ORODISPERSIBLE TABLET

Abstract

The present invention is directed to a composition in the form of an orodispersible tablet comprising a non-steroidal anti-inflammatory drug (NSAID) and a taste-masking agent wherein the NSAID is uncoated and has an average particle size of less than 100 μm. The present invention is further directed to the use of malic acid as a taste-masking agent.

Claims

1. A composition in the form of an orodispersible tablet comprising a non-steroidal anti-inflammatory drug (NSAID) and a taste-masking agent wherein the NSAID is uncoated and has an average particle size of less than 100 μm.

2. The composition as claimed in claim 1, wherein the average particle size of the uncoated NSAID is 40-60 μm.

3. The composition as claimed in claim 2, wherein the average particle size is 50 μm.

4. The composition as claimed in claim 1, wherein the NSAID comprises ibuprofen and its pharmaceutically acceptable salts or hydrates.

5. The composition as claimed in claim 1, wherein the taste-masking agent is selected from the group consisting of ascorbic acid, monosodium citrate, fumaric acid, malic acid, and combinations thereof.

6. The composition as claimed in claim 5, wherein the taste-masking agent is malic acid.

7. The composition as claimed in claim 5, wherein the amount of taste-masking agent is 0.1-15% by weight of the composition.

8. The composition as claimed in claim 7, wherein the amount of malic acid is 5-10% by weight.

9. The composition as claimed in claim 7, wherein the amount of malic acid is 7-9% by weight.

10. The composition as claimed in claim 1, wherein the ratio by weight of the non-steroidal anti-inflammatory drug (NSAID) and the taste-masking agent in the composition can be from 1:1-8:1.

11. The composition as claimed in claim 10, wherein the ratio of the NSAID and the tastemasking agent is 3:1-5:1.

12. The composition as claimed in claim 11, wherein the ratio of the NSAID and the tastemasking agent is 4:1 by weight.

13. The composition as claimed in claim 1, wherein the composition comprises a blend of a cellulosic binder, a sugar alcohol filler and a disintegrant.

14. The composition as claimed in claim 13, wherein the cellulosic binder is microcrystalline cellulose, the sugar alcohol is mannitol and the disintegrant is cross-linked polyvinylpyrrolidone (crospovidone).

15. The composition as claimed in claim 13, wherein the composition contains 2-4 parts by weight of cellulosic binder per part by weight of disintegrant, and 8-12 parts by weight of sugar alcohol binder per part by weight of disintegrant.

16. The composition as claimed in claim 15, wherein the composition contains cellulosic binder, sugar alcohol filler and disintegrant in a weight ratio of about of 3:11-12:1.

17. The composition as claimed in claim 1, wherein the composition has a friability of up to 2% w/w and a hardness of between 40N and 100N.

18. The composition as claimed in claim 17, wherein the composition has a friability of less than 1% w/w and a hardness of greater than 50N.

19. The composition as claimed in claim 17, wherein the composition has a friability of less than 0.5% w/w and a hardness of greater than 80N.

20. The composition as claimed in claim 1, wherein the composition comprises: an uncoated non-steroidal anti-inflammatory drug (NSAID); a taste-masking agent; and a disintegrant, wherein the uncoated NSAID has an average particle size of less than 100 μm, the taste-masking agent is malic acid which is present in an amount of 0.1-15% by weight of the composition, and the disintegrant is cross-linked polyvinylpyrrolidone (crospovidone) which is present in an amount of 1-10% by weight of the composition.

21. The composition as claimed in claim 1, wherein the composition comprises: an uncoated non-steroidal anti-inflammatory drug (NSAID); a taste-masking agent; and a disintegrant, wherein the uncoated NSAID has an average particle size of less than 100 μm, the taste-masking agent is malic acid which is present in an amount of 0.1-15% by weight of the composition, and wherein the ratio of the uncoated non-steroidal anti-inflammatory drug (NSAID) to taste-masking agent is 4:1 by weight.

22. The composition as claimed in claim 19, wherein the composition further comprises a disintegrant which is cross-linked polyvinylpyrrolidone (crospovidone) and which is present in an amount of 1-10% by weight of the composition.

23. The composition as claimed in claim 1, wherein the composition comprises ibuprofen, a taste-masking agent and a disintegrant wherein the weight ratio of ibuprofen:taste-masking agent:disintegrant is from about 10:5:1 to about 5:1:1.

24. The composition as claimed in claim 23 wherein the weight ratio of ibuprofen:taste-masking agent:disintegrant is from about 8:2:1 to about 7:1:1.

25. The composition as claimed in claim 1, wherein the composition comprises: uncoated ibuprofen; a taste-masking agent; and a disintegrant, wherein the uncoated ibuprofen has an average particle size of 50 μm, the taste-masking agent is malic acid which is present in an amount of 7-9% by weight of the composition, wherein the ratio of the uncoated ibuprofen to taste-masking agent is 4:1 by weight and the disintegrant is cross-linked polyvinylpyrrolidone (crospovidone) which is present in an amount of 3-6% by weight of the composition, and wherein the weight ratio of ibuprofen:taste-masking agent:disintegrant is from about 8:2:1 to about 7:1:1.

26. The composition as claimed in claim 1, wherein the composition comprises: an uncoated non-steroidal anti-inflammatory drug (NSAID); a taste-masking agent; a binder; a disintegrant; and a filler, wherein the uncoated NSAID has an average particle size of less than 100 μm, the taste-masking agent is present in an amount of 0.1-15% by weight of the composition, wherein the ratio of the NSAID to taste-masking agent is 4:1 by weight, and wherein the composition contains 2-4 parts by weight of binder per part by weight of disintegrant, and 8-12 parts by weight of filler per part by weight of disintegrant.

27. The composition as claimed in claim 26, wherein the composition is in the form of an orodispersible tablet comprising: uncoated ibuprofen, a taste-masking agent, a cellulosic binder, a disintegrant and a sugar alcohol filler, wherein the ibuprofen has an average particle size of 50 μm, the taste-masking agent is malic acid and is present in an amount of 0.1-15% by weight of the composition, wherein the ratio of the uncoated ibuprofen to taste-masking agent is 4:1 by weight, the cellulosic binder is microcrystalline cellulose and is present in an amount of 2-25% by weight of the composition, the disintegrant is cross-linked polyvinylpyrrolidone (crospovidone) and is present in an amount of 1-10% by weight of the composition, the filler is mannitol and is present in an amount of 20-70% by weight of the composition, wherein the composition contains 2-4 parts by weight of cellulosic binder per part by weight of disintegrant, and 8-12 parts by weight of sugar alcohol filler per part by weight of disintegrant, and wherein the weight ratio of ibuprofen:malic acid:cross-linked polyvinylpyrrolidone is from about 10:5:1 to about 5:1:1.

28. The composition as claimed in claim 1, wherein the composition comprises: 20-35% of an uncoated NSAID having an average particle size of less than 100 μm or a pharmaceutically acceptable salt thereof; 20-70% of a filler; 0.5-5% of a lubricant; 5-10% of a taste-masking agent; and 1-10% of a disintegrant.

29. The composition as claimed in claim 28 wherein the composition comprises: 25-30% of an uncoated NSAID having an average particle size of less than 100 μm or a pharmaceutically acceptable salt thereof; 40-50% of a filler; 0.5-5% of a lubricant; 5-10% of a taste-masking agent; and 1-10% of a disintegrant.

30. The composition as claimed in claim 28, wherein the composition further comprises one or more additional excipients selected from: 0.1-5% of a glidant; and 2-25% of a binder.

31. The composition as claimed in claim 28, wherein the composition further comprises: 28-30% of an uncoated NSAID having an average particle size of less than 100 μm or a pharmaceutically acceptable salt thereof; 0.5-1.5% of a glidant; 42-47% of a filler; 0.75-1.5% of a lubricant; 8-12% of a binder; 6-8% of a taste-masking agent; and 3-5% of a disintegrant.

32. The composition as claimed in claim 28, wherein the composition comprises: 25-30% of uncoated ibuprofen having an average particle size of less than 100 μm or a pharmaceutically acceptable salt thereof; 0.1-5% of colloidal silica; 40-50% of mannitol; 0.5-5% of sodium stearyl fumarate; 5-15% of microcrystalline cellulose; 5-10% of malic acid; and 1-10% of crospovidone.

33. The composition as claimed in claim 28, wherein the composition comprises: 28-30% of uncoated ibuprofen having an average particle size of less than 100 μm or a pharmaceutically acceptable salt thereof; 0.5-1.5% of colloidal silica; 42-47% of mannitol; 0.75-1.5% of sodium stearyl fumarate; 8-12% of microcrystalline cellulose; 6-8% of malic acid; and 3-5% of crospovidone.

34. The composition as claimed in claim 28, wherein the average particle size of the uncoated ibuprofen is from 40-60 μm.

35. A method of using malic acid as a taste-masking agent in a composition in the form of an orodispersible tablet that comprises an uncoated ibuprofen particle having an average particle size of 40-60 μm.

36. The method of use as claimed in claim 35, wherein the average particle size of the uncoated ibuprofen is 50 μm.

37. The method of use as claimed in claim 35, wherein the ratio by weight of the uncoated ibuprofen particle and the malic acid in the composition is from 1:1-8:1.

38. The method of use as claimed in claim 37, wherein the ratio by weight of the uncoated ibuprofen particle and the malic acid in the composition is from 3:1-5:1.

39. The method of use as claimed in claim 38, wherein the ratio by weight of the uncoated ibuprofen particle and the malic acid in the composition is from 4:1.

40. A method of using malic acid as a taste-masking agent in a composition in the form of an orodispersible tablet that comprises an uncoated ibuprofen particle having an average particle size of 50 μm wherein the ratio by weight of the uncoated ibuprofen particle and the malic acid is 4:1.

Description

[0262] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying FIGURES in which:

[0263] FIG. 1 illustrates dissolution data for compositions of both the present invention and the prior art.

EXAMPLES

[0264]

TABLE-US-00001 Component Example 1 (wt %) Example 2 (wt %) Ibuprofen 28.57 28.57 Colloidal Silica 1.00 1.00 Mannitol 45.63 44.18 Microcrystalline cellulose 10.00 10.00 Crospovidone 4.00 4.00 Malic Acid 7.14 7.14 Sodium stearyl fumarate 1.25 1.25 Sucralose 0.86 0.86 Flavour 1.55 3.00 TOTAL 100.00 100.00

[0265] The orodispersible tablet may be prepared by a process involving dry blending or wet or dry granulation. However, it is preferred to use a manufacturing method which involves direct compression into an orodispersible tablet without an intermediate, e.g. a wet or dry granulation stage.

[0266] The composition may be made by dry mixing the active ingredient with one or more of the other ingredients, e.g. the lubricant and diluents and disintegrant, e.g. in a powder blending machine. The active agent can be blended with the silica. The remaining ingredients can be blended together separately. The two mixtures can be then be blended together. It is particularly preferred that the active ingredients are dispersed by progressive dilution with agitation in a proportion, e.g. about one-half, of the excipients so as to achieve even distribution of the active ingredient in the excipients, and then to add the remainder of the excipients with further agitation and mixing. The mixture may then be compressed in a tablet forming machine.

[0267] The taste and mouthfeel characteristics of the compositions were assessed. Participants in the assessment of the compositions of the present invention were provided with 2 tablets—the first was an orodispersible tablet in accordance with the present invention and the second was a sample of a commercially available orodispersible tablet.

[0268] The participants sampled each orodispersible tablet and recorded their observations for each characteristic by giving a rating out of 10. The participants were given water to cleanse their mouth between sampling each orodispersible tablet.

[0269] The table below illustrates the assessment average of 10 participants who compared the orodispersible tablets.

TABLE-US-00002 Example of present Comparative Characteristic invention (Ave) Example (Ave) Acceptability of mouth sensation 7.5 6.7 Acceptability of texture 6.8 5.6 Acceptability of flavour 7.7 6.7 Acceptability of duration in mouth 6.9 6.2 Overall Rating 7.2 6.6

[0270] As can be seen the composition of the present invention was given a significantly higher rating than the comparative example by the panellists.

[0271] FIG. 1 illustrates the dissolution profile for a composition of the present invention and an orodispersible tablet that is currently available. As can be seen, the dissolution of the ibuprofen in the orodispersible tablets of the present invention is significantly faster than that of a comparable existing tablet.

[0272] The dissolution of the ibuprofen was measured using a pH change dissolution method. The pH change method uses standard Ph Eur paddle apparatus and UV detection. This method is designed to more accurately reflect the change in pH that occurs between the stomach and the intestine and provide a more bio-relevant comparison for products. A composition of the present invention and a current commercially available orodispersible tablet are subjected to 9.5 minutes dissolution in 500 ml of pH 1.2 (using 0.1M HCL) and then to this is added 400 ml of a concentrated buffer solution. The dissolution is continued until the defined endpoint (this final solution has a pH of between 6-8). The amount of ibuprofen dissolved is measured via UV absorbance every 5 minutes up to 90 minutes.

[0273] Hardness and friability were measured using the relevant European Pharmacopoeial methods as outlined in sections 2.9.8 and 2.9.7 respectively.

[0274] An advantage of the present invention is that there is provided an orodispersible tablet that comprises an uncoated ibuprofen particle and has a good organoleptic profile with effective taste-masking, disintegrates in the mouth in less than one minute. As can be seen from FIG. 1, the use of an uncoated ibuprofen particle results in a significantly better dissolution profile than the dissolution profile of a product that comprises a coated ibuprofen.

[0275] The present invention is not intended to be limited to the exemplary embodiments described herein. Further modifications can be made without departing from the scope of the invention described herein.