Claims for Patent: 10,213,393

Summary for Patent: 10,213,393

Title:	Composition and method for treating neurological disease
Abstract:	The present disclosure is directed to methods of treating neurological disorders in a patient such as Parkinson's disease, drug-induced extrapyramidal reactions, and/or levodopa-induced dyskinesia comprising administering to the patient once daily in the morning a pharmaceutical composition comprising about 50 mg to about 400 mg of extended-release amantadine or a pharmaceutically acceptable salt thereof.
Inventor(s):	Meyer; Glenn A. (Wilmington, NC), Faour; Joaquina (Ciudad Autonoma de Buenos Aires, AR), Pastini; Ana Cristina (Ciudad Autonoma de Buenos Aires, AR), Befumo; Marcelo Fernando (Ciudad Autonoma de Buenos Aires, AR)
Assignee:	Osmotica Kereskedelmi es Szolgaltato Korlatolt Feleossegu Tarsasag (Budapest, HU)
Application Number:	15/898,143
Patent Claims:	1. A method of treating Parkinson's disease in a patient, comprising: i) administering to the patient once daily in the morning a pharmaceutical composition comprising about 129 mg of amantadine free base equivalent for one week; ii) increasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition comprising about 193 mg of amantadine free base equivalent; wherein each of the pharmaceutical compositions comprises i) an extended release component comprising amantadine free base equivalent; and ii) an immediate release component comprising about 48 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions is an osmotic device comprising an osmotic agent and an osmotic coating, wherein the maximum daily dose of amantadine is about 322 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions provides a mean change in amantadine plasma concentration as a function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, and wherein the dC/dT values are measured in a single dose human pharmacokinetic study over the time period between 0 and 4 hours after administration. 2. A method of treating Parkinson's disease in a patient, comprising: i) administering to the patient once daily in the morning a pharmaceutical composition comprising about 129 mg of amantadine free base equivalent for one week; ii) increasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition comprising about 193 mg of amantadine free base equivalent for one week; iii) increasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition comprising about 258 mg of amantadine free base equivalent; wherein each of the pharmaceutical compositions comprises i) an extended release component comprising amantadine free base equivalent; and ii) an immediate release component comprising about 48 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions is an osmotic device comprising an osmotic agent and an osmotic coating, wherein the maximum daily dose of amantadine is about 322 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions provides a mean change in amantadine plasma concentration as a function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, and wherein the dC/dT values are measured in a single dose human pharmacokinetic study over the time period between 0 and 4 hours after administration. 3. The method of claim 2, further comprising iv) decreasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition comprising about 193 mg of amantadine free base equivalent for at least one week; and v) decreasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition comprising about 129 mg of amantadine free base equivalent for at least one week; wherein each of the pharmaceutical compositions comprises i) an extended release component comprising amantadine free base equivalent; and ii) an immediate release component comprising about 48 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions in steps iv) and v) provides a mean change in amantadine plasma concentration as a function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, and wherein the dC/dT values are measured in a single dose human pharmacokinetic study over the time period between 0 and 4 hours after administration. 4. A method of treating Parkinson's disease in a patient, comprising: i) administering to the patient once daily in the morning a pharmaceutical composition consisting essentially of about 129 mg of amantadine free base equivalent for one week; ii) increasing the dose of amantadine by administering to the patient once daily in the morning a pharmaceutical composition consisting essentially of about 193 mg of amantadine free base equivalent; wherein each of the pharmaceutical compositions consists of i) an extended release component consisting essentially of amantadine free base equivalent and ii) an immediate release component consisting essentially of about 48 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions is an osmotic device comprising an osmotic agent and an osmotic coating, wherein the maximum daily dose of amantadine is about 322 mg of amantadine free base equivalent, wherein each of the pharmaceutical compositions provides a mean change in amantadine plasma concentration as a function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, and wherein the dC/dT values are measured in a single dose human pharmacokinetic study over the time period between 0 and 4 hours after administration. 5. The method of claim 1, wherein the T.sub.max of each pharmaceutical composition after a single-dose administration is between about 5 and about 12 hours. 6. The method of claim 5, wherein the median T.sub.max of each pharmaceutical composition after a single-dose administration is about 7.5 hours. 7. The method of claim 2, wherein the mean C.sub.max of the pharmaceutical composition comprising about 258 mg of amantadine free base equivalent after a single-dose administration is between about 540 and about 895 ng/ml. 8. The method of claim 1, wherein the mean C.sub.max of the pharmaceutical composition comprising about 193 mg of amantadine free base equivalent after a single-dose administration is between about 370 and about 550 ng/ml. 9. The method of claim 1, wherein the mean C.sub.max of the pharmaceutical composition comprising about 129 mg of amantadine free base equivalent after a single-dose administration is between about 265 and about 390 ng/ml. 10. The method of claim 2, wherein the mean AUC.sub.0-.infin. of the pharmaceutical composition comprising about 258 mg of amantadine free base equivalent after a single-dose administration is between about 12,000 and about 26,000 ngh/mL. 11. The method of claim 1, wherein the mean AUC.sub.0-.infin. of the pharmaceutical composition comprising about 193 mg of amantadine free base equivalent after a single-dose administration is between about 8,000 and about 20,000 ngh/mL. 12. The method of claim 1, wherein the mean AUC.sub.0-.infin. of the pharmaceutical composition comprising about 129 mg of amantadine free base equivalent after a single-dose administration is between about 6,000 and about 12,000 ngh/mL. 13. The method of claim 1, wherein each pharmaceutical composition has an in vitro dissolution profile ranging between about 0.1% to about 50% in about 0.5 hour, about 20% to about 80% in about 2.5 hours, about 40% to about 90% in about 4 hours, and no less than about 85% in about 8 hours as measured in water using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C. 14. The method of claim 2, wherein the pharmaceutical composition comprising about 258 mg of amantadine free base equivalent has an in vitro dissolution profile ranging between about 28% to about 48% in about 0.5 hour, about 39% to about 63% in about 2.5 hours, about 61% to about 85% in about 4 hours, and no less than about 85% in about 8 hours as measured in water using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C. 15. The method of claim 1, wherein the pharmaceutical composition comprising about 193 mg of amantadine free base equivalent has an in vitro dissolution profile ranging between about 15% to about 35% in about 0.5 hour, about 29% to about 53% in about 2.5 hours, about 53% to about 77% in about 4 hours, and no less than about 85% in about 8 hours as measured in water using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C. 16. The method of claim 1, wherein the pharmaceutical composition comprising about 129 mg of amantadine free base equivalent has an in vitro dissolution profile ranging between about 9% to about 29% in about 0.5 hour, about 37% to about 62% in about 2.5 hours, about 59% to about 83% in about 4 hours, and no less than about 85% in about 8 hours as measured in water using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37.+-.0.5 C. 17. The method of claim 1, wherein the relative bioavailability of amantadine or a pharmaceutically acceptable salt thereof is approximately the same under fed and fasting conditions. 18. The method of claim 1, wherein each pharmaceutical composition is administered as a combination with a second agent, wherein the second agent comprises one or more compounds selected from the group consisting of aromatic-L-amino-acid decarboxylase inhibitors, dopamine agonists, COMT (catechol O-methyltransferase) inhibitors, MAO-B (monoamine oxidase B) inhibitors, anticholinergics, benzodiazepines, SSRIs (selective serotonin reuptake inhibitors), tricyclic and tetracyclic antidepressants, nonsteroidal anti-inflammatory agents, non-narcotic analgesic, narcotic analgesics, ADORA2A (adenosine A2A receptor) antagonists, anti-epileptic agents, and any combinations thereof. 19. The method of claim 2, wherein the mean C.sub.max of the pharmaceutical composition comprising about 193 mg of amantadine free base equivalent after a single-dose administration is between about 370 and about 550 ng/ml. 20. The method of claim 2, wherein the mean C.sub.max of the pharmaceutical composition comprising about 129 mg of amantadine free base equivalent after a single-dose administration is between about 265 and about 390 ng/ml. 21. The method of claim 2, wherein the mean AUC.sub.0-.infin. of the pharmaceutical composition comprising about 193 mg of amantadine free base equivalent after a single-dose administration is between about 8,000 and about 20,000 ngh/mL. 22. The method of claim 2, wherein the mean AUC.sub.0-.infin. of the pharmaceutical composition comprising about 129 mg of amantadine free base equivalent after a single-dose administration is between about 6,000 and about 12,000 ngh/mL. 23. The method of claim 2, wherein the pharmaceutical composition comprising about 193 mg of amantadine free base equivalent has an in vitro dissolution profile ranging between about 15% to about 35% in about 0.5 hour, about 29% to about 53% in about 2.5 hours, about 53% to about 77% in about 4 hours, and no less than about 85% in about 8 hours as measured in water using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37.+-.0.5.degree. C. 24. The method of claim 2, wherein the pharmaceutical composition comprising about 129 mg of amantadine free base equivalent has an in vitro dissolution profile ranging between about 9% to about 29% in about 0.5 hour, about 37% to about 62% in about 2.5 hours, about 59% to about 83% in about 4 hours, and no less than about 85% in about 8 hours as measured in water using a USP type II (paddle) dissolution system at 50 rpm, at a temperature of 37.+-.0.5.degree. C. 25. The method of claim 2, wherein the relative bioavailability of amantadine or a pharmaceutically acceptable salt thereof is approximately the same under fed and fasting conditions. 26. A method of treating Parkinson's disease in a patient, comprising: i) administering to the patient once daily in the morning a pharmaceutical composition comprising about 129 mg of amantadine free base equivalent, and ii) increasing the dose of amantadine in weekly intervals to a maximum daily dose of 322 mg administered once daily in the morning, wherein the pharmaceutical composition consists of i) an extended release component consisting essentially of amantadine free base equivalent, and ii) an immediate release component consisting essentially of about 48 mg of amantadine free base equivalent, wherein the pharmaceutical composition is an osmotic device comprising an osmotic agent and an osmotic coating, wherein the pharmaceutical composition provides a mean change in amantadine plasma concentration as a function of time (dC/dT) that is between about 40% and about 70% of the dC/dT provided by the same quantity of amantadine or a pharmaceutically acceptable salt thereof in an immediate release form, and wherein the dC/dT values are measured in a single dose human pharmacokinetic study over the time period between 0 and 4 hours after administration.