IMMEDIATE-RELEASE PHARMACEUTICAL COMPOSITIONS CONTAINING KETOPROFEN LYSINE SALT

Abstract

The present invention in general relates to an immediate-release pharmaceutical composition containing ketoprofen lysine salt and mannitol. In particular, the present invention relates to an immediate-release pharmaceutical composition in the form of tablet. The invention also provides a process for manufacturing such composition.

Claims

1-12. (canceled)

13. An immediate-release pharmaceutical composition comprising ketoprofen lysine salt (KLS) having a particle size distribution with a d(0.9) comprised between 150 m and 250 m and/or a d(0.5) greater than 65 m and/or a d(0.1) greater than 1.5 m as the active principle, and mannitol wherein the ratio of ketoprofen lysine salt to mannitol is from about 100:100 to about 100:250.

14. The immediate-release pharmaceutical composition according to claim 13, wherein the mannitol has a particle size distribution with maximum of 35% greater than 150 m and/or minimum of 70% greater than 75 m.

15. The immediate-release pharmaceutical composition according to claim 13, further comprising at least one superdisintegrant.

16. The immediate-release pharmaceutical composition according to claim 15, wherein the at least one superdisintegrant is present in an amount ranging from 25 to 50% by weight of the amount of ketoprofen lysine salt.

17. The immediate release pharmaceutical composition according to claim 16, wherein the at least one superdisintegrant is present in an amount ranging from 30 to 45% by weight of the amount of ketoprofen lysine salt.

18. The immediate release pharmaceutical composition according to claim 16, wherein the at least one superdisintegrant is present in an amount ranging from 35 to 45% by weight of the amount of ketoprofen lysine salt.

19. The immediate-release pharmaceutical composition according to claim 15, wherein the at least one superdisintegrant is selected from the group consisting of crospovidone, croscarmellose, sodium starch glycolate, pregelatinized starch and mixtures thereof.

20. The immediate-release pharmaceutical composition according to claim 19, wherein the superdisintegrant is crospovidone.

21. The immediate-release pharmaceutical composition according to claim 13, further comprising at least one lubricant and/or at least one glidant.

22. The immediate-release pharmaceutical composition according to claim 21, wherein the at least one lubricant is present in an amount ranging from 0 to 4.0%, by weight of the composition and/or the at least one glidant is present in an amount ranging from 0 to 2.0% by weight of the composition.

23. The immediate-release pharmaceutical composition according to claim 22, wherein the at least one lubricant is present in an amount ranging from 1.5 to 2.5% by weight of the composition.

24. The immediate-release pharmaceutical composition according to claim 22, wherein the at least one lubricant is present in an amount ranging from 1.75 to 2.25% by weight of the composition.

25. The immediate-release pharmaceutical composition according to claim 22, wherein the at least one glidant is present in an amount ranging from 0.5 to 1.5% by weight of the composition.

26. The immediate-release pharmaceutical composition according to claim 22, wherein the at least one glidant is present in an amount ranging from 0.75 to 1.25% by weight of the composition.

27. The immediate-release pharmaceutical composition according to claim 21, wherein the at least one lubricant is selected from the group consisting of magnesium stearate, stearic acid, talc, sodium laurylsulfate, sodium stearyl fumarate, glyceryl behenate and mixtures thereof, preferably sodium laurylsulfate and sodium stearyl fumarate.

28. The immediate-release pharmaceutical composition according to claim 27, wherein the at least one lubricant is selected from the group consisting of sodium laurylsulfate and sodium stearyl fumarate and mixtures thereof.

29. The immediate-release pharmaceutical composition according to claim 21, wherein the at least one glidant is selected from the group consisting of colloidal silica, talc, stearic acid and mixture thereof.

30. The immediate-release pharmaceutical composition according to claim 29, wherein the glidant is colloidal silica.

31. The immediate-release pharmaceutical composition according to claim 13, in the form of tablet.

32. The immediate-release tablet according to claim 31, wherein the table is obtainable by direct compression with a tableting strength from 7 to 15 kN.

33. The immediate release tablet according to claim 32, wherein the tableting strength is from 7 to 10 kN.

34. A process for the preparation of the immediate-release tablet according to claim 31, comprising the following steps: a) providing ketoprofen lysine salt particles having a particle size distribution with a d(0.9) comprised between 150 m and 250 m and/or a d(0.5) greater than 65 m and/or a d(0.1) greater than 1.5 m, and mannitol wherein the ratio of ketoprofen lysine salt to mannitol is from about 100:100 to about 100:250; b) mixing the ingredients of step a) in a suitable mixer to achieve a homogeneous mixture; c) optionally mixing the blend of step b) with at least one superdisintegrant, and/or at least one lubricant, and/or at least one glidant until a homogeneous powder is obtained; d) compressing the powder mixture of step c) into a tablet; e) optionally coating the tablet of step d).

Description

DESCRIPTION OF THE FIGURES

[0025] FIG. 1 shows the dissolution profile of batches according to the invention containing different superdisintegrants at pH 1.0;

[0026] FIG. 2 shows dissolution profiles of batches according to the invention containing different fillers and superdisintegrants at pH 1.0;

[0027] FIG. 3 shows dissolution profiles of batches (reference) containing different fillers and superdisintegrants at pH 1.0;

[0028] FIG. 4 shows dissolution profiles of dyed and not dyed coated tablets at pH 1.0;

[0029] FIG. 5 shows the dissolution profile of batches according to the invention at pH 1.0;

[0030] FIG. 6 shows dissolution profiles of tablets produced with different compression forces, at pH 1.0;

[0031] FIG. 7 shows the particle size distribution of the not-micronized ketoprofen lysine salt;

[0032] FIG. 8 shows the particle size distribution of the micronized ketoprofen lysine salt;

[0033] FIG. 9 shows dissolution profiles of batches with ketoprofen lysine salts with different particle size distribution at pH 1.0.

DETAILED DESCRIPTION OF THE INVENTION

[0034] As it will be disclosed in details in the Experimental Section, the present inventors have found that a pharmaceutical composition containing ketoprofen lysine salt having specific particle size distribution and mannitol allows to obtain immediate-release tablets suitable for oral administration with water.

[0035] Accordingly, a first object of the present invention is an immediate-release pharmaceutical composition containing ketoprofen lysine salt (KLS) having a particle size distribution with a d(0.9) comprised between 150 m and 250 m and/or a d(0.5) greater than 65 m and/or a d(0.1) greater than 1.5 m as the active principle, and mannitol wherein the ratio of ketoprofen lysine salt to mannitol is from about 100:100 to about 100:250.

[0036] Mannitol is used as binder for direct compression and as filler.

[0037] According to a preferred embodiment of the present invention, the mannitol has a particle size distribution with maximum of 35% greater than 150 m and/or minimum of 70% greater than 75 m.

[0038] The pharmaceutical composition according to the present invention, further comprising at least one superdisintegrant.

[0039] The superdisintegrants may be present in an amount ranging from 25 to 50%, preferably from 30 to 45% and more preferably from 35 and 40% by weight of the amount of ketoprofen lysine salt.

[0040] Suitable superdisintegrants for the present invention may be selected from the group comprising cross-linked polyvinyl pyrrolidone (crospovidone), cross-linked carboxymethylcellulose sodium (croscarmellose), sodium starch glycolate, pregelatinized starch and mixtures thereof. The preferred superdisintegrant is crospovidone.

[0041] In a preferred embodiment, the pharmaceutical composition according to the invention further comprising at least one lubricant and/or at least one glidant. Lubricant as described herein may be selected from a group comprising magnesium stearate, stearic acid, talc, sodium laurylsulfate, sodium stearyl fumarate, glyceryl behenate, and mixtures thereof. The preferred lubricants are sodium laurylsulfate and sodium stearyl fumarate.

[0042] A hydrophilic lubricant, like sodium stearyl fumarate, can be used in order to keep the disintegration time as short as possible, in order to guarantee a prompt release of the API. In particular, it gives faster dissolution rates, harder tablets, protection from over-blending, faster formulation development and scale-up and enhanced lubrication efficiency.

[0043] The lubricant may be present in an amount ranging from 0 to 4.0%, preferably from 1.5 to 2.5 and more preferably from 1.75 to 2.25% by weight of the composition.

[0044] Glidant as described herein may be selected from the group comprising colloidal silica, talc, and mixtures thereof. The preferred glidant is colloidal silica.

[0045] The glidant may be present in an amount ranging from 0 to 2.0%, preferably from 0.5 to 1.5% and more preferably from 0.75 to 1.25% by weight of the composition. The lubricants and glidants can be used in order to improve the dissolution rate of the API in the first minutes, in order to have a rapid effect in terms of release of the API. The immediate-release pharmaceutical composition according to the present invention is in the form of tablet.

[0046] The present inventors have surprisingly found that the selection of a specific mix of binders and disintegration agents promotes the breakup of the tablet in an aqueous environment thereby increasing the available surface area and promoting a more rapid release of the drug substance.

[0047] An immediate-release tablet according to the present invention is obtainable by direct compression with a tableting strength from 7 to 15 kN, preferably from 7 to 10 kN. Other ingredients, such as a coating film can also be used for organoleptic compliance. Suitable film-coating systems for the present invention may be the Opadry HPMC-based or PVA-based, preferably PVA-based.

[0048] Opadry is a mixture of polyvinyl alcohol or hydroxypropylmethylcellulose, polyethylene glycol/macrogol, titanium dioxide, talc and pigments.

[0049] The presence of a dye does not influence the dissolution rate of the tablets.

[0050] The second object of the present invention is a process for the preparation of an immediate-release tablet according to the invention, comprising the following steps:

[0051] a) providing ketoprofen lysine salt particles having a particle size distribution with a d(0.9) comprised between 150 m and 250 m and/or a d(0.5) greater than 65 m and/or a d(0.1) greater than 1.5 m, and mannitol wherein the ratio of ketoprofen lysine salt to mannitol is from about 100:100 to about 100:250;

[0052] b) mixing the ingredients of step a) in a suitable mixer to achieve a homogeneous mixture;

[0053] c) optionally mixing the blend of step b) with at least one superdisintegrant, and/or at least one lubricant, and/or at least one glidant until a homogeneous powder is obtained;

[0054] d) compressing the powder mixture of step c) into a tablet;

[0055] e) optionally coating the tablet of step d).

[0056] Phase b) and c)Powder Mixing

[0057] Each ingredient has to be sieved to remove possible agglomerates, using a mesh size of 1 mm.

[0058] API is mixed with part of the total amount of the glidant; then the superdisintegrant, one of the lubricants (such as SOS) and a part of the filler are added and mixed with the first fraction. This procedure will mimic a geometric dilution of the API, and will contribute to its homogeneous dispersion in the final mixture.

[0059] The last step consist of the addition of the other lubricant (such as sodium stearyl fumarate), the glidant and the rest of the filler.

[0060] Phase d)Tableting

[0061] Different rotational speeds and compression forces were tested in order to obtain a tablet with the desired technological properties (crushing strength, thickness, average mass, friability, disintegration time, dissolution rate of the API).

[0062] The evaluation of the ejection forces and the aspect of the tablets were relevant to choose the optimal conditions.

[0063] Phase e)Film-Coating

[0064] In order to obtain a taste-masking film coating a low viscosity polymer was chosen, the amount of that was selected considering the visual aspect of the tablets in terms of color uniformity, appearance and the weight.

[0065] A blue color was chosen for a distinctive recognition of the product, and for compliance purposes. The presence of a dye does not influence the dissolution rate. In order to mask the API taste during the administration and to have a product recognizable and appealing, a non-functional film-coating system can be added. Suitable film-coating systems for the present invention may be the Opadry HPMC-based (Opadry II 57U18539) or PVA-based (Opadry II 85F16422), preferably PVA-based.

[0066] Opadry is a mixture of polyvinyl alcohol or hydroxypropylmethylcellulose, polyethylene glycol/macrogol, titanium dioxide, talc and pigments.

[0067] To assess the ability of the Opadry coating to cover the off-taste of the tablets, the uniform distribution of the dye was monitored during the deposition of the film. It was observed that, after the application of 6 mg/tablet of Opadry, the coloration resulted homogeneous and consistent from tablet to tablet. This was taken as a signal of the end of the coating process. The weight gain of the tablets suggests that an even layer of coating film was applied on the surface of the tablet, therefore giving a taste-masking effect to the tablet itself.

[0068] The final weight of the tablet (156 mg) and the small dimension (7 mm diameter) was chosen to increase compliance of patients allowing an easy swallowing of the product.

[0069] Possible immediate-release pharmaceutical compositions of the invention are provided in the following examples, which, however, are only intended to illustrate and not to limit the invention.

EXAMPLES

Example 1

[0070] The formulations according to the present invention as described in the Table 1 were prepared and tested. The tablets were prepared as reported above, using a direct compression.

TABLE-US-00001 TABLE 1 Ingredients 05214 F 05914 F 06014 F Mannitol (Pearlitol 100) 62.00% 62.00% 62.00% KLS 26.67% 26.67% 26.67% Crospovidone 10.00% Croscarmellose sodium 10.00% Sodium starch glycolate 10.00% Sodium stearylfumarate 1.33% 1.33% 1.33%

[0071] The dissolution profiles of the batches containing different superdisintegrants at pH 1.0 are reported in FIG. 1. The dissolution tests are carried out according to Ph. Eur. 2.9.3, current edition (37 C., 900 ml, 50 rpm) on 12 tablets sampling after 5, 10, 15, 30, 45 and 60 minutes. Since pH 1.0 corresponds to the profile which best resembles the stomach conditions (where the dissolution takes place) and where KSL results less soluble than pH 4.5 and 6.8, it could be considered as critical and for this reason it was selected as pH dissolution medium. In addition, the formulations according to the invention is intended to dissolve rapidly in the stomach and to have a prompt bioavailability.

[0072] As shown in the FIG. 1, while croscarmellose gives the highest plateau concentration of KLS in time, crospovidone seems to be quicker in the first minutes of dissolution.

Example 2

[0073] The formulations according to the present invention as described in the Table 2 were prepared and tested. The tablets according to the invention were prepared as reported above, using a direct compression.

[0074] The formulations were prepared using these concentrations of superdisintegrants: [0075] Crospovidone (10.00%) [0076] Croscarmellose sodium (5.00%)+crospovidone (5.00%) [0077] Croscarmellose sodium (10.00%)

[0078] Two different diluents were tested in the same conditions, to see if the behavior of the superdisintegrant changes with the presence of calcium phosphate instead of mannitol.

TABLE-US-00002 TABLE 2 05214 F 05814 F 05914 F 04814 F 05514 F 04014 F DILUENT: DILUENT: Ingredients MANNITOL CALCIUM PHOSPHATE Mannitol 62.00% 62.00% 62.00% (Pearlitol 100) Ca.sub.2HPO.sub.4 67.00% 62.00% 67.00% (Di Cafos A150) KLS 26.67% 26.67% 26.67% 26.67% 26.67% 26.67% Crospovidone 10.00% 5.00% 5.00% 5.00% Croscarmellose 5.00% 10.00% 5.00% 5.00% sodium Sodium stearyl 1.33% 1.33% 1.33% 1.33% 1.33% 1.33% fumarate

[0079] The dissolution profiles of batches containing different diluents and superdisintegrants at pH 1.0 are reported in FIGS. 2 and 3.

[0080] The tablets prepared using mannitol as diluent according to the present invention (FIG. 2), showed the quicker dissolution with respect to those prepared using calcium phosphate (FIG. 3). The mannitol-based tablets dissolve rapidly in the stomach and have a prompt bioavailability.

Example 3

[0081] A formulation according to the present invention as described in the Table 3 was prepared and tested. The tablets according to the invention were prepared as reported above, using a direct compression and a final film coating.

TABLE-US-00003 TABLE 3 Ingredients 07814 F mg 07814 F % KLS 40.00 25.64% Mannitol 93.00 59.62% Crospovidone 15.00 9.62% Sodium stearyl fumarate 2.00 1.28% Opadry II 85F205092 Blue 6.00 3.85% TOT 156.00 100%

[0082] Results shown in FIG. 4 indicate that the presence of a dye does not influence the dissolution rate of the tablets.

Example 4

[0083] A composition containing also colloidal silica and sodium laurylsulfate according to the present invention as described in the Table 4 was prepared and tested.

TABLE-US-00004 TABLE 4 Ingredients 08114 F KLS 26.67% Mannitol 60.00% Crospovidone 10.00% SLS 1.00% Silica, Colloidal anhydrous 1.00% Sodium stearyl fumarate 1.33%

[0084] The results shown in FIG. 5 indicate that the composition reported in Table 4, pressed at 7 KN, improves the dissolution profile of the API in the tablet at pH 1.0.

Example 5

[0085] A composition containing a fine particles-grade of sodium laurylsulfate (e.g. Kolliphor SLS fine) according to the present invention as described in the Table 5 was prepared and tested.

TABLE-US-00005 TABLE 5 09314 F Ingredients Amount (mg) Formula % KLS 40 25.64 Pearlitol 100SD 89 57.05 (Mannitol DC) Kollidon CL 15 9.62 (Crospovidone) Kolliphor SLS fine 1.5 0.96 (Sodium Laurylsulfate) Aerosil 200 1.5 0.96 (Silica, Colloidal anhydrous) PRUV 3 1.92 (Sodium stearyl fumarate) Opadry II 85F205092 Blue 6 3.85 Tot 156 100

[0086] Different compression forces (7 KN and 10 KN) were used for the production of the tablets, using the same bulk. Dissolution profiles, shown in FIG. 6, demonstrate that both compression forces give good dissolution performances of the tablets.

Example 6

[0087] A formulation according to the present invention as described in the Table 5 was prepared and tested.

[0088] The dissolution profiles were evaluated at three different pH (pH 1.0, 4.5 and 6.8). The dissolution parameters are setting on the basis of the requirement reported in the guideline CPMP/EWP/QWP/1401/98 Rev.1. The results are reported in Tables 6-8.

TABLE-US-00006 TABLE 6 Dissolution Rate Test (DRT) - Dissolution medium pH 1.0 Coefficient of Time (minutes) % KLS dissolved variation (CV %) 0 0.00 0 5 91.33 2 10 99.19 1 15 100.00 1 30 100.21 2 45 100.02 2 60 99.36 2

TABLE-US-00007 TABLE 7 Dissolution Rate Test (DRT) - Dissolution medium pH 4.5 Time (minutes) % KLS dissolved CV % 0 0.00 0 5 93.17 3 10 97.72 3 15 98.33 2 30 97.59 2 45 96.61 2 60 95.69 1

TABLE-US-00008 TABLE 8 Dissolution Rate Test (DRT) - dissolution medium pH 6.8 Time (minutes) % KLS dissolved CV % 0 0.00 0 5 95.82 3 10 97.47 2 15 101.84 2 30 101.88 2 45 100.86 2 60 99.67 2

[0089] As shown in the above dissolution profiles, the formulation according to the present invention ensures an overall complete release of the API at each pH tested.

Example 7

[0090] Two different ketoprofen lysine salts (micronized and not-micronized) were used and tested in their dissolution behavior,

[0091] The KLS used were the not-micronized (batch 30003605), wherein its particle size distribution is shown in FIG. 7 and the micronized (batch AA00707), wherein its particle size distribution is shown in FIG. 8.

[0092] The formulations produced with the aforementioned KLSs are reported in Table 9.

TABLE-US-00009 TABLE 9 05214 F 06714 F Mannitol 62.00% 60.00% (Pearlitol 100) KLS - batch 26.67% 30003605 KSI - batch 33.67% AA00707 Crospovidone 10.00% 5.00% Sodium stearyl 1.33% 1.33% fumarate

[0093] Dissolution profiles shown in FIG. 9 indicate that the use of a micronized KLS does not improve the dissolution rate of the tablets. Moreover, micronized KLS would result in a worse industrialization of the product, since it tends to stick to walls and gives poor flow properties to the bulk to be pressed.

[0094] Therefore, a particle size distribution according to the present invention allows to obtain immediate-release tablets dissolving rapidly in the stomach and having a prompt bioavailability.