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Claims for Patent: 8,361,500

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Claims for Patent: 8,361,500

Title:Tablet formulations containing 8-[{1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaz- a-spiro[4.5]decan-2-one salts and tablets made therefrom
Abstract: Pharmaceutical formulations containing a salt of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I, which are suitable for forming into a tablet dosage form, as well as tablet dosage forms are disclosed. Disclosed also are methods of treatment utilizing such dosage forms.
Inventor(s): Qiu; Zhihui (Bridgewater, NJ), Cho; Wing-Kee Philip (Princeton, NJ), Zhao; Na (Belle Mead, NJ), Wong; Victor Ming-she (Berkeley Heights, NJ)
Assignee: Opko Health, Inc. (Miami, FL)
Application Number:12/531,966
Patent Claims: 1. A powdered pharmaceutical formulation comprising: (a) a granulate comprising: at least one crystalline salt of (5S,8S)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4.5]decan-2-one; intragranular microcrystalline cellulose, optionally wherein the microcrystalline cellulose has a mean average particle diameter of less than about 70 microns; lactose monohydrate; a first disintegrant; and a binder; and dry-blended therewith (b) extragranular microcrystalline cellulose, optionally wherein the microcrystalline cellulose has a mean average particle diameter of greater than about 70 microns; a second disintegrant; and magnesium stearate, wherein optionally the wt. ratio of first disintegrant to second disintegrant is about 1:1.5 and wherein the formulation provides, upon compression in a tablet press, a pressed tablet having a hardness of at least 10 kp.

2. The formulation of claim 1 wherein said first and said second disintegrant are croscarmellose sodium and said binder is selected from povidone K30, pregelatinized starch and hypromellose 2910, 6 cps, wherein: (a) when the binder used to form the granulate is starch it is used in an amount the that provides the formulation with from about 10 wt. % to about 20 wt. % starch; (b) when the binder used to form the granulate is povidone K30 it is used in an amount that provides the formulation with from about 3 wt. % to about 10 wt. % of povidone K30; and (c) when the binder used to form the granulate is hypromellose 2910, 6 cps, it is used in an amount that provides the formulation with from about 3 wt. % to about 6 wt. % of hypromellose 2910, 6 cps.

3. The formulation of claim 1, wherein the intragranular microcrystalline cellulose is used in an amount comprising from about 8 wt. % to about 20 wt. % of the formulation and wherein optionally the extragranular microcrystalline cellulose is used in an amount comprising from about 19 wt. % to about 40 wt. % of the formulation.

4. The formulation of claim 1, wherein said granulate is prepared by a process comprising: (a) dry blending: (i) a crystalline form 1 hydrochloride monohydrate salt of (5S,8S)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4.5]decan-2-one (API); (ii) intragranular microcrystalline cellulose having a mean particle size of less than about 70 microns; (iii) lactose monohydrate; and (iv) intragranular croscarmellose sodium to provide a first dry-blended powder; (b) agglomerating the first dry-blended powder prepared in Step "a" in a high shear granulator using a granulating fluid comprising water and povidone K-30, optionally wherein the amount of povidone K-30 employed is about 12.5 wt. % of the amount of API employed; (c) forming a granulate by wet milling the agglomerate prepared in Step "b" optionally carrying out the wet-milling process until a granulate having an average particle size of 2 mm is produced; (d) drying the wet milled granulate from step "c", and optionally carrying out the drying process until the dried granulate has a moisture content of less than about 3.0 wt. %; and (e) dry-milling the dried granulate from Step "d" to provide a granulate having an average particle size of 250 microns; wherein the first dry-blended powder contains intragranular croscarmellose sodium in an amount that is about 5.0 wt % of the amount of API contained in the first dry-blended powder and optionally wherein the intragranular microcrystalline cellulose present in said first dry-blended powder in an amount that is about 25 wt % of the amount of API present in the first dry-blended and optionally wherein the amount of lactose monohydrate present in said first dry-blended powder is from about 51 wt. % to about 52 wt. % of the amount of API present in said first dry-blended powder.

5. The formulation of claim 4 wherein the dried granulate in Step "d" has a bulk density of from about 0.54 g/ml to about 0.57 g/ml and a tapped density of from about 0.67 g/ml to about 0.7 g/ml.

6. The formulation of claim 1 wherein the first disintegrant and the second disintegrant comprise croscarmellose sodium and the total amount of croscarmellose sodium used in the formulation is from about 2 wt. % to about 8 wt. %, and the wt, ratio of the amount of first disintegrant to second disintegrant used is from about 1:1 to about 1:1.5.

7. The formulation of claim 1, wherein the intragranular microcrystalline cellulose is used in an amount comprising from about 8 wt. % to about 20 wt. % of the product formulation.

8. The formulation of claim 1 wherein the intragranular microcrystalline cellulose is present in said first dry-blended powder in an amount that is about 25 wt. % of the amount of API present in the first dry-blended powder.

9. A powdered pharmaceutical formulation comprising: (a) a granulate comprising: at least one crystalline salt of (5S,8S)-8-[{(1R)-1-(3,5-bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-ph- enyl-1,7-diazaspiro[4.5]decan-2-one; intragranular microcrystalline cellulose, optionally wherein the microcrystalline cellulose has a mean average particle diameter of less than about 70 microns; lactose monohydrate; a first disintegrant; and a binder; and dry-blended therewith (b) extragranular microcrystalline cellulose, optionally wherein the microcrystalline cellulose has a mean average particle diameter of greater than about 70 microns; a second disintegrant; and magnesium stearate, wherein optionally the wt. ratio of first disintegrant to second disintegrant is about 1:1.5 and wherein the formulation provides, upon compression in a tablet press, can provide tablets with a hardness of about 10 kp.
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