Pharmaceutical compositions and oral dosage forms of a levodopa prodrug and methods of use
View Patent ↗Pharmaceutical compositions and oral dosage forms of (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate and methods of treating diseases comprising orally administering such pharmaceutical compositions and dosage forms are disclosed.
1. A pharmaceutical composition comprising granules, wherein the granules are prepared using high shear wet granulation and comprise:
90 wt % to 99 wt % anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate; and
0.5 wt % to 2 wt % C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition of claim 1 , wherein the C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof is sodium lauryl sulfate.
3. The pharmaceutical composition of claim 1 , comprising one or more pharmaceutically acceptable excipients.
4. A pharmaceutical composition comprising:
about 50 wt-% to about 90 wt-% anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate;
about 0.5 wt-% to about 2.0 wt-% C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof;
about 6 wt-% to about 20 wt-% hydroxypropylmethylcellulose; and
about 0.5 wt-% to about 2.0 wt-% magnesium stearate;
wherein wt-% is based on the total dry weight of the composition.
5. The pharmaceutical composition of claim 1 , comprising an L-aromatic amino acid decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, or a combination of an L-aromatic amino acid decarboxylase inhibitor and a catechol-O-methyltransferase inhibitor.
6. An oral tablet dosage form comprising granules prepared using high shear wet granulation, wherein the granules comprise:
anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate; and
a C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof.
7. The dosage form of claim 6 , wherein the C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof is sodium lauryl sulfate.
8. The dosage form of claim 6 , comprising one or more pharmaceutically acceptable excipients.
9. An oral tablet dosage form comprising:
about 50 wt-% to about 90 wt-% anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate;
about 0.5 wt-% to about 2.0 wt-% C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof;
about 6 wt-% to about 20 wt-% hydroxypropylmethylcellulose; and
about 0.5 wt-% to about 2 wt-% magnesium stearate;
wherein wt-% is based on the total dry weight of the dosage form.
10. The dosage form of claim 7 , comprising an L-aromatic amino acid decarboxylase inhibitor, a catechol-O-methyltransferase inhibitor, or a combination of an L-aromatic amino acid decarboxylase inhibitor and a catechol-O-methyltransferase inhibitor.
11. The dosage form of claim 6 , which when placed in 0.1 N HCl, pH 1.2 at 37° C. and agitated at 50 rpm, releases about 28% to about 58% of the anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate within about 2 hours, about 40% to about 70% within about 4 hours, about 67% to about 97% within about 9 hours, and greater than about 80% within about 18 hours.
12. The dosage form of claim 6 , which is a bilayer tablet dosage form comprising:
a first layer comprising granules comprising anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate and a C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof; and
a second layer comprising an L-aromatic amino acid decarboxylase inhibitor.
13. The dosage form of claim 12 , wherein the C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof is sodium lauryl sulfate, and the L-aromatic amino acid decarboxylase inhibitor is carbidopa.
14. An oral tablet dosage form, which a is bilayer tablet dosage form, wherein:
the first layer comprises the granules comprising about 70 wt-% to about 95 wt-% anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate and about 0.5 wt-% to about 3 wt-% C 6-18 alkylsulfate or pharmaceutically acceptable salt thereof; and
the second layer comprises about 15 wt-% to about 30 wt-% of an L-aromatic amino acid decarboxylase inhibitor.
15. The dosage form of claim 12 , which when placed in 0.1 N HCl, pH 1.2 or pH 5.0 at 37° C. and agitated at 50 rpm, releases about 28% to about 58% of the anhydrous crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate within about 2 hours, about 50% to about 80% within about 4 hours, and greater than about 80% within about 12 hours.
16. A method of treating a disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 1 , wherein the disease is chosen from schizophrenia, a cognitive impairment disorder, restless legs syndrome, a periodic limb movement disorder, tardive dyskinesia, Huntington's disease, hypertension, and excessive daytime sleepiness.
17. A method of treating Parkinson's disease in a patient comprising administering to a patient in need of such treatment a therapeutically effective amount of the pharmaceutical composition of claim 1 .
18. A method of treating a disease in a patient comprising administering to a patient in need of such treatment the tablet dosage form of any one of claim 6 and 12 , wherein the disease is chosen from schizophrenia, a cognitive impairment disorder, restless legs syndrome, a periodic limb movement disorder, tardive dyskinesia, Huntington's disease, hypertension, and excessive daytime sleepiness.
19. A method of treating Parkinson's disease in a patient comprising administering to a patient in need of such treatment the tablet dosage form of any one of claim 6 and 12 .
20. The pharmaceutical composition of claim 1 , wherein the granules are substantially free of crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate, hydrate.
21. The oral dosage form of claim 6 , wherein the granules are substantially free of crystalline (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate, hydrate.