Claims for Patent: 5,688,529

Summary for Patent: 5,688,529

Title:	Mycophenolate mofetil high dose oral suspensions
Abstract:	High dose, dry granulations or powder blends and aqueous oral suspensions of mycophenolate mofetil or mycophenolic acid, contain: active compound (7.5-30%), suspending/viscosity agent, sweetener, flavor, buffer (to a pH of 5-7.5), and optionally contain flavor enhancer, wetting agent, antimicrobial agent and color.
Inventor(s):	Deborah Marilyn Lidgate, Li-hua Wang-Kessler, Bindu Joshi, Sayee Gojanan Hegde, Leo Gu
Assignee:	Hoffmann La Roche Inc , Roche Holdings Inc
Application Number:	US08/412,645
Patent Claims:	1. A pharmaceutical formulation comprising: ______________________________________ Ingredient % wt/vol ______________________________________ mycophenolate mofetil 20 hydroxypropylmethylcellulose 0.25 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol, 70% solution 30-50 maltitol syrup 10-30 sucrose 0-10 fructose 0-10 aspartame 0-0.5 lecithin 0-0.1 citric acid 0.02-0.25 sodium phosphate dibasic 0.19-0.67 methyl paraben 0-0.20 propyl paraben 0-0.02 flavor 0.3-1.0 flavor enhancer/bitter maskant 0-1 color 0.005 purified water q.s. to 100 ______________________________________ as a liquid suspension suitable for oral administration. 2. A pharmaceutical formulation consisting essentially of: ______________________________________ Ingredient % wt/vol ______________________________________ mycophenolate mofetil 20 hydroxypropylmethylcellulose 0.25 microcrystalline cellulose 0.25 xanthan gum 0.1 sorbitol solution 50 sucrose 10 maltitol syrup 10 lecithin 0.1 methyl paraben 0.036 propylparaben 0.004 grape 1.0 anise 0.01 color (red 28: blue 1, 90:10) 0.005 citric acid 0.0542 sodium phosphate dibasic 0.673 purified water q.s. to 100 ______________________________________ adjusted to a pH of 7, as a liquid suspension suitable for oral administration. 3. A pharmaceutical formulation comprising: ______________________________________ Ingredient % wt/vol ______________________________________ mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70% solution 30-50 maltitol syrup 10-30 sucrose 0-10 fructose 0-10 aspartame 0-0.5 lecithin 0-0.5 citric acid 0.02-0.25 sodium phosphate dibasic 0.15-1.0 methyl paraben 0-0.2 propyl paraben 0-0.02 flavor 0.1-3.0 flavor enhancer/bitter maskant 0-1 color 0.02 purified water q.s. to 100 ______________________________________ as a liquid suspension suitable for oral administration. 4. The pharmaceutical formulation of claim 3, consisting essentially of: ______________________________________ Ingredient % wt/vol ______________________________________ mycophenolate mofetil 20 microcrystalline cellulose 0.2 xanthan gum 0.1 sorbitol, 70% solution 50 maltitol syrup 10 sucrose 10 soy lecithin 0.1 citric acid 0.06 sodium phosphate dibasic 0.7 methyl paraben 0.04 flavor ≦0.3 color <0.02 purified water q.s. to 100 ______________________________________ adjusted to a pH of 7, as a liquid suspension suitable for oral administration. 5. A process for the preparation of a pharmaceutical formulation comprising: ______________________________________ Ingredient % wt/vol ______________________________________ mycophenolate mofetil or mycophenolic acid 7.5-30.0 suspending/viscosity agent 0.1-3.0 wetting agent 0-0.5 sweeteners 30.0-70.0 flavor 0.1-2.0 flavor enhancer/bitter maskant 0-1.0 buffering to pH 5.0-7.5 0.15-2.0 antimicrobial agent 0-10.0 color 0-0.03 purified water q.s. to 100 ______________________________________ as a liquid suspension for oral administration, the process comprising: I. a. adding and dispersing the antimicrobial agent to heated water, followed by adding the suspending and/or viscosity agent(s);b. dissolving, with mixing, the buffer(s), followed by adding the sweetener(s), wetting agent(s), dye(s), flavor enhancer(s), and flavor(s); and c. adding the active compound to the mixture from step b, followed by mixing the liquids well to form a suspension; or II. a. adding and dissolving with mixing the antimicrobial agent and water;b. dispersing the suspending and/or viscosity increasing agent(s) in the dispersion of step a; c. adding with mixing the sweetener(s) to the dispersion of step b; followed by adding the suspending and/or viscosity agent(s) with mixing; followed by adding the sweetener(s) with mixing; d. dissolving the buffer(s) in water, followed by adding and dissolving sweetener(s), followed by adding and dispersing the wetting agent(s), followed by adding and dispersing the active compound; e. combining the dispersions of steps c and d with mixing; f. adding the dye(s) and flavor(s) to the dispersion of step e; and g. bringing the dispersion of step f to volume with purified water. 6. A pharmaceutical formulation comprising: ______________________________________ Ingredient mg/mL ______________________________________ mycophenolate mofetil 200 xanthan gum 0.5-1.5 colloidal silicon dioxide 5-10 soy lecithin 1-2 sorbitol 0-550 aspartame 0-3 citric acid 0-1.5 sodium citrate 0-20 sodium methyl paraben 0-10 flavor 0.1-3 color (to complement the flavor) 0-0.2 ______________________________________ as a dry granulation or powder blend suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water. 7. The pharmaceutical formulation of claim 6 provided in a container marked to be filled with purified water to a final predetermined volume. 8. The pharmaceutical formulation of claim 7, comprising: ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 sodium methyl paraben 900 berry flavor 1,350 color (FD&C red #3 13.5 FD&C blue #1 2.7 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 450 mL. 9. The pharmaceutical formulation of claim 7, comprising: ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 135,000 aspartame 450 citric acid 495 sodium citrate 4,500 sodium methyl paraben 900 berry flavor 1,350 color (FD&C red #3 13.5 FD&C blue #1 2.7 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 450 mL. 10. The pharmaceutical formulation of claim 7, comprising: ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 90,000 xanthan gum 675 colloidal silicon dioxide 4,500 soy lecithin 900 sorbitol 180,000 aspartame 450 sodium methyl paraben 1,035 mixed fruit flavor 900 color (FD&C red #3 3.6 FD&C yellow #6) 0.9 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 450 mL. 11. The pharmaceutical formulation of claim 7, comprising: ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 90,000 xanthan gum 450 colloidal silicon dioxide 2,250 soy lecithin 450 sorbitol 247,500 aspartame 225 citric acid 495 sodium citrate 4,500 sodium methyl paraben 1,035 mixed fruit flavor 900 color (FC&C red #3 3.96 FD&C yellow #6) 0.855 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 450 mL. 12. The pharmaceutical formulation of claim 7, comprising ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 45,000 xanthan gum 225 colloidal silicon dioxide 1,125 soy lecithin 225 sorbitol 123,750 aspartame 112.5 citric acid 247.5 sodium citrate 2,250 sodium methyl paraben 517.5 mixed fruit flavor 450 color (FD&C red #3 1.98 FD&C yellow #6) 0.43 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 240 mL. 13. The pharmaceutical formulation of claim 7, comprising ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 22,500 xanthan gum 112.5 colloidal silicon dioxide 562.5 soy lecithin 112.5 sorbitol 61,875 aspartame 56.25 citric acid 123.75 sodium citrate 1,125 sodium methyl paraben 258.75 mixed fruit flavor 225 color (FD&C red #3 0.99 FD&C yellow #6) 0.22 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 120 mL. 14. The pharmaceutical formulation of claim 7, comprising: ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 90,000 xanthan gum 675 colloidal silicon dioxide 4,500 soy lecithin 900 sorbitol 180,000 aspartame 450 citric acid 495 sodium citrate 4,500 sodium methyl paraben 1,035 orange flavor 450 color (FD&C yellow #6) 90 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 450 mL. 15. A pharmaceutical formulation, comprising: ______________________________________ Ingredient mg/mL ______________________________________ mycophenolate mofetil 200 sodium carboxymethylcellulose 20 sorbitol 300 sucrose 100 pluronic F68 4 potassium sorbate 5.0 cherry 10 color (red 40:blue 1, 90:10) 0.01 ______________________________________ as a dry granulation or powder blend suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water. 16. The pharmaceutical formulation of claim 15 provided in a container marked to be filled with purified water to a final predetermined volume. 17. The pharmaceutical formulation of claim 16, comprising: ______________________________________ Ingredient mg ______________________________________ mycophenolate mofetil 90,000 sodium carboxymethylcellulose 9,000 sorbitol 135,000 sucrose 45,000 pluronic F68 1,800 postassium sorbate 2,250 cherry 4,500 color (red 28:blue 1, 90:10) 4.5 ______________________________________ in a container marked to be filled with purified water to a final predetermined volume of 450 mL. 18. A process for the preparation of a pharmaceutical formulation comprising: ______________________________________ Ingredient mg/mL ______________________________________ mycophenolate mofetil or mycophenolic acid 75-300 suspending/viscosity agent 1-30 wetting agent 0-10 sweeteners 1-1200 flavor 0.1-100 flavor enhancer/bitter maskant 0-50 buffering agents 0-25 antimicrobial agent 0-10 color 0-2 ______________________________________ as a dry granulation or powder blend suitable, when constituted with water, for forming a suspension for oral administration, where mg/mL represents concentration after constitution with water, the process comprising: I. a. combining the active compound, sweetener(s), wetting agent(s), suspending and/or viscosity increasing agent(s), flavor(s) and antimicrobial agent(s) in a mixer;b. dissolving the dye(s) and buffer(s) in water; c. combining the solution of step (b) to the mixer bowl of step (a) and mixing until a desired granulation size is obtained; d. drying the granulation then milling to reduce particle size; e. adding the suspending and/or viscosity increasing agent(s) to the granulation of step (d) using a blender; or II. a. combining the active compound, sweetener(s), wetting agent(s), suspending and/or viscosity increasing agent(s), dye(s), and buffer(s) and mixing to form a powder blend.