Oral liquid compositions of celecoxib
Liquid pharmaceutical compositions, including suspensions, of celecoxib are provided herein. Methods of preparing the liquid pharmaceutical compositions and methods of using the compositions to treat diseases or disorders are also provided. Methods of determining the dissolution profile of liquid pharmaceutical compositions containing celecoxib are also provided.
1 . A liquid pharmaceutical composition comprising:
from 0.1 mg/mL to 100 mg/mL celecoxib,
suspending agents comprising xanthan gum and from 0.1% w/v to 0.75% w/v of a synthetic magnesium aluminometasilicate, wherein the xanthan gum and synthetic magnesium aluminometasilicate are present in a weight ratio of 1:1, and
a liquid carrier,
wherein the composition is in the form of a suspension.
2 . The liquid pharmaceutical composition of claim 1 , wherein the celecoxib is present at a concentration from 1 mg/mL to 20 mg/mL.
3 . The liquid pharmaceutical composition of claim 1 , wherein the celecoxib is present at a concentration from 5 mg/mL to 15 mg/mL.
4 . The liquid pharmaceutical composition of claim 1 , wherein the celecoxib is present at a concentration of 10 mg/mL.
5 . The liquid pharmaceutical composition of claim 1 , wherein the celecoxib is celecoxib polymorphic Form III.
6 . The liquid pharmaceutical composition of claim 1 , wherein the composition comprises celecoxib-containing particles having a particle size distribution with a D10 of from 1 to 5 μm, a D50 from 8 to 12 μm, and a D90 from 20 to 26 μm.
7 . The liquid pharmaceutical composition of claim 1 , wherein the composition comprises celecoxib-containing particles having a particle size distribution with a D10 of not less than (NLT) 1 μm, a D50 from 5 μm to 12.5 μm, and a D90 of not more than (NMT) 30 μm.
8 . The liquid pharmaceutical composition of claim 1 , wherein the suspending agents consist essentially of a mixture of xanthan gum and from 0.1% w/v to 0.75% w/v of a synthetic magnesium aluminometasilicate.
9 . The liquid pharmaceutical composition of claim 1 , wherein the xanthan gum is present in an amount from 0.25% w/v to 0.75% w/v of the composition.
10 . The liquid pharmaceutical composition of claim 1 , wherein the synthetic magnesium aluminometasilicate is present in an amount from 0.2% w/v to 0.6% w/v of the composition.
11 . The liquid pharmaceutical composition of claim 1 , wherein the xanthan gum is present in an amount from 0.25% w/v to 0.6% w/v of the composition and the synthetic magnesium aluminometasilicate is present in an amount from 0.25% w/v to 0.6% w/v of the composition.
12 . The liquid pharmaceutical composition of claim 1 , wherein the synthetic magnesium aluminometasilicate exhibits one or more or all of the following properties: (a) the synthetic magnesium aluminometasilicate is in amorphous form, (b) the synthetic magnesium aluminometasilicate has a loose bulk density from 0.06 to 0.11 g/mL, (c) the synthetic magnesium aluminometasilicate has a tapped bulk density from 0.1 to 0.17 g/mL, and (d) the synthetic magnesium aluminometasilicate has an average particle size of 3.1 μm.
13 . The liquid pharmaceutical composition of claim 1 , further comprising one or more pharmaceutically acceptable excipients selected from preservatives, sweetening agents, buffering agents, coloring agents, flavoring agents, and pH modifiers.
14 . The liquid pharmaceutical composition of claim 1 , wherein the liquid carrier comprises water and a wetting agent.
15 . The liquid pharmaceutical composition of claim 14 , wherein the wetting agent is selected from glycols, glycol ether, glycerin, polyoxyethylene alcohols, polyoxyethylene fatty acid esters, and combinations thereof.
16 . The liquid pharmaceutical composition of claim 1 comprising:
from 1 mg/mL to 20 mg/mL celecoxib;
suspending agents comprising from 0.25% w/v to 0.6% w/v xanthan gum and from 0.25% w/v to 0.6% w/v of a synthetic magnesium aluminometasilicate;
from 0.01% w/v to 1% w/v of a preservative;
from 0.1% w/v to 2% w/v of a buffering agent;
from 0.01% w/v to 1% w/v of a sweetening agent; and
a liquid carrier comprising from 80% w/v to 95% w/v water and from 1% w/v to 20% w/v of a wetting agent.
17 . The liquid pharmaceutical composition of claim 1 comprising:
10 mg/mL celecoxib;
suspending agents comprising 0.5% w/v xanthan gum and 0.5% w/v of a synthetic magnesium aluminometasilicate;
from 0.05% w/v to 0.5% w/v of a preservative;
from 0.1% w/v to 2% w/v of a buffering agent;
from 0.05% w/v to 0.5% w/v of a sweetening agent; and
a liquid carrier comprising from 80% w/v to 90% w/v water and from 10% w/v to 20% w/v of a wetting agent.
18 . The liquid pharmaceutical composition of claim 17 , wherein:
the preservative comprises methyl paraben and propyl paraben,
the buffering agent comprises citric acid and sodium citrate dihydrate,
the sweetening agent comprises sucralose, and
the liquid carrier comprises water and glycerin.
19 . The liquid pharmaceutical composition of claim 1 , wherein the composition has a pH from 3 to 9.
20 . The liquid pharmaceutical composition of claim 1 , wherein the composition has a pH above 5.2.
21 . The liquid pharmaceutical composition of claim 1 , wherein the composition exhibits one or more or all of the following properties:
(a) the pH of the composition does not change by more than 0.5 following storage for one month at 25° C.;
(b) the composition, when in the form of a suspension, exhibits one or both of (i) a uniformity difference in celecoxib content between the top of the composition and the bottom of the composition of less than 5% following storage in a closed bottle at 25° C. in an upright orientation for six months and (ii) a uniformity difference in celecoxib content between the top of the composition and the bottom of the composition of less than 5% following storage in a closed bottle at 40° C. in an upright orientation for six months, wherein the composition is shaken for 30 seconds prior to measuring celecoxib content;
(c) the composition, when subjected to dissolution testing at 37° C. at a paddle speed of 75 rpm in 1000 ml of dissolution media consisting of 0.04M sodium phosphate tribasic, pH adjusted to 11.1 with H 3 PO 4 , with a sodium dodecyl sulfate (SDS) concentration of 0.5%, exhibits a celecoxib release profile characterized by:
(i) from 5% to 45% celecoxib release in 5 minutes,
(ii) from 15% to 50% celecoxib release in 10 minutes,
(iii) from 30% to 75% celecoxib release in 15 minutes,
(iv) from 55% to 85% celecoxib release in 20 minutes, and
(v) greater than 80% celecoxib release in 30 minutes
(d) oral administration to a subject of a dose of the liquid pharmaceutical composition in the form of a suspension comprising from 50 mg to 200 mg celecoxib is bioequivalent to oral administration of a capsule formulation containing the same amount of celecoxib, wherein the liquid pharmaceutical composition in the form of a suspension comprises 1% w/v celecoxib, 0.5% w/v xanthan gum, 0.5% w/v synthetic magnesium aluminometasilicate, 0.7% w/v citric acid anhydrous, 1.1% w/v sodium citrate dihydrate, 0.15% w/v methylparaben, 0.05% w/v propylparaben, 0.1% w/v sucralose, 15.0% w/v glycerin, and water, and wherein the capsule formulation comprises celecoxib, A croscarmellose sodium, edible inks, gelatin, lactose monohydrate, magnesium stearate, povidone, and sodium lauryl sulfate;
(e) the composition has an acid neutralizing capacity from 2 mEq to 5 mEq per 200 mg dose.
22 . The liquid pharmaceutical composition of claim 1 , wherein the composition does not include one or more or all of sodium lauryl sulfate, propylene glycol, and purified natural magnesium aluminum silicate.