PHARMACEUTICAL LIQUID COMPOSITIONS OF MELOXICAM
The present invention relates to stable injectable compositions comprising meloxicam or its pharmaceutically acceptable salts, solvates, or hydrates thereof, wherein the composition is provided in a sealed container, e.g., an ampoule, vial and pre-filled syringe. Further, the present invention relates to a stable injectable solution comprising meloxicam or its pharmaceutically acceptable salts, solvates, or hydrates thereof, suitable for subcutaneous, intravenous or intramuscular administration. The invention relates to methods for manufacturing stable injectable solutions of meloxicam. The present invention further relates to a method of treating pain by parenterally administering to a patient in need thereof a composition comprising a stable solution of meloxicam, wherein said solution provides rapid onset of action for pain relief compared to a reference composition.
1 . A composition comprising a stable solution of meloxicam suitable for parenteral administration comprising:
(a) a therapeutically effective amount of meloxicam,
(b) one or more pharmaceutically acceptable solvents;
(c) one or more solubilizers;
(d) optionally, a nucleation inhibitor;
and optionally, one or more other pharmaceutically acceptable excipients.
2 . The composition according to claim 1 , wherein the solution has a pH in the range of about 5 to about 12.
3 . The composition according to claim 1 , wherein the solution has an osmolality value of between about 100 mOsm and about 2000 mOsm.
4 . The composition according to claim 1 , wherein the solubilizers are selected from a group comprising meglumine, cyclodextrin, cyclodextrin derivative, monoethanolamine, diethanolamine, tromethamine, hydroxypropyl methyl cellulose (HPMC), L-arginine, L-lysine, polysorbate 80 (Tween® 80), polysorbate 20 (Tween® 20), poloxamer, propylene glycol, glycerin, ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide, and polyethoxylated castor oil (Cremophor® EL) or mixtures thereof.
5 . The composition according to claim 1 , wherein the nucleation inhibitor is selected from polyvinylpyrrolidone (PVP), crospovidone, hydroxypropyl methyl cellulose (HPMC), polysorbate, phospholipids such as dimyristoylphosphatidyl glycerol (DMPG), disteroylphosphatidylethanolamine (DSPE), 1,2-Distearoyl phosphatidyl ethanolamine methyl-polyethylene glycol conjugate (DSPE-mPEG), or any combination thereof.
6 . The composition of claim 1 , wherein said meloxicam solution stored for 6 months at 40° C./75% RH has an amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/w of meloxicam of the total composition.
7 . A composition comprising a stable solution of meloxicam suitable for parenteral administration comprising:
(a) a therapeutically effective amount of meloxicam,
(b) one or more pharmaceutically acceptable solvents;
(c) one or more solubilizers;
(d) optionally, one or more other pharmaceutically acceptable excipients, and wherein a subject administered with said composition exhibits increased average paw withdrawal latency when compared to a subject administered with reference composition.
8 . The composition according to claim 7 , wherein the subject is a rat or a human.
9 . The composition according to claim 7 , wherein said composition stored for 6 months at 40° C./75% RH has an amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/w of meloxicam of the total composition.
10 . A composition comprising a stable solution of meloxicam suitable for parenteral administration comprising:
(a) a therapeutically effective amount of meloxicam,
(b) one or more pharmaceutically acceptable solvents;
(c) one or more solubilizers; and
(d) optionally, a nucleation inhibitor;
(e) optionally, one or more other pharmaceutically acceptable excipients, wherein said composition upon administration exhibits a bioequivalence to a reference composition; and
wherein said bioequivalence is established by at least one of: (i) a confidence interval for mean AUC 0-t between about 80% and about 125%; (ii) a confidence interval for mean AUC 0-infinity between about 80% and about 125%; (iii) a confidence interval for mean C max between about 80% and about 125%.
11 . A method of treating pain by parenterally administering to a patient in need thereof a composition comprising a stable solution of meloxicam, wherein said solution provides rapid onset of action for pain relief compared to a reference composition.
12 . The method of claim 11 , wherein said composition comprises meloxicam in a solubilized form.
13 . The method of claim 11 , wherein said composition comprises meloxicam, one or more solubilizers; a nucleation inhibitor; one or more pharmaceutically acceptable solvents; and optionally one or more other pharmaceutically acceptable excipients.
14 . The method of claim 13 , wherein the meloxicam dose is 30 mg.
15 . The method of claim 13 , wherein the solubilizer is selected from a group comprising meglumine, cyclodextrin, cyclodextrin derivative, monoethanolamine, diethanolamine, tromethamine, hydroxypropyl methyl cellulose (HPMC), L-arginine, L-lysine, polysorbate 80 (Tween® 80), polysorbate 20 (Tween® 20), poloxamer, propylene glycol, glycerin, ethanol, polyethylene glycol (300 and 400), sorbitol, dimethylacetamide, and polyethoxylated castor oil (Cremophor® EL) or combinations thereof.
16 . The method of claim 13 , wherein the nucleation inhibitor is povidone.
17 . The method of claim 11 , wherein the administration of said composition provides the patient a rapid onset of pain relief without the use of a second NSAID.
18 . The composition of claim 1 , wherein said meloxicam solution stored for 1 month at 40° C./75% RH has an amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/w of meloxicam of the total composition.
19 . The method of claim 11 , wherein said composition stored for 6 months at 40° C./75% RH has an amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/w of meloxicam of the total composition.
20 . The method of claim 11 , wherein said composition stored for 1 month at 40° C./75% RH has an amount of 2-Amino-5-methylthiazole that is less than about 0.2% w/w of meloxicam of the total composition.