Claims for Patent: 12,042,484

Summary for Patent: 12,042,484

Title:	Tizanidine liquid preparation and use thereof
Abstract:	A tizanidine liquid preparation and use of the tizanidine liquid preparation in the preparation of a medicament for treating muscle spasm, wherein the tizanidine liquid preparation comprises an active ingredient, disodium EDTA and other pharmaceutical excipients, wherein the active ingredient is one or more of tizanidine or a pharmaceutically acceptable salt, solvate and hydrate thereof.
Inventor(s):	Gang Chen, Gongzheng CHEN, Song Lin, Rashmi Rohit PRASADE, Ganesh Dattatray CHAVAN PATIL
Assignee:	Fidelity Biopharma Co
Application Number:	US18/395,225
Patent Claims:	1. A liquid pharmaceutical composition, comprising a) about 0.1-2 mg/mL of tizanidine hydrochloride; b) about 0.5-5 mM of EDTA; c) water, d) about 2-6 mM citric acid, e) about 0.5-3 mM sodium citrate, and a pharmaceutically acceptable excipient, wherein pH of the liquid pharmaceutical composition is between 3.5 and 6.1, and wherein the liquid pharmaceutical composition retains at least 99% tizanidine concentration as measured by USP assay when stored at room temperature for at least 30 days. 2. The pharmaceutical composition of claim 1, further comprising f) about 2-10 mM of sodium methylparaben; and g) about 0.2-1 mM of sodium propylparaben. 3. The pharmaceutical composition of claim 2, further comprising h) about 0.5-5 mM of sucralose. 4. The pharmaceutical composition of claim 1, wherein the EDTA is disodium EDTA. 5. The pharmaceutical composition of claim 1, wherein the liquid pharmaceutical composition retains at least 99% tizanidine concentration as measured by USP assay when stored at room temperature for at least 180 days. 6. The pharmaceutical composition of claim 1, wherein the liquid pharmaceutical composition has a formula selected from the group consisting of Formula I-Formula V: Formula I: tizanidine hydrochloride 0.46 mg/ml, hydroxypropyl cellulose 0.025 g/mL, colloidal silicon dioxide 5 mg/mL, 70% sorbitol solution 0.15 g/mL, sodium methylparaben 1 mg/mL, sodium propylparaben 0.1 mg/mL, disodium EDTA 1 mg/mL, sucralose 0.5 mg/mL, citric acid 0.90 mg/mL, sodium citrate 0.46 mg/mL, with remainder being water and optionally flavoring agent; Formula II: tizanidine hydrochloride 0.46 mg/mL, 70% sorbitol solution 0.25 g/mL, sodium methylparaben 1 mg/mL, sodium propylparaben 0.1 mg/mL, disodium EDTA 1 mg/mL, sucralose 0.5 mg/mL, citric acid 0.90 mg/mL, sodium citrate 0.35 mg/mL, with remainder being water and optionally flavoring agent; Formula III: tizanidine hydrochloride 0.46 mg/mL, hydroxypropyl cellulose 0.025 g/mL, 70% sorbitol solution 0.15 g/mL, sodium methylparaben 1 mg/mL, sodium propylparaben 0.1 mg/mL, disodium EDTA 1 mg/mL, sucralose 0.5 mg/mL, citric acid 0.90 mg/mL, sodium citrate 0.46 mg/mL, with remainder being water and optionally flavoring agent; Formula IV: tizanidine hydrochloride 0.46 mg/mL, sodium methylparaben 1 mg/mL, sodium propylparaben 0.1 mg/mL, disodium EDTA 1 mg/mL, sucralose 0.5 mg/mL, citric acid 0.83 mg/mL, sodium citrate 0.42 mg/mL, with remainder being water and optionally flavoring agent; and Formula V: tizanidine hydrochloride 0.46 mg/mL, hydroxypropyl cellulose 0.05 g/mL, sodium benzoate 1 mg/mL, glycerin 0.15 g/mL, 70% sorbitol solution 0.25 g/mL, disodium EDTA 1 mg/mL, sucralose 0.5 mg/mL, with remainder being water and optionally flavoring agent. 7. A liquid pharmaceutical composition for treating muscle spasm in a subject, comprising a) about 0.1-2 mg/mL of tizanidine hydrochloride; b) about 0.5-5 mM of EDTA; and c) water, and a pharmaceutically acceptable excipient, wherein pH of the pharmaceutical composition is between 3.5 and 6.1, and wherein the liquid pharmaceutical composition retains at least 99% tizanidine concentration as measured by USP assay for at least 30 days when stored at room temperature, wherein said liquid pharmaceutical composition causes lower incidence rate of adverse effect in the subject as compared to incidence rate of adverse effect caused by solid tablets or capsules of tizanidine at the same dosage. 8. The pharmaceutical composition of claim 7, wherein the adverse effect comprises at least one of: headache, dizziness, sedation, vomiting, nausea drowsiness, asthenia, vertigo, or combination thereof. 9. The liquid pharmaceutical composition of claim 7, wherein the liquid pharmaceutical composition causes less drowsiness when administered to patients with muscle spasm as compared to drowsiness caused by solid tablets or capsules of tizanidine at the same dosage. 10. The liquid pharmaceutical composition of claim 7, wherein the liquid pharmaceutical composition causes lower incidence rate of drowsiness when administered to patients with muscle spasm as compared to incidence rate of drowsiness caused by solid tablets or capsules of tizanidine at the same dosage. 11. The pharmaceutical composition of claim 7, further comprising d) about 2-6 mM citric acid, and e) about 0.5-3 mM sodium citrate. 12. The pharmaceutical composition of claim 11, further comprising f) about 2-10 mM of sodium methylparaben; and g) about 0.2-1 mM of sodium propylparaben. 13. The pharmaceutical composition of claim 12, further comprising h) about 0.5-5 mM of sucralose. 14. The pharmaceutical composition of claim 13, wherein the pharmaceutical composition further comprises a flavoring agent. 15. The pharmaceutical composition of claim 3, wherein the strawberry aromatic agent is present in the pharmaceutical composition at about 0.5 mg/mL. 16. A method of administering tizanidine to a subject in need thereof for muscle relaxation, comprising administering a liquid pharmaceutical composition orally to said subject, wherein the pharmaceutical composition comprises a) about 0.1-2 mg/mL of tizanidine hydrochloride; b) about 0.5-5 mM of EDTA; and c) water, wherein pH of the liquid pharmaceutical composition is between 3.5 and 6.1, and wherein the liquid pharmaceutical composition retains at least 99% tizanidine concentration as measured by USP assay when stored at room temperature for at least 30 days. 17. The method of claim 16, wherein the liquid pharmaceutical composition of claim 1 is administered to the subject either before meal or after meal with same clinical effect. 18. The method of claim 16, wherein said liquid pharmaceutical composition causes less or fewer adverse effects in the subject as compared to side effects caused by solid tablets or capsules of tizanidine at the same dosage. 19. The method of claim 16, wherein the pharmaceutical composition further comprises d) about 2-6 mM citric acid, and e) about 0.5-3 mM sodium citrate. 20. The method of claim 19, wherein the pharmaceutical composition further comprises f) about 2-10 mM of sodium methylparaben; and g) about 0.2-1 mM of sodium propylparaben. 21. The method of claim 20, wherein the pharmaceutical composition further comprises h) about 0.5-5 mM of sucralose. 22. The method of claim 18, wherein the adverse effect comprises at least one of headache, dizziness, sedation, nausea drowsiness, asthenia, vertigo, or combination thereof. 23. The method of claim 22, wherein the liquid pharmaceutical composition causes lower incidence rate of drowsiness when administered to the subject as compared to incidence rate of drowsiness caused by solid tablets or capsules of tizanidine at the same dosage. 24. The pharmaceutical composition of claim 1, wherein when a single dose of the liquid pharmaceutical composition is administered to a subject, the mean value of Cmax, AUC0-t, or AUC0-∞ is within 80% to 125% of the mean value of Cmax, AUC0-t, or AUC0-∞, respectively, of the same amount of tizanidine in a solid dosage form. 25. The pharmaceutical composition of claim 1, wherein when a single dose of the pharmaceutical composition is administered to a subject under fasting condition, mean value of Cmax is between 4055 and 6336 pg/mL, or between 3751 and 5861 pg/mL, or mean value of AUC0-t is between 11286 and 17635 hr*pg/mL, or between 10200 and 15938 hr*pg/mL, or mean value of AUC0-∞ is between 11752 and 18362 hr*pg/mL or between 10655 and 16648 hr*pg/mL. 26. The pharmaceutical composition of claim 1, wherein when a single dose of the pharmaceutical composition is administered to a subject under fed condition, mean value of Cmax is between 4378 and 6841 pg/mL, or between 4092 and 6395 pg/mL, or mean value of AUC0-t is between 15404 and 24070 hr*pg/mL, or between 13983 and 21848 hr*pg/mL, or mean value of AUC0-∞ is between 15807 and 24698 hr*pg/mL or between 14379 and 22467 hr*pg/mL. 27. The pharmaceutical composition of claim 7, wherein when a single dose of the liquid pharmaceutical composition is administered to a subject, the mean value of Cmax, AUC0-t, or AUC0-∞ is within 80% to 125% of the mean value of Cmax, AUC0-t, or AUC0-∞, respectively, of the same amount of tizanidine in a solid dosage form. 28. The pharmaceutical composition of claim 7, wherein when a single dose of the pharmaceutical composition is administered to a subject under fasting condition, mean value of Cmax is between 4055 and 6336 pg/mL, or between 3751 and 5861 pg/mL, or mean value of AUC0-t is between 11286 and 17635 hr*pg/mL, or between 10200 and 15938 hr*pg/mL, or mean value of AUC0-∞ is between 11752 and 18362 hr*pg/mL or between 10655 and 16648 hr*pg/mL. 29. The pharmaceutical composition of claim 7, wherein when a single dose of the pharmaceutical composition is administered to a subject under fed condition, mean value of Cmax is between 4378 and 6841 pg/mL, or between 4092 and 6395 pg/mL, or mean value of AUC0-t is between 15404 and 24070 hr*pg/mL, or between 13983 and 21848 hr*pg/mL, or mean value of AUC0-∞ is between 15807 and 24698 hr*pg/mL or between 14379 and 22467 hr*pg/mL.