Solid dosage form of coated bisphosphonate particles

Abstract

A solid dosage form comprises coated particles of bisphosphonate or a pharmaceutically acceptable analog or derivative thereof.

Claims

1. A solid oral dosage form obtained by a method comprising: (i) combining particles of bisphosphonate with a coating solution or suspension consisting essentially of a coating and a solvent, wherein the coating contains a pharmaceutically acceptable, water soluble sugar and the amount of coating is from 10% to 70% by weight of the uncoated particles; (ii) drying the solution or suspension to form coated particles of bisphosphonate; (iii) mixing the coated particles of (ii) with excipients; and (iv) forming the coated particles and excipients into a solid dosage form, wherein the solid dosage form is formulated as a tablet and the tablet is not coated and consists essentially of: colloidal silicon dioxide; sodium stearyl fumarate; 20% to 40% by weight coated particles of bisphosphonate; and 30% to 80% by weight of one or more disintegrants selected from the group consisting of croscarmellose cellulose, crospovidone, microcrystalline cellulose, croscarmellose sodium, and sodium starch glycolate.

2. The solid oral dosage form of claim 1, wherein the bisphosphonate is selected from the group consisting of risedronate, ibandronate, pamidronate, clodronate, zoledronate, etidronate, tiludronate, and alendronate.

3. The solid oral dosage form of claim 1, wherein the pharmaceutically acceptable water soluble sugar is selected from the group consisting of sorbitol, mannitol, xylitol, and maltitol.

4. The solid oral dosage form of claim 1, wherein the amount of coating is from 20% to 50% by weight of the uncoated particles.

5. The solid oral dosage form of claim 1, wherein the tablet of step (iv) has a weight that does not exceed 200 mg.

6. The solid oral dosage form of claim 1, wherein the tablet of step (iv) has a weight that does not exceed 240 mg.

7. The solid oral dosage form of claim 1, wherein the tablet of step (iv) has a weight that does not exceed 320 mg.

8. The solid oral dosage form of claim 1, wherein the tablet of step (iv) has a weight that does not exceed 640 mg.

9. A solid oral dosage form obtained by a method comprising: (i) combining particles of bisphosphonate with a coating solution or suspension consisting essentially of a coating and a solvent, wherein the coating contains a pharmaceutically acceptable, water soluble sugar and the amount of coating is from 10% to 70% by weight of the uncoated particles; (ii) drying the solution or suspension to form coated particles of bisphosphonate; (iii) mixing the coated particles of (ii) with excipients; and (iv) forming the coated particles and excipients into a solid dosage form, wherein the solid dosage form is formulated as a tablet and the tablet is not coated and consists of: colloidal silicon dioxide; sodium stearyl fumarate; 20% to 40% by weight coated particles of bisphosphonate; and 30% to 80% by weight of one or more disintegrants selected from the group consisting of croscarmellose cellulose, crospovidone, microcrystalline cellulose, croscarmellose sodium, and sodium starch glycolate.

10. The solid oral dosage form of claim 9, wherein the bisphosphonate is selected from the group consisting of risedronate, ibandronate, pamidronate, clodronate, zoledronate, etidronate, tiludronate, and alendronate.

11. The solid oral dosage form of claim 9, wherein the pharmaceutically acceptable water soluble sugar is selected from the group consisting of sorbitol, mannitol, xylitol, and maltitol.

12. The solid oral dosage form of claim 9, wherein the amount of coating is from 20% to 50% by weight of the uncoated particles.

13. The solid oral dosage form of claim 9, wherein the tablet of step (iv) has a weight that does not exceed 200 mg.

14. The solid oral dosage form of claim 9 wherein the tablet of step (iv) has a weight that does not exceed 240 mg.

15. The solid oral dosage form of claim 9 wherein the tablet of step (iv) has a weight that does not exceed 320 mg.

16. The solid oral dosage form of claim 9 wherein the tablet of step (iv) has a weight that does not exceed 640 mg.

Description

EXAMPLE 1

(1) A tablet containing ibandronate coated with sorbitol was formulated as follows:

(2) 38 g sorbitol was dissolved in an ethanol/water mix containing 31 ml absolute ethanol and 20 ml purified water. The solution was mixed thoroughly until the sorbitol was in solution, the solution being heated to around 37 C. to aid dissolution of the sorbitol. The solution was added to 253.1 g ibandronate sodium monohydrate and the mixture granulated in a high shear granulator in a 1 l bowl. The granulate was then dried at around 35 C. in a fluid bed dryer for between 60 and 90 minutes. The dried granulate was sieved through a number 30 mesh screen.

(3) A further 38 g sorbitol was dissolved in an ethanol/water mix containing 31 ml absolute ethanol and 20 ml purified water. The solution was mixed thoroughly until the sorbitol was in solution. (If necessary, the solution was heated to around 37 C. to aid dissolution of the sorbitol.) The solution was then added to the dried and sieved granulate, the mixture was granulated in a high shear granulator and the granulate dried at around 35 C. in a fluid bed dryer for between 60 and 90 minutes. The dried granulate was then sieved through a number 30 mesh screen.

(4) 462.9 g microcrystalline cellulose, 8.1 g colloidal silicon dioxide and 25.5 g croscarmellose sodium were pre-screened through a number 20 mesh screen, added to the dried and sieved granulate and then blended in a 5 l V-Tumble Blender for 20 minutes. 16.2 g sodium stearyl fumarate was pre-screened through a number 40 mesh screen, added to the blended mixture, and the mixture blended for a further 10 minutes.

(5) The blended mixture was then compressed into tablets with a target weight of 200 mg on a Korsch XL100 Tablet Press.

(6) Thus, tablets having the following composition were obtained: lbandronate sodium monohydrate: 56.25 mg Sorbitol: 16.9 mg Microcrystalline cellulose: 114.55 mg Colloidal silicon dioxide: 2.0 mg Croscarmellose sodium: 6.3 mg Sodium stearyl fumarate: 4.0 mg

EXAMPLE 2

(7) A tablet containing ibandronate coated with colloidal silicon dioxide was formulated as follows:

(8) 2.3 g povidone was dissolved in 100 ml absolute ethanol and mixed thoroughly. 253.1 g ibandronate sodium monohydrate and 50.6 g colloidal silicon dioxide were mixed together for 5 minutes in a high shear mixer and then the povidone/ethanol mix was added and granulated in a high shear granulator in a 3 l bowl.

(9) Alternatively, the colloidal silicon dioxide was added to the povidone/ethanol mix to form a slurry which was then deposited or granulated onto the ibandronate sodium monohydrate.

(10) The granulate was then dried at around 35 C. in a fluid bed dryer for between 60 and 90 minutes. The dried granulate was sieved through a number 30 mesh screen.

(11) 462.4 g microcrystalline cellulose, 7.5 g colloidal silicon dioxide and 25.7 g croscarmellose sodium were pre-screened through a number 14 mesh screen, added to the dried and sieved granulate and then blended in a 5 l V-Tumble Blender for 20 minutes. 15.5 g sodium stearyl fumarate was pre-screened through a number 40 mesh screen, added to the blended mixture, and the mixture blended for a further 10 minutes.

(12) The blended mixture was then compressed into tablets with a target weight of 200 mg on a Korsch XL100 Tablet Press.

(13) Thus, tablets having the following composition were obtained: Ibandronate sodium monohydrate: 56.25 mg Colloidal silicon dioxide (coating): 11.25 mg Povidone: 0.50 mg Microcrystalline cellulose: 119.35 mg Colloidal silicon dioxide (extra-granular excipient): 2.0 mg Croscarmellose sodium: 6.65 mg Sodium stearyl fumarate: 4.0 mg

EXAMPLE 3

(14) A tablet containing risedronate coated with sorbitol was formulated as follows:

(15) 44.8 g sorbitol was dissolved in an ethanol/water mix containing 39 ml absolute ethanol and 26 ml purified water. The solution was mixed thoroughly until the sorbitol was in solution, the solution being heated to around 37 C. to aid dissolution of the sorbitol. The solution was added to 298.2 g risedronate sodium and the mixture granulated in a high shear granulator in a 1 l bowl. The granulate was then dried at around 35 C. in a fluid bed dryer for around 60 minutes. The dried granulate was sieved through a number 30 mesh screen.

(16) A further 44.8 g sorbitol was dissolved in an ethanol/water mix containing 39 ml absolute ethanol and 26 ml purified water. The solution was mixed thoroughly until the sorbitol was in solution. (If necessary, the solution was heated to around 37 C. to aid dissolution of the sorbitol.) The solution was then added to the dried and sieved granulate, the mixture was granulated in a high shear granulator and the granulate dried at around 35 C. in a fluid bed dryer for about 60 minutes. The dried granulate was then sieved through a number 30 mesh screen.

(17) 868.6 g microcrystalline cellulose, 9.9 g colloidal silicon dioxide and 31.1 g croscarmellose sodium were pre-screened through a number 14 mesh screen, added to the dried and sieved granulate and then blended in a 5 l V-Tumble Blender for 20 minutes. 19.7 g sodium stearyl fumarate was pre-screened through a number 40 mesh screen, added to the blended mixture, and the mixture blended for a further 10 minutes.

(18) The blended mixture was then compressed into tablets with a target weight of 240 mg on a Korsch XL100 Tablet Press.

(19) Thus, tablets having the following composition were obtained: Risedronate sodium: 39.76 mg Sorbitol: 11.94 mg Microcrystalline cellulose: 176.0 mg Colloidal silicon dioxide: 2.0 mg Croscarmellose sodium: 6.3 mg Sodium stearyl fumarate: 4.0 mg

EXAMPLE 4

(20) A tablet containing risedronate coated with colloidal silicon dioxide was formulated as follows:

(21) 3.75 g povidone was dissolved in 100 ml absolute ethanol and mixed thoroughly. 298.2 g risedronate sodium and 59.63 g colloidal silicon dioxide were mixed together for 5 minutes in a high shear mixer and then the povidone/ethanol mix was added and granulated in a high shear granulator in a 3 l bowl.

(22) Alternatively, the colloidal silicon dioxide was added to the povidone/ethanol mix to form a slurry which was then deposited or granulated onto the risedronate sodium.

(23) The granulate was then dried at around 35 C. in a fluid bed dryer for about 60 minutes. The dried granulate was sieved through a number 30 mesh screen.

(24) 1032.5 g microcrystalline cellulose, 11.5 g colloidal silicon dioxide and 36.3 g croscarmellose sodium were pre-screened through a number 14 mesh screen, added to the dried and sieved granulate and then blended in a 10 l V-Tumble Blender for 20 minutes. 23.0 g sodium stearyl fumarate was pre-screened through a number 40 mesh screen, added to the blended mixture, and the mixture blended for a further 10 minutes.

(25) The blended mixture was then compresed into tablets with a target weight of 240 mg on a Korsch XL100 Tablet Press.

(26) Thus, tablets having the following composition were obtained: Risedronate sodium: 39.76 mg Colloidal silicon dioxide (coating): 7.95 mg Povidone: 0.50 mg Microcrystalline cellulose: 179.49 mg Colloidal silicon dioxide (extra-granular excipient): 2.0 mg Croscarmellose sodium: 6.3 mg Sodium stearyl fumarate: 4.0 mg

EXAMPLE 5

(27) A tablet containing risedronate coated with polyethylene glycol was formulated by dissolving polyethylene glycol in ethanol and then spray granulating the mixture onto risedronate sodium. The coated risedronate sodium was then dried and sieved to form a granulate.

(28) Microcrystalline cellulose, colloidal silicon dioxide and croscarmellose sodium were pre-screened through a number 14 mesh screen, added to the dried and sieved granulate and then blended in a 10 l V-Tumble Blender for 20 minutes. Sodium stearyl fumarate was pre-screened through a number 40 mesh screen, added to the blended mixture, and the mixture blended for a further 10 minutes.

(29) The blended mixture was then compressed into tablets on a Korsch XL100 Tablet Press.

EXAMPLES 6-9

(30) Further tablets were made in accordance with the invention using the active risedronate which was coated with sorbitol then incorporated into a tablet.

(31) TABLE-US-00001 Example 6 7 8 9 5 mg 30 mg 35 mg 75 mg Risedronate 5.00 30.00 35.00 75.00 Sodium (Theoretical) Sorbitol 9.60 9.60 9.60 19.20 Crystalline Microcrystalline 50.00 25.00 20.00 35.00 Cellulose 102 Water q.s. q.s. q.s. q.s. Microcrystalline 126.00 151.00 156.00 317.00 Cellulose 102 Sorbitol 113.40 88.40 83.40 161.80 Crystalline Colloidial 3.20 3.20 3.20 6.40 Silicon Dioxide Croscarmellose 6.40 6.40 6.40 12.80 Sodium Sodium Stearyl 6.40 6.40 6.40 12.80 Fumarate Total Tablet 320.00 320.00 320.00 640.00 Weight, mg: Notes Measured as mg of active 3% Sorbitol in solution to coat MCC to the same granulation weight. Total MCC = 176.0 mg/ tab (or 55%) Total Sorbitol = 128 - (active) mg/tab 1% SiO2 2% Croscarmellose Na 2% SSF Active and sorbitol only adjustments <10%

(32) These examples included a carrier excipient, microcrystalline cellulose, already present as filler and disintegrant, found to improve milling of material after coating.

(33) Although the examples describe how to formulate a tablet according to the present invention, it will be understood that a person skilled in the art will be able to formulate a capsule according to the present invention by, for example, encapsulating the blended mixture into capsules instead of compressing the blended mixture into tablets.

(34) The present invention thus provides a solid dosage form of a bisphosphonate.