to 15 minutes, respectively, with higher maximum rate values for the formulations using the salified form of ibuprofen.

Example 4: Film-Coated Tablets of Ibuprofen Sodium Salt Obtained by Granulation in a Polar Aprotic Solvent

[0093] The formulation below resulted from Example 2 above. After addition of the external phase and compression to form the tablet, it is finished with a polyvinyl alcohol-based film-forming composition:

TABLE-US-00008 TABLE 8 512 mg/ Ingredients % m/m film-coated tablet Sodium ibuprofen dihydrate 52.15 512.00 (acetone granulation) Copovidone 8.15 80.00 Mannitol 24.71 242.62 Croscarmellose sodium 4.72 46.35 Hydrated colloidal silica 4.69 46.00 Magnesium stearate 1.73 17.00 Poly(vinyl alcohol) composition 3.85 37.76 Total per film-coated tablet 100.00 981.73

[0094] Its dissolution rate was tested in comparison to the product NUROFEN® FLASH 684 mg lysine salt (equivalent to 400 mg of ibuprofen):

[0095] A study of its pharmacokinetics in 20 healthy volunteers after administration of a dose of 512 mg, equivalent to 400 mg of Ibuprofen in acid form, was conducted in comparison to that of a dose of 400 mg of the acid form (NUROFEN® 400 mg).

[0096] The results below demonstrate that, advantageously and unexpectedly, the formulation according to the invention (IBUNA) reaches maximum concentration at t=0.62 h (37 min.) as opposed to t=1 h for the reference product (NUROFEN®) corresponding to the acid form of Ibuprofen. The maximum concentrations reached are significantly different, the difference being 30% in favor of the formulation according to the invention.

TABLE-US-00009 TABLE 9 IBUNA 512 mg NUROFEN ® 400 mg Batch 715860 Batch DL365 (N = 20) (N = 20) Parameter (Unit) Average (C.V. %) Average (C.V. %) C.sub.max (μg/mL) 47.576 (21.8) 34.183 (21.4) In (C.sub.max) 3.8401  (5.6) 3.5097  (6.2) T.sub.max (hours).sup.a 0.62 (0.33-0.83) 1.00 (0.62-4.00) AUC.sub.0-T (μg .Math. h/mL) 123.106 (25.7) 128.293 (24.3) In (AUC.sub.0-T) 4.7821  (5.3) 4.8273  (4.9) AUC.sub.0-∞ (μg .Math. h/mL) 126.271 (26.5) 132.598 (24.7) In (AUC.sub.0-∞) 4.8058  (5.4) 4.8593  (5.0) Residual area (%) 2.33 (52.3) 3.13 (59.0) λ.sub.Z (hours.sup.−1) 0.3118 (15.7) 0.3025 (16.4) T.sub.half (hours) 2.27 (15.1) 2.36 (19.3)

[0097] The corresponding curves are shown in FIG. 3.

[0098] Moreover, the correlation between the dissolution kinetics results in vitro (pH=6,8) and in vivo was verified (FIG. 4).

[0099] Briefly, for the same abscissa (time in min.), the dissolved percentage (% dissolution) and the measured serum concentration expressed as a percentage of measured maximum concentration (% C.sub.max) are reported on the ordinate. After a wait time of 10 minutes, corresponding to the difference in the disintegration times of the tablets according to the invention in vitro and in vivo, we observe a parallelism of the two curves indicating a constant rate of absorption of the active ingredient. This rate is perfectly simulated by the dissolution curve. Beginning at 20 minutes, the 2 curves converge near 100% on the ordinate, reached in 30 minutes.

[0100] FIG. 6 shows that in both the film-coated tablets according to the invention and the granules according to the invention, the crystalline structure of the ibuprofen sodium salt dihydrate is maintained. In fact, it is observed that the characteristic peaks of ibuprofen sodium salt dihydrate (from 16° to 21° and at 22° (2-Theta angle)) are retained in each of these products.

Example 5: Tablets of Ibuprofen Sodium Salt Dihydrate 512 mg+Anhydrous Caffeine 100 mg

[0101] Anhydrous caffeine according to the European Pharmacopoeia is preferred, and is added directly to the external phase of the formulation of the ibuprofen sodium salt dihydrate 512 mg tablet.

TABLE-US-00010 TABLE 10 IBUCAF - Batch 729740 EXAMPLE 5 Ingredients mg/tablet Internal Phase Ibuprofen sodium salt dihydrate 512.00 Copovidone (PLASDONE ® S630) 80.00 Acetone (intermediate solvent) External phase Caffeine 100.00 Mannitol (PEARLITOL ® SD200) 242.62 Croscarmellose sodium (VIVASOL ®) 46.35 Hydrated Silica (SYLOID ®) 46.00 Magnesium stearate 17.00 Poly(vinyl alcohol) composition 42.00 Total per film-coated tablet 1085.97 Mixture before compression Flow time (g/sec.) 7.47 Apparent volumes (mL) V0 182 V1250 132 Density D0 (g/mL) 0.55 Compressibility index 27.5 Hausner ratio 1.38 Tablets Average mass (mg) 1086 Hardness (N) 118 Disaggregation (min.) 11:07 Friability % 0.2 Capping 0 Binding 0

Example 6: Capsules of Ibuprofen Sodium Salt Dihydrate 256 and 512 mg

[0102] Starting with the granule prepared according to the invention, it is possible to add into the external phase both mannitol to correct variations in the density of the granule and a lubricant, such as stearic acid for example, and directly produce capsules, particularly of size 2, by force filling/trimming.

[0103] It is also possible to add mannitol into the external phase without a lubricant, then directly produce capsules, particularly of size 1 or OEL, by force filling/trimming.

Example 7: Capsules of Ibuprofen Sodium Salt Dihydrate 256 mg and Pseudoephedrine Hydrochloride 30 mg

[0104] Alternatively, starting with the granule prepared according to the invention, it is possible to produce a combination with pseudoephedrine hydrochloride, which is added into the external phase along with mannitol and a lubricant. Mannitol is added in variable quantities in order to correct variations in the density of the granule and enable the production of a capsule, particularly of size 1, by force filling/trimming.