Methods of treating urea cycle disorders and maple syrup urine disease
The present invention provides methods for the treatment of urea cycle disorders and Maple Syrup Urine Disease.
1. A method of treating a urea cycle disorder, the method comprising orally administering a therapeutically effective amount of sodium phenylbutyrate in a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a plurality of taste-masked, layered particles having a volume-based particle size distribution in which at least 90% of the layered particles in the plurality of layered particles are smaller than 500 μm, wherein the layered particles comprise (i) a seed core; (ii) a drug layer comprising sodium phenylbutyrate; and (iii) a taste-mask coating, wherein the pharmaceutical composition comprises about 10 to 20% by total weight of the seed core, about 5% to 25% by total weight taste-mask coating, and greater than 60% by total weight of the sodium phenylbutyrate, and wherein the taste-masked coating comprises a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.
2. The method of claim 1 , wherein, upon administration to the subject, the pharmaceutical composition is bioequivalent to compared to a sodium phenylbutyrate formulation that does not comprise a taste-mask coating.
3. The method of claim 1 , wherein the pharmaceutical composition is administered in combination with a dosing vehicle.
4. The method of claim 3 , wherein the dosing vehicle comprises modified food starch, maltodextrin, or a combination thereof.
5. The method of claim 4 , wherein the modified food starch is modified corn starch.
6. The method of claim 1 , wherein the therapeutically effective amount is 450-600 mg/kg/day in subjects weighing less than 20 kg or 9.9-13.0 g/m 2 /day in larger subjects.
7. The method of claim 1 , wherein the subject is on a protein restricted diet.
8. The method of claim 1 , further comprising administering essential amino acids to the subject.
9. The method of claim 1 , wherein the therapeutically effective amount is administered in equally divided amounts with each meal or feeding.
10. The method of claim 1 , wherein the therapeutically effective amount is administered three to six times per day.
11. The method of claim 1 , wherein the urea cycle disorder is caused by a mutation in N-acetylglutamate synthetase, carbamoyl phosphate synthetase I, ornithine transcarbamylase, argininosuccinic acid sythetase, argininosuccinic acid lyase, or arginase.
12. The method of claim 1 , wherein the plurality has a volume-based particle size distribution in which at least 90% of the layered particles in the plurality of layered particles are smaller than 500 μm.
13. The method of claim 1 , wherein the subject is a human.
14. The method of claim 1 , wherein the administration results in removal of excess ammonia from the blood of the subject.
15. A method of treating maple syrup urine disease, the method comprising orally administering a therapeutically effective amount of sodium phenylbutyrate in a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a plurality of taste-masked, layered particles having a volume-based particle size distribution in which at least 90% of the layered particles in the plurality of layered particles are smaller than 500 μm, wherein the layered particles comprise (i) a seed core; (ii) a drug layer comprising sodium phenylbutyrate; and (iii) a taste-mask coating, wherein the pharmaceutical composition comprises about 10 to 20% by total weight of the seed core, about 5% to 25% by total weight taste-mask coating, and greater than 60% by total weight of the sodium phenylbutyrate, and wherein the taste-masked coating comprises a polymer formed from dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate.
16. The method of claim 15 , wherein the pharmaceutical composition is administered in combination with a dosing vehicle.
17. The method of claim 16 , wherein the dosing vehicle comprises modified food starch, maltodextrin, or a combination thereof.
18. The method of claim 17 , wherein the modified food starch is modified corn starch.
19. The method of claim 15 , wherein the therapeutically effective amount is 450-600 mg/kg/day in subjects weighing less than 20 kg or 9.9-13.0 g/m 2 /day in larger subjects.
20. The method of claim 15 , wherein the therapeutically effective amount is administered in equally divided amounts with each meal or feeding.
21. The method of claim 15 , wherein the therapeutically effective amount is administered three to twelve times per day.
22. The method of claim 15 , wherein the plurality has a volume-based particle size distribution in which at least 90% of the layered particles in the plurality of layered particles are smaller than 500 μm.
23. The method of claim 15 , wherein the subject is a human.
24. The method of claim 15 , wherein the therapeutically effective amount is sufficient to lower the plasma level of a branched chain amino acid (BCAA).
25. The method of claim 24 , wherein the BCAA is leucine, and the level is lowered to 200-500 μmol/L.
26. The method of claim 24 , wherein the BCAA is isoleucine, and the level is lowered to 100-200 μmol/L.
27. The method of claim 24 , wherein the BCAA is valine, and the level is lowered to 100-300 μmol/L.