STABLE PHARMACEUTICAL COMPOSITIONS OF HYDROXYUREA
The present invention relates to stable oral pharmaceutical compositions in the form of a solution comprising: hydroxyurea at a concentration of about 10 mg/mL to about 500 mg/mL; at least one pharmaceutically acceptable liquid vehicle; and one or more amino acids selected from the group consisting of glycine, alanine, glutamic acid, L-arginine, lysine, L-cysteine, methionine and mixtures thereof, wherein the level of carbamoyloxyurea in the solution is less than 0.5 % w/w as measured by HPLC when the solution is stored at 25° C./60% RH for at least 3 months. The invention further relates to processes for the production of the compositions, methods for their administration, and their use for treatment of diseases treatable by hydroxyurea.
1 . A pharmaceutical composition comprising:
(i) hydroxyurea at a concentration of about 10 mg/mL to about 500 mg/mL;
(ii) at least one pharmaceutically acceptable liquid vehicle; and
(iii) one or more amino acids selected from the group consisting of glycine, alanine, glutamic acid, L-arginine, lysine, L-cysteine, methionine and mixtures thereof,
wherein the composition is in the form of a solution suitable for oral administration, and
wherein the solution is stable, such that the level of carbamoyloxyurea in the solution is less than 0.5% w/w as measured by HPLC, when the solution is stored at 25° C./60% RH for at least 3 months.
2 . The composition according to claim 1 , wherein hydroxyurea is present at a concentration of about 100 mg/mL.
3 . The composition according to claim 1 , wherein the solution is stable, such that the level of carbamoyloxyurea in the solution is less than 0.5% w/w as measured by HPLC, when the solution is stored at 2-8° C. for at least 12 months.
4 . The composition according to claim 1 , wherein the amount of amino acids is in the range of 0.1% to 10.0% based on the total weight of the composition.
5 . The composition according to claim 1 , wherein the concentration of amino acids is in the range of 0.1 mg/mL to 10.0 mg/mL.
6 . The composition according to claim 1 , wherein the solution is free of sodium hydroxide, potassium hydroxide, sodium bicarbonate, or sodium carbonate as pH adjusters or pH modifiers.
7 . The composition according to claim 1 , wherein the solution resists pH change such that the pH remains within a range of 4.0 to 9.0.
8 . The composition according to claim 7 , wherein the pH remains within a range of 5.0 to 8.0.
9 . The composition according to claim 7 , wherein the pH remains within a range of 6.0 to 7.0.
10 . The composition according to claim 7 , wherein the pH remains within a range of 5.0 to 6.0.
11 . The composition according to claim 7 , wherein the pH remains within a range of 4.0 to 6.0.
12 . The composition according to claim 7 , wherein the pH remains within a range of 7.0 to 9.0.
13 . The composition according to claim 7 , wherein the pH remains within a range of 7.0 to 8.0.
14 . The composition according to claim 1 , wherein the pharmaceutically acceptable liquid vehicle is selected from group consisting of water, glycerin, alcohols, propylene glycol, polyethylene glycol, and mixtures thereof.
15 . The composition according to claim 1 , wherein the solution further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of stabilizers, solubilizers, pH modifiers, pH adjusting agents, buffering agents, preservatives, thickening agents, antioxidants, chelating agents, flavoring agents, sweetening agents, coloring agents and mixtures thereof.
16 . The composition according to claim 1 , wherein the solution is free of preservatives.
17 . A pharmaceutical composition comprising:
(i) hydroxyurea at a concentration of about 10 mg/mL to about 500 mg/mL; and
(ii) at least one pharmaceutically acceptable liquid vehicle, wherein the composition is in the form of a solution suitable for oral administration and wherein the solution is free of sodium hydroxide, potassium hydroxide, sodium bicarbonate, or sodium carbonate as pH adjusters or pH modifiers; and wherein the solution is stable, such that the level of carbamoyloxyurea in the solution is less than 0.5 % w/w as measured by HPLC, when the solution is stored at 25° C./60% RH for at least 3 months or 2-8° C. for at least 12 months.
18 . A pharmaceutical composition comprising:
(i) hydroxyurea at a concentration of about 10 mg/mL to about 500 mg/mL; and
(ii) at least one pharmaceutically acceptable liquid vehicle,
wherein the composition is in the form of a solution suitable for oral administration, and
wherein the solution resists pH change such that the pH remains within a range of 4.0 to 6.0 or 7.0 to 9.0 when stored at 25° C./60% RH for at least 3 months or at 2-8° C. for at least 12 months.
19 . The composition according to claim 18 , wherein the solution is stable, such that the level of carbamoyloxyurea in the solution is less than 0.5 % w/w as measured by HPLC, when the solution is stored at 25° C./60% RH for at least 3 months or 2-8° C. for at least 12 months.
20 . A method of reducing the frequency of painful crises and/or reducing the need for blood transfusions in pediatric or adult patients with sickle cell anemia with recurrent moderate to severe painful crises comprising administering the composition according to claim 1 to the patient.