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Claims for Patent: 7,695,734

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Claims for Patent: 7,695,734

Title:Extended release tablet formulation containing pramipexole or a pharmaceutically acceptable salt thereof
Abstract:An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least one water swelling polymer other than pregelatinized starch.
Inventor(s): Friedl; Thomas (Ochsenhausen, DE), Eisenreich; Wolfram (Ulm, DE)
Assignee: Boehringer Ingelheim International GmbH (Ingelheim am Rhein, DE)
Application Number:11/202,713
Patent Claims: 1. An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water swelling hydrophilic polymers other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer and the other is a substantially neutral polymer, and wherein the formulation does not contain pregelatinized starch, the resulting tablet formulation providing a pH-dependent release rate in the range of pH<4.5, and a pH-independent release rate in the range from pH 4.5 to 7.5, wherein the release rate in the range of pH<4.5 is higher than the release rate in the range from pH 4.5 to 7.5, when the formulation is tested in the following pH media: simulated gastric juice at pH 1.2, McIlvaine buffer at pH 4.5 and phosphate buffer at pH 6.8, wherein the content of the anionic polymer is from about 0.5 wt.-% to about 15 wt.-% and the content of the substantially neutral polymer is from about 25 wt.-% to about 65 wt.-%.

2. The extended release tablet formulation according to claim 1, wherein the anionic polymer is selected from the group consisting of optionally crosslinked acrylic acid polymers, and carboxymethyl cellulose.

3. The extended release tablet formulation according to claim 2, wherein the anionic polymer is an optionally crosslinked acrylic acid polymer.

4. The extended release tablet formulation according to claim 3, wherein the anionic polymer is an optionally crosslinked acrylic acid polymer, and wherein the content of the optionally crosslinked acrylic acid polymer in the matrix is from about 1 wt.-% to about 10 wt.-%.

5. The extended release tablet formulation according to claim 1, wherein the substantially neutral polymer is hydroxypropyl cellulose or hydroxypropyl methyl cellulose.

6. The extended release tablet formulation according to claim 5, wherein the substantially neutral polymer is hydroxypropyl methyl cellulose.

7. The extended release tablet formulation according to claim 1, wherein the matrix comprises about: (a) 0.05 to 5 wt.-% of pramipexole or a salt thereof (b) 0.5 to 15 wt.-% of anionic water swelling polymer(s); (c) 25 to 65 wt.-% of neutral water swelling polymer(s); and (d) to 100 wt.-% of further excipients.

8. The extended release tablet formulation of claim 1, consisting of pramipexole dihydrochloride monohydrate, hypromellose 2208, corn starch, Carbomer 941, colloidal silicon dioxide, and magnesium stearate.

9. An extended release tablet formulation, according to claim 1, wherein the contained amount of pramipexole or pharmaceutically acceptable salt thereof is sufficient to provide a daily dose administered at one time.

10. A method of manufacturing an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water swelling hydrophilic polymers other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer and the other is a substantially neutral polymer, and wherein the formulation does not contain pregelatinized starch, the resulting tablet formulation providing a pH-dependent release rate in the range of pH<4.5, and a pH-independent release rate in the range from pH 4.5 to 7.5, wherein the release rate in the range of pH<4.5 is higher than the release rate in the range from pH 4.5 to 7.5, when the formulation is tested in the following pH media: simulated gastric juice at pH 1.2, McIlvaine buffer at pH 4.5 and phosphate buffer at pH 6.8, wherein the content of the anionic polymer is from about 0.5 wt.-% to about 15 wt.-% and the content of the substantially neutral polymer is from about 25 wt.-% to about 65 wt.-% by a direct compression process comprising the steps of: (1) producing an active ingredient trituration wherein the active ingredient is pramipexole or a pharmaceutically acceptable salt thereof by preblending it with a portion of water swelling polymer(s) and/or excipient(s) in a mixer, wherein pramipexole or the pharmaceutically acceptable salt thereof is milled prior to use; (2) premixing the active ingredient trituration of step (1), the main portion of the water swelling polymer(s) and/or excipients in a mixer to obtain a pre-mixture; (3) optionally dry screening the pre-mixture through a screen in order to segregate cohesive particles and to improve content uniformity; (4) mixing the pre-mixture of step (2) or (3) in a mixer, optionally by adding remaining excipients to the mixture and continuing mixing; and (5) tabletting the final mixture by compressing it on a suitable tablet press to produce matrix tablets.

11. The method according to claim 10, wherein the pramipexole or the pharmaceutically acceptable salt thereof is peg-milled prior to use in step (1).

12. A method of manufacturing an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water swelling hydrophilic polymers other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer and the other is a substantially neutral polymer, and wherein the formulation does not contain pregelatinized starch, the resulting tablet formulation providing a pH-dependent release rate in the range of pH<4.5, and a pH-independent release rate in the range from pH 4.5 to 7.5, wherein the release rate in the range of pH<4.5 is higher than the release rate in the range from pH 4.5 to 7.5, when the formulation is tested in the following pH media: simulated gastric juice at pH 1.2, McIlvaine buffer at pH 4.5 and phosphate buffer at pH 6.8, wherein the content of the anionic polymer is from about 0.5 wt.-% to about 15 wt.-% and the content of the substantially neutral polymer is from about 25 wt.-% to about 65 wt.-% by a wet granulation process comprising the steps of: (1) producing an active ingredient trituration wherein the active ingredient is pramipexole or a pharmaceutically acceptable salt thereof by blending it with a portion of the excipients in a mixer, wherein pramipexole or the pharmaceutically acceptable salt thereof is milled prior to use; (2) granulating the active ingredient trituration of step (1) by adding the granulation liquid; (3) drying the granules of step (2) in a fluidized bed dryer or a drying oven; (4) mixing the dried granules of step (3) with the water swelling polymer(s) and/or excipients in a mixer to obtain the final mixture; and (5) tabletting the final mixture of step (4) by compressing it on a suitable tablet press to produce matrix tablets.

13. The method according to claim 12, wherein the pramipexole or the pharmaceutically acceptable salt thereof is peg-milled prior to use in step (1).

14. The method according to claim 12, wherein the granulation liquid of step (2) is water.

15. A method of manufacturing an extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising at least two water swelling hydrophilic polymers other than pregelatinized starch, and wherein at least one of the at least two polymers is an anionic polymer and the other is a substantially neutral polymer, and wherein the formulation does not contain pregelatinized starch, the resulting tablet formulation providing a pH-dependent release rate in the range of pH<4.5, and a pH-independent release rate in the range from pH 4.5 to 7.5, wherein the release rate in the range of pH<4.5 is higher than the release rate in the range from pH 4.5 to 7.5, when the formulation is tested in the following pH media: simulated gastric juice at pH 1.2, McIlvaine buffer at pH 4.5 and phosphate buffer at pH 6.8, wherein the content of the anionic polymer is from about 0.5 wt.-% to about 15 wt.-% and the content of the substantially neutral polymer is from about 25 wt.-% to about 65 wt.-% by a dry granulation process comprising the steps of: (1) mixing the active ingredient pramipexole or a pharmaceutically acceptable salt thereof with either a portion of the fillers or all the excipients in a mixer, wherein pramipexole or the pharmaceutically acceptable salt thereof is milled prior to use; (2) compaction of the mixture of step (1) on a suitable roller compactor; (3) reducing the ribbons obtained during step (1) to small granules by suitable milling or sieving steps; (4) optionally mixing the granules of step (3) with the remaining excipients in a mixer to obtain the final mixture; and (5) tabletting the granules of step (3) or the final mixture of step (4) by compressing it on a suitable tablet press to produce matrix tablets.

16. The method according to claim 15, wherein the pramipexole or the pharmaceutically acceptable salt thereof is peg-milled prior to use in step (1).

17. The extended release tablet formulation according to claim 1, wherein the formulation does not have a coating.

18. The extended release tablet formulation according to claim 1, wherein the formulation has a non-functional coating as the only coating.

19. The extended release tablet formulation according to claim 1, consisting of: (a) 0.1 to 2% by weight of pramipexole or a salt thereof; (b) 25 to 65% by weight of hydroxypropyl methyl cellulose; (c) 0 to 40% by weight of carboxymethyl cellulose sodium; (d) 0 to 75% by weight of corn starch; (e) 0.5 to 15% by weight of acrylic polymerisate; and (f) 0.5 to 50% by weight of excipients.

20. The extended release tablet formulation according to claim 1, consisting of: (a) 0.1 to 2% by weight of pramipexole or a salt thereof; (b) 25 to 65% by weight of hydroxypropyl methyl cellulose; (c) 0 to 40% by weight of carboxymethyl cellulose sodium; (d) 0 to 75% by weight of corn starch; (e) 0.5 to 15% by weight of acrylic polymerisate; (f) 0.5 to 50% by weight of excipients; and (g) optionally a non-functional coating as the only coating.

21. The extended release tablet formulation according to claim 19, wherein the acrylic polymerisate is carbomer 941.

22. The extended release tablet formulation according to claim 19, wherein the excipients are selected from one or more of the following: colloidal silicon dioxide, magnesium stearate, lactose monohydrate, mannitol, microcrystalline cellulose, dibasic anhydrous calcium phosphate, hydroxypropyl cellulose, povidone, copovidone, talc, macrogols, sodium dodecylsulfate, iron oxides, and titanium dioxide.

23. The extended release tablet formulation according to claim 19, wherein the acrylic polymerisate is carbomer 941 and the excipients are selected from one or more of the following: colloidal silicon dioxide, magnesium stearate, lactose monohydrate, mannitol, microcrystalline cellulose, dibasic anhydrous calcium phosphate, hydroxypropyl cellulose, povidone, copovidone, talc, macrogols, sodium dodecylsulfate, iron oxides, and titanium dioxide.

24. The extended release tablet formulation according to claim 20, wherein the acrylic polymerisate is carbomer 941.

25. The extended release tablet formulation according to claim 20, wherein the excipients are selected from one or more of the following: colloidal silicon dioxide, magnesium stearate, lactose monohydrate, mannitol, microcrystalline cellulose, dibasic anhydrous calcium phosphate, hydroxypropyl cellulose, povidone, copovidone, talc, macrogols, sodium dodecylsulfate, iron oxides, and titanium dioxide.

26. The extended release tablet formulation according to claim 20, wherein the acrylic polymerisate is carbomer 941 and the excipients are selected from one or more of the following: colloidal silicon dioxide, magnesium stearate, lactose monohydrate, mannitol, microcrystalline cellulose, dibasic anhydrous calcium phosphate, hydroxypropyl cellulose, povidone, copovidone, talc, macrogols, sodium dodecylsulfate, iron oxides, and titanium dioxide.

27. An extended release tablet formulation comprising pramipexole or a pharmaceutically acceptable salt thereof in a matrix comprising: at least one water swelling hydrophilic anionic polymer, at least one water swelling hydrophilic substantially neutral polymer and optionally excipients, the resulting tablet providing a pH-dependent release rate in the range of pH<4.5, and a pH-independent release rate in the range from pH 4.5 to 7.5, wherein the release rate in the range of pH<4.5 is higher than the release rate in the range from pH 4.5 to 7.5, when the formulation is tested in the following pH media: simulated gastric juice at pH 1.2, McIlvaine buffer at pH 4.5 and phosphate buffer at pH 6.8, wherein the content of anionic polymer in the matrix is from about 0.5 to 15 wt.-% and wherein the content of the neutral polymer in the matrix is from about 25 wt.-% to about 65 wt.-%, wherein said tablet either does not have a coating or has a non-functional coating as the only coating and wherein the formulation does not contain pregelatinized starch.

28. The extended release tablet formulation according to claim 6, wherein the content of hydroxypropyl methyl cellulose in the matrix is from about 35 wt.-% to about 55 wt. %.

29. The extended release tablet formulation according to claim 1, wherein the content of pramipexole or a pharmaceutically acceptable salt thereof is from about 0.05 wt.-% to about 5 wt.-%.

30. The extended release tablet formulation according to claim 1, wherein the content of pramipexole or a pharmaceutically acceptable salt thereof is from about 0.1 mg to about 10 mg.

31. The extended release tablet formulation according to claim 1, wherein the content of pramipexole or a pharmaceutically acceptable salt thereof is from about 0.1 mg to about 5 mg.
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