DESC:FIELD OF INVENTION
The present invention relates to an aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof. The invention particularly relates to a ready-to-dilute composition comprising celecoxib or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of acute pain, especially post-operative pain.

BACKGROUND OF INVENTION
Acute pain is a significant problem for inpatients and can occur secondary to acute illness or disease processes, trauma, or operative procedures. A study of acute pain management in the postoperative setting showed that 77% of adults experienced inadequately treated pain after surgery: 71% still experienced pain even after being administered medication, and most of these (80%) described the pain as moderate to extreme. It is a physiological result of stimulation of both the somatic and visceral pain pathways. As a result, inflammatory mediators are major players in acute postoperative pain, and management needs to be approached in a multimodal fashion by including agents capable of inhibiting the perception of pain peripherally and centrally in combination with other synergistic analgesics.
Opioids have been the mainstream treatment for postoperative pain. However, they mainly act within the central nervous system to provide analgesia; they do not interrupt the inflammatory component of pain. Addressing the inflammatory response may reduce the overall need for opioid analgesics and improve recovery after surgical procedures and uninjured tissue. The American Society of Anesthesiologists notes that, unless contraindicated, patients should receive an around-the-clock regimen of NSAIDs, COX inhibitors, or acetaminophen as part of a postoperative multimodal pain management regimen.
The pain-relieving properties relate to the inhibition of PGE2 and its effects peripherally and centrally. COX-1 and COX-2 in the spinal cord are released in response to painful peripheral stimuli to form prostaglandins which sensitizes peripheral nerve endings. Prostaglandins PGE2 and PGI2 are responsible for inflammation including edema formation and leucocyte infiltration through the promotion of blood flow. Inhibition by COX enzymes reduce edema and suppresses the immunologic response associated with inflammation. Adequate relief of acute pain may be dependent on several factors such as time to onset of analgesia, maximum analgesic effect, and duration of analgesic effect. Clinical data have shown that COX-2- selective inhibitors have efficacy equivalent to NSAIDs but have significantly lower risk of side effects such as GI ulceration, inhibition of platelet aggregation, or increased bleeding time. Therefore, COX-2–selective inhibitors have potential for use in the perioperative setting. While nonselective NSAIDs inhibit PG broadly, inhibiting both COX-2 and COX-1 isoenzymes, COX inhibitors inhibit only COX-2. Therefore, by inhibiting COX-2, the primary noxious mediator can be blocked and the action of second- and third-order downstream mediators may be reduced.
Celecoxib is a widely used Cox-2 inhibitor for the management of acute pain. Currently, celecoxib is available only in an oral capsule dosage form Celebrex® in the United States. However, there is a need for an early onset of action and duration of analgesia in pain management, especially in post-operative care. Injectable compositions release the drug in the blood stream directly and can provide a quick onset of action and increased duration depending on the infusion time. This would significantly enhance the patient comfort in a post-operative care setting.
The present invention addresses this specific unmet need by providing an aqueous injectable composition of celecoxib or its pharmaceutically acceptable salts thereof, and its application for treatment of acute pain, especially post-operative pain.
OBJECT OF THE INVENTION
An object of the invention is to provide an aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof.
Another object of the invention is to provide an aqueous injectable composition comprising (a) celecoxib or its pharmaceutically acceptable salts thereof and (b) atleast one solubility enhancing agent.
One more object of the invention is to provide a process for preparing an aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof.
A further object of the present invention is to provide safe, efficacious, and easy to use aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide an aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof which is free of polyethylene glycol.
An object of the present invention is to provide a method of treating acute pain by administering a ready-to-dilute aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION
The present invention relates to an aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof. The invention particularly relates to a ready-to-dilute composition comprising celecoxib or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of acute pain, especially post-operative pain.
One embodiment relates to an aqueous injectable composition comprising (a) celecoxib or its pharmaceutically acceptable salts thereof, and (b) atleast one solubility enhancing agent. In another embodiment, the aqueous injectable composition of the present invention comprises greater than 65% w/v of a solubility enhancing agent.
In one embodiment, the aqueous injectable composition of the present invention is free of polyethylene glycol.
In an embodiment, the aqueous injectable composition of the present invention comprises about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 4 % w/v celecoxib or its pharmaceutically acceptable salts thereof. In another preferred embodiment, the aqueous injectable composition of the present invention comprises about 3 % w/v celecoxib or its pharmaceutically acceptable salts thereof. In one more preferred embodiment, the aqueous injectable composition of the present invention comprises about 2 % w/v celecoxib or its pharmaceutically acceptable salts thereof.
In one more embodiment, the aqueous injectable composition of the present invention comprises about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof.
In one more embodiment, the aqueous injectable composition of the present invention comprises about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 100 mg celecoxib or its pharmaceutically acceptable salts thereof. In another preferred embodiment, the aqueous injectable composition of the present invention comprises about 150 mg celecoxib or its pharmaceutically acceptable salts thereof. In a further preferred embodiment, the aqueous injectable composition of the present invention comprises about 200 mg celecoxib or its pharmaceutically acceptable salts thereof.
In a further embodiment, the solubility enhancing agent is selected from pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene, 1-chlorobutane, tetrahydrofuran, 1,4-dioxane, glycerin/glycerol, D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, poloxamer, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, Polyoxyl 40 Hydrogenated castor oil, Polysorbate, Polysorbate 20, Polysorbate 40, Polyoxyl 60 stearate, Polysorbate 85, Polysorbate 60, poloxamer 331, polyoxyethylene fatty acid esters, Polyoxyl 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, Sodium desoxycholate, Sodium lauryl sulfate, Sorbitan monolaurate, polyoxyethylene sorbitan monooleate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan trioleate, N-Carbamoyl methoxypolyethylene glycol 2000-1,2-distearol, myristic acid, Steareth, Stearic acid, Polyoxyl 40 stearate, Sucrose stearate, Tocopherol, polyoxyl castor oil, Triglyceride synthetic, Trimyristin, Tristearin, magnesium stearate, lecithin, lauryl sulfate, Vitamin E, egg yolk phosphatides, docusate sodium, Polysorbate 80, dimyristoyl phosphatidylglycerol, dimyristoyl lecithin, Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate), deoxycholate, cholesterol, Cremophor EL, Propylene glycol alginate, Croval A-10 (PEG 60 almond glycerides), Labrafil 1944 (oleoyl macrogol-6 glycerides), Labrafil 2125 (linoleoyl macrogol-6 glycerides), Labrasol (caprylocaproyl macrogol-8 glycerides), Lauroglycol 90 (propylene glycol monolaurate), Lauroglycol FCC (propylene glycol laurate), calcium stearate, Lecithin Centromix E, Lecithin Centrophase 152, Lecithin Centrol 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3-diisostearate), Plurol Oleique CC, POE 20 Sorbitan trioleate, Tagat TO (polyoxyethylene glycerol trioleate), or Solutol (macrogol-15 hydroxystearate).
In a preferred embodiment, the solubility enhancing agent is selected from polyoxyethylene sorbitan monooleate, propylene glycol, ethanol and polyoxyl-35 castor oil and combinations thereof.
In one embodiment, the aqueous injectable composition of the present invention comprises about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 40% w/v polyoxyethylene sorbitan monooleate.
In one more embodiment, the aqueous injectable composition of the present invention comprises about 1500 mg to about 2500 mg polyoxyethylene sorbitan monooleate. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 2000 mg polyoxyethylene sorbitan monooleate.
In a further embodiment, the aqueous injectable composition of the present invention comprises about 20% w/v to about 40% w/v propylene glycol. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 30% w/v propylene glycol.
In one embodiment, the aqueous injectable composition of the present invention comprises about 1000 mg to about 2000 mg propylene glycol. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 1500 mg propylene glycol.
In an embodiment, the aqueous injectable composition has a volume of about 1ml to about 10 ml, preferably 5 ml.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg to about 2500 mg polyoxyethylene sorbitan monooleate, (c) about 1000 mg to about 2000 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 100 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 150 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 200 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v propylene glycol and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v propylene glycol and (d) water.
In one another embodiment, the aqueous injectable composition of the present invention comprises (a) about 4% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v propylene glycol and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 3% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v propylene glycol and (d) water.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 2% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v propylene glycol and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises about 20% w/v to about 40% w/v ethanol. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 30% w/v ethanol.
In one more embodiment, the aqueous injectable composition of the present invention comprises about 1000 mg to about 2000 mg ethanol. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 1500 mg ethanol.
In a further embodiment, the aqueous injectable composition of the present invention comprises about 30% w/v to about 50% w/v polyoxyl-35 castor oil. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 40% w/v polyoxyl-35 castor oil.
In one embodiment, the aqueous injectable composition of the present invention comprises about 1500 mg to about 2500 mg polyoxyl-35 castor oil. In a preferred embodiment, the aqueous injectable composition of the present invention comprises about 2000 mg polyoxyl-35 castor oil.
In an embodiment, the aqueous injectable composition has a volume of about 1ml to about 10 ml, preferably 5 ml.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1000 mg to about 2000 mg ethanol, (c) about 1500 mg to about 2500 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 100 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 150 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 200 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 20% w/v to about 40% w/v ethanol, (c) about 30% w/v to about 50% w/v polyoxyl-35 castor oil and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 20% w/v to about 40% w/v ethanol, (c) about 30% w/v to about 50% w/v polyoxyl-35 castor oil and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 4% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v ethanol, (c) about 40% w/v polyoxyl-35 castor oil and (d) water.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 3% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v ethanol, (c) about 40% w/v polyoxyl-35 castor oil and (d) water.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 2% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v ethanol, (c) about 40% w/v polyoxyl-35 castor oil and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg to about 2500 mg polyoxyethylene sorbitan monooleate, (c) about 1000 mg to about 2000 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 100 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 150 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 200 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v ethanol and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v ethanol and (d) water.
In one another embodiment, the aqueous injectable composition of the present invention comprises (a) about 4% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v ethanol and (d) water.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 3% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v ethanol and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 2% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v ethanol and (d) water.
An embodiment of the present invention relates to treatment of acute pain by the aqueous injectable composition of the present invention. A further embodiment relates to use of the aqueous injectable composition of the present invention for the treatment of acute pain.
Other objects, features and advantages of the present invention will be apparent to those of ordinary skill in the art in view of the following detailed description of the invention and accompanying drawings.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an aqueous injectable composition comprising celecoxib or its pharmaceutically acceptable salts thereof. The invention particularly relates to a ready-to-dilute composition comprising celecoxib or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients, process of preparing the composition and its use in the treatment of acute pain, especially post-operative pain.
Acute pain is a physiological result of stimulation of both the somatic and visceral pain pathway and is a significant problem for inpatients and can occur secondary to acute illness or disease processes, trauma, or operative procedures. As a result, inflammatory mediators are major players in acute postoperative pain, and management needs to be approached in a multimodal fashion. Opioids have their own limitations and hence the American Society of Anesthesiologists recommends that patients should receive an around-the-clock regimen of NSAIDs, COX inhibitors, or acetaminophen as part of a postoperative multimodal pain management regimen. Cox-2 inhibitors have been shown to be better than NSAIDs because of their higher specificity and lower side effects. Among Cox-2 inhibitors, Celecoxib is a widely used Cox-2 inhibitor for the management of acute pain. Currently, celecoxib is available only in an oral capsule dosage form Celebrex® in the United States. Oral dosage forms have their limitation in delayed onset of action and limited duration of action. Post-operative pain management demands a quick onset of action and increased duration of effect. The present invention fulfils this unmet need by providing an injectable composition which release the drug in the blood stream directly and can provide a quick onset of action and increased duration depending on the infusion time. This would significantly enhance the patient comfort in a post-operative care setting.
Celecoxib is designated chemically as 4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide and is a diaryl-substituted pyrazole with a molecular formula C17H14F3N3O2S and molecular weight 381.38. The chemical formula is given below:

Celecoxib is hydrophobic (log P is 3.5) and is practically insoluble in aqueous media at physiological pH range. Owing to the low water solubility, it is very difficult to formulate an aqueous injectable composition of celecoxib and yet demonstrating physical and chemical stability throughout the shelf life.
The inventors of the present invention have done rigorous experimentation to choose the components of the injectable composition so as to solubilize the celecoxib and providing physical and chemical stability throughout the shelf life of the composition.
It is well known that polyethylene glycol when administered in an injection dosage form can cause toxicity and also adverse effects like hypersensitivity and irritation at the injection site. Hence, an injectable composition which is devoid of polyethylene glycol is desirable. However, owing to the significant solubilizing potential of polyethylene glycol coupled with the low solubility of celecoxib, it is very difficult to formulate an aqueous injectable composition without polyethylene glycol. The inventors of the present invention have provided an aqueous injectable composition of celecoxib wherein the composition is free of polyethylene glycol.
The aqueous injectable composition of the present invention comprises celecoxib or its pharmaceutically acceptable salt thereof along with excipients. In one embodiment, the aqueous injectable composition of the present invention is free of polyethylene glycol. The term “celecoxib” as used herein includes celecoxib or its pharmaceutically acceptable salts which are well known in the art and also embrace any polymorph, pseudo-polymorph, solvate, hydrate, crystalline or amorphous form of celecoxib and any prodrug of celecoxib which can be delivered in a vehicle and manner described herein for celecoxib. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the pharmaceutically active substance, having a freebase function, with a suitable organic acid or inorganic acid.
The particle size is a critical attribute for improving the solubilization of celecoxib. The particle size of celecoxib as per the present invention may have a D90 about 10 µm to about 200 µm, preferably from about 15 µm to about 100 µm. In some embodiments, the particle size of celecoxib or its pharmaceutically acceptable salt thereof may have a D90 of at least about 10 µm, 20 µm, 30 µm, 40 µm, 50 µm, and 60 µm. The aqueous injectable composition of the present invention may comprise about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg celecoxib or its pharmaceutically acceptable salts thereof. In some embodiments, the composition contains about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salt thereof, more preferably about 100 mg to about 200 mg. In a specific embodiment, the composition contains about 100 mg celecoxib or a pharmaceutically acceptable salt thereof. In another specific embodiment, the composition contains about 150 mg celecoxib or a pharmaceutically acceptable salt thereof. In a more specific embodiment, the composition contains about 200 mg celecoxib or a pharmaceutically acceptable salt thereof. In some embodiments, the composition contains about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salt thereof. In another embodiments, the composition contains about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salt thereof. In a preferred embodiment, the composition contains about 4% w/v celecoxib or its pharmaceutically acceptable salt thereof. In another preferred embodiment, the composition contains about 3% w/v celecoxib or its pharmaceutically acceptable salt thereof. In one more preferred embodiment, the composition contains about 2% w/v celecoxib or its pharmaceutically acceptable salt thereof.
The following description sets forth exemplary embodiments of the present technology. It should be recognized, however, that such description is not intended as a limitation on the scope of the present disclosure but is instead provided as a description of exemplary embodiments.
As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used indicates otherwise.
Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. Also, to the term “about X” includes description of “X”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.
The aqueous injectable composition of the present invention comprises (a) celecoxib or its pharmaceutically acceptable salts thereof, and (b) atleast one solubility enhancing agent. In one embodiment, the aqueous injectable composition of the present invention is free of polyethylene glycol.
The aqueous injectable composition of the present invention comprises a solubility enhancing agent in an amount to solubilize celecoxib in the aqueous composition and also to impart physical and chemical stability to the composition throughout the shelf life of the composition.
Suitable examples of the solubility enhancing agent, include, but are not limited to pentane, 2-methylbutane (isopentane), heptane, hexane, cyclopentane and cyclohexane, methanol, ethanol, 2-methoxyethanol, isopropanol, n-butanol, t-butyl alcohol, octanol, ethyl acetate, 2-methoxyethyl acetate, butyl acetate, benzyl benzoate, benzene, toluene, pyridine, xylene, diethyl ether, 2-ethoxyethyl ether, ethylene glycol dimethyl ether, methyl t-butyl ether, formaldehyde, glutaraldehyde, acetone, 3-pentanone (diethyl ketone), ethylene glycol, propylene glycol, formic acid, acetic acid, trifluoroacetic acid, phosphoric acid, acetic anhydride, piperidine, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfoxide (DMSO), benzonitrile, acetonitrile, hydrazine, dichloromethane, chloroform, carbon tetrachloride, 1,2-dichlorobenzene, 1,2-dichloroethane, tetrachloroethylene, 1-chlorobutane, tetrahydrofuran, 1,4-dioxane, glycerin/glycerol, D-a-Tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS), polysorbate or polyethoxylated castor oil, Polyoxyl 20 stearate, Polyoxyl 35 castor oil, poloxamer, polyoxyethylene sorbitan monoisostearate, polyethylene glycol 40 sorbitan diisostearate, Polyoxyl 40 Hydrogenated castor oil, Polysorbate, Polysorbate 20, Polysorbate 40, Polyoxyl 60 stearate, Polysorbate 85, Polysorbate 60, poloxamer 331, polyoxyethylene fatty acid esters, Polyoxyl 40 castor oil, poloxamer 188, polyoxyethylene polyoxypropylene 1800, oleic acid, Sodium desoxycholate, Sodium lauryl sulfate, Sorbitan monolaurate, polyoxyethylene sorbitan monooleate, Sorbitan monooleate, Sorbitan monopalmitate, Sorbitan trioleate, N-Carbamoyl methoxypolyethylene glycol 2000-1,2-distearol, myristic acid, Steareth, Stearic acid, Polyoxyl 40 stearate, Sucrose stearate, Tocopherol, polyoxyl castor oil, Triglyceride synthetic, Trimyristin, Tristearin, magnesium stearate, lecithin, lauryl sulfate, Vitamin E, egg yolk phosphatides, docusate sodium, Polysorbate 80, dimyristoyl phosphatidylglycerol, dimyristoyl lecithin, Capryol 90 (propylene glycol monocaprylate), Capryol PGMC (propylene glycol monocaprylate), deoxycholate, cholesterol, Cremophor EL, Propylene glycol alginate, Croval A-10 (PEG 60 almond glycerides), Labrafil 1944 (oleoyl macrogol-6 glycerides), Labrafil 2125 (linoleoyl macrogol-6 glycerides), Labrasol (caprylocaproyl macrogol-8 glycerides), Lauroglycol 90 (propylene glycol monolaurate), Lauroglycol FCC (propylene glycol laurate), calcium stearate, Lecithin Centromix E, Lecithin Centrophase 152, Lecithin Centrol 3F21B, POE 26 glycerin, Olepal isosteariques (PEG-6 isostearate), Plurol diisostearique (polyglycerol-3-diisostearate), Plurol Oleique CC, POE 20 Sorbitan trioleate, Tagat TO (polyoxyethylene glycerol trioleate), or Solutol (macrogol-15 hydroxystearate).
The present invention relates to an aqueous injectable composition of celecoxib or its pharmaceutically acceptable salt thereof, wherein the composition contains atleast about 65% w/v of a solubility enhancing agent. The inventors have done rigorous experimentation to find out that the concentration of solubility enhancing agent is critical to maintain the stability of the composition of the present invention.
The below table represents the effect of concentration of solubility enhancing agents on the physical stability of the compositions.
Ingredient Quantity in % w/v
Celecoxib 2 2 2 2 2 2 2 3 3 3 3 3
Ethanol 30 40 30 30 40 30 40 30 30 30 30 45
Polyoxyethylene sorbitan monooleate (Tween 80) 10 10 20 35 30 40 40 20 35 40 45 40
Water for injection 58 48 48 48 28 28 18 47 32 27 22 17
pH - - 6.80 6.80 7.40 7.56 7.83 6.25 6.90 7.63 7.84 7.93
Physical stability Ppt Ppt Ppt Clear Clear Clear Clear Ppt Clear Clear Clear Clear
Conc. of solubility enhancing agents 40 50 50 65 70 70 80 50 65 70 75 85
Ppt= Precipitation observed
It can be seen from the above table that compositions containing atleast 65% w/v of solubility enhancing agents are seen to be physically stable whereas the compositions containing solubility enhancing agents below 65% w/v showed precipitation immediately after formulation of the compositions.
In a preferred embodiment, the solubility enhancing agent is selected from polyoxyethylene sorbitan monooleate, propylene glycol, ethanol and polyoxyl-35 castor oil and combinations thereof.
The present invention relates to an aqueous injectable composition of celecoxib or its pharmaceutically acceptable salt thereof, wherein the solubility enhancing agent is polyoxyethylene sorbitan monooleate. In one embodiment, the aqueous injectable composition comprises about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate. In a preferred embodiment, the aqueous injectable composition comprises about 40% w/v polyoxyethylene sorbitan monooleate. In one more embodiment, the aqueous injectable composition comprises about 1500 mg to about 2500 mg polyoxyethylene sorbitan monooleate. In a preferred embodiment, the aqueous injectable composition comprises about 2000 mg polyoxyethylene sorbitan monooleate.
The present invention relates to an aqueous injectable composition of celecoxib or its pharmaceutically acceptable salt thereof, wherein the solubility enhancing agent is propylene glycol. In one embodiment, the aqueous injectable composition comprises about 20% w/v to about 40% w/v propylene glycol. In a preferred embodiment, the aqueous injectable composition comprises about 30% w/v propylene glycol. In one more embodiment, the aqueous injectable composition comprises about 1000 mg to about 2000 mg propylene glycol. In a preferred embodiment, the aqueous injectable composition comprises about 1500 mg propylene glycol.
The present invention relates to an aqueous injectable composition of celecoxib or its pharmaceutically acceptable salt thereof, wherein the solubility enhancing agent is ethanol. In one embodiment, the aqueous injectable composition comprises about 20% w/v to about 40% w/v ethanol. In a preferred embodiment, the aqueous injectable composition comprises about 30% w/v ethanol. In one more embodiment, the aqueous injectable composition comprises about 1000 mg to about 2000 mg ethanol. In a preferred embodiment, the aqueous injectable composition comprises about 1500 mg ethanol.
The present invention relates to an aqueous injectable composition of celecoxib or its pharmaceutically acceptable salt thereof, wherein the solubility enhancing agent is polyoxyl-35 castor oil. In one embodiment, the aqueous injectable composition comprises about 30% w/v to about 50% w/v polyoxyl-35 castor oil. In a preferred embodiment, the aqueous injectable composition comprises about 40% w/v polyoxyl-35 castor oil. In one more embodiment, the aqueous injectable composition comprises about 1500 mg to about 2500 mg polyoxyl-35 castor oil. In a preferred embodiment, the aqueous injectable composition comprises about 2000 mg polyoxyl-35 castor oil.
The aqueous injectable composition of the present invention has a volume of about 1ml to about 10 ml, preferably about 5 ml.
The present invention relates to an aqueous injectable composition comprising (a) celecoxib or its pharmaceutically acceptable salts thereof, and (b) atleast one solubility enhancing agent. The inventors of the present invention have done rigorous experimentation to select the quantities of the solubility enhancing agent such that celecoxib is solubilized in the aqueous injectable composition and also imparts physical and chemical stability to the composition throughout its shelf life. The inventors have specifically found that a concentration of atleast about 65% w/v solubilizing agent is critical to solubilize the celecoxib as well as critical for maintaining the physical as well as chemical stability of the aqueous injectable composition as per the present invention.
The aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg to about 2500 mg polyoxyethylene sorbitan monooleate, (c) about 1000 mg to about 2000 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 100 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 150 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 200 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg propylene glycol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v propylene glycol and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v propylene glycol and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 4% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v propylene glycol and (d) water.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 3% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v propylene glycol and (d) water.
In another embodiment, the aqueous injectable composition of the present invention comprises (a) about 2% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v propylene glycol and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1000 mg to about 2000 mg ethanol, (c) about 1500 mg to about 2500 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 100 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 150 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 200 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg ethanol, (c) about 2000 mg polyoxyl-35 castor oil and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 20% w/v to about 40% w/v ethanol, (c) about 30% w/v to about 50% w/v polyoxyl-35 castor oil and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 20% w/v to about 40% w/v ethanol, (c) about 30% w/v to about 50% w/v polyoxyl-35 castor oil and (d) water.
In one embodiment, the aqueous injectable composition of the present invention comprises (a) about 4% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v ethanol, (c) about 40% w/v polyoxyl-35 castor oil and (d) water.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 3% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v ethanol, (c) about 40% w/v polyoxyl-35 castor oil and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 2% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v ethanol, (c) about 40% w/v polyoxyl-35 castor oil and (d) water.
The aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 1500 mg to about 2500 mg polyoxyethylene sorbitan monooleate, (c) about 1000 mg to about 2000 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 50 mg to about 300 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 100 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In another embodiment, the aqueous injectable composition of the present invention comprises (a) about 150 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In a further embodiment, the aqueous injectable composition of the present invention comprises (a) about 200 mg celecoxib or its pharmaceutically acceptable salts thereof, (b) about 2000 mg polyoxyethylene sorbitan monooleate, (c) about 1500 mg ethanol and (d) water. In a preferred embodiment, the aqueous injectable composition has a volume of about 5 ml.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v ethanol and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v ethanol and (d) water.
In one another embodiment, the aqueous injectable composition of the present invention comprises (a) about 4% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v ethanol and (d) water.
In one more embodiment, the aqueous injectable composition of the present invention comprises (a) about 3% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v ethanol and (d) water.
In an embodiment, the aqueous injectable composition of the present invention comprises (a) about 2% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 40% w/v polyoxyethylene sorbitan monooleate, (c) about 30% w/v ethanol and (d) water.
The term "stable" refers to an aqueous injectable composition of the present invention which is physically as well as chemically stable as demonstrated by compliance to acceptable specification when the composition is stored at convenient temperature, such as between about 0°C and about 60°C, for a commercially reasonable period of time, such as at least about 1 day, at least about 1 week, at least about 1 month, at least about 3 months, at least about 6 months, at least about 1 year, or at least about 2 years. The term “stable” also refers to an injectable composition as per the present invention which exhibits physical stability for a sufficiently long time to allow for infusion of the product upon dilution with compatible admixture diluent such as sterile water for injection, saline or dextrose. The aqueous injectable compositions of the present invention remain stable after dilution with a compatible admixture diluent for a sufficient time to allow for infusion to be completed. Suitably, the aqueous injectable composition of celecoxib of the present invention remains physically stable, with no precipitation or crystallization or color change upon storage and the shelf life period of 18-24 months. Suitably, aqueous injectable composition of celecoxib remains chemically stable, wherein various parameters such as the drug content (assay of celecoxib) and content of related substances, i.e. known and unknown impurities remains within specified limits such as those specified according to ICH guidelines, upon storage for a prolonged period of time such as at least 12 months, preferably 18 months, more preferably 24 months or longer.
The aqueous injectable composition of the present invention is substantially free of impurities. For purposes of the present invention, "substantially free of impurities' shall be understood to include celecoxib containing aqueous injectable compositions in which the amount of total impurities is less than about 5% of the sum of peak areas of all degradants, as calculated on a normalized peak area response ("PAR) basis as determined by high performance liquid chromatograph ("HPLC) after a period of about 18 months at a temperature of from about 2° C to about 8° C and at 25°C. The amount of impurities is further calculated as being based upon the original amount of celecoxib being present in the composition. Preferably, the said aqueous injectable compositions of celecoxib prevent degradation of celecoxib such that not more than 2 % , not more than 1%, not more than 0.4%, not more than 0.2% of celecoxib impurity or impurities are formed over the storage period. In yet another preferred embodiment the value of assay of celecoxib remains within the specified limit of 90-110% by weight of the label claim.
The ICH storage stability studies were performed on the aqueous injectable composition of the present invention packaged in the proposed commercial primary packaging and closure system. The stability study samples were stored at 2-8°C, 25°C, 30°C, and 40°C. The necessary parameters viz., assay, related substances, particle size distribution, pH, and osmolality were tested and found to be within specification at both stability conditions. In some preferred aspects of the invention, the time for which long term storage is contemplated include periods of at least about 24 months or longer with such that the composition is substantially free of impurities.
The present invention also relates to a process of preparing aqueous injectable composition of celecoxib or its pharmaceutically acceptable salts thereof, a process comprising (i) Dissolving celecoxib or its pharmaceutically acceptable salt thereof in atleast one solubility enhancing agent to obtain a clear solution, (ii) adjusting volume with water for injection, (iii) filtering the solution of step (ii) through 0.22 micron filter and (iv) filling solution of step (iii) in appropriate container.
Preferably, the process of preparation of the aqueous injectable composition of the present invention is carried out under nitrogen purging or blanketing. The aqueous injectable composition of the present invention may be sterilized under aseptic conditions well known in the art, preferably sterilization by filtration.
The aqueous injectable compositions of the present invention can be packaged in any suitable sterile vial or prefilled syringe or container fit for the sterile storage of pharmaceuticals. The aqueous injectable composition of the present invention can be provided in a kit or package that includes a container enclosing the composition. Suitable containers can be glass vials, i.e. Schott treated vials, molded glass vials, and CZ resin vials, polypropylene or polyethylene vials or other special purpose containers. Suitable containers can be prefilled syringe such as glass prefilled syringes, plastic prefilled syringes. Containers are of a size sufficient to hold one or more doses of celecoxib. The container may be part of a syringe or separate from the syringe. The kit or package also includes a needle that can be suitably mounted to the syringe. The size of the needle, in some embodiments, is equal to or smaller than 18G, 19G, 20G, 21G, 22G, 23G, 24G, or 25G. In one embodiment, the needle has a size that is 20G or smaller. In one embodiment, the needle has a size that is 21G or smaller. In one embodiment, the needle has a size that is 22G or smaller. In one embodiment, the needle has a size that is 23G or smaller. In one embodiment, the aqueous injectable composition of the present invention may be administered without the need of an in-line filter during administration, demonstrating the absence of particulate matter throughout its shelf life. In another embodiment, the aqueous injectable composition of the present invention may be filtered by using an in-line filter before administration.
The present invention provides a method of treating acute pain by the aqueous injectable composition of the present invention. A further embodiment relates to the use of the aqueous injectable composition of the present invention for the treatment of acute pain. As used herein the term “acute pain” shall refer to all types of pain such as, post-operative pain, acute lower back pain, opioid-resistant pain, visceral pain, breakthrough pain, surgical pain, bone injury pain, pain during labor and delivery, pain resulting from burns, including sunburn, post-partum pain, and genitourinary tract related pain including cystitis, the term shall also refer to nociceptive pain or nociception.
Examples
The following examples are for the purpose of illustration of the invention only and
are not intended to limit the scope of the present invention in any manner whatsoever.

Example 1:
Ingredients Quantity in mg/vial Quantity in %w/v
Celecoxib 200 4
Polyoxyethylene sorbitan monooleate 2000 40
Propylene glycol 1500 30
Water for injection q.s. 5ml q.s.100%

Manufacturing process:
1. Celecoxib was dissolved in a mixture of Polyoxyethylene sorbitan monooleate and propylene glycol till a clear solution was obtained.
2. Volume was made up with water for injection.
3. Filter the solution of step 2 using 0.22 micron filter.
4. Fill the solution of step 3 in vials.

Example 2:
Ingredients Quantity in mg/vial Quantity in %w/v
Celecoxib 200 4
Polyoxyl-35 castor oil 2000 40
Ethanol 1500 30
Water for injection q.s. 5ml q.s.100%

Manufacturing process:
1. Celecoxib was dissolved in a mixture of ethanol and Polyoxyl-35 castor oil till a clear solution was obtained.
2. Volume was made up with water for injection.
3. Filter the solution of step 2 using 0.22 micron filter.
4. Fill the solution of step 3 in vials.

The composition of Example 2 was subjected to stability studies at conditions laid down by ICH guidelines and the below data represents the results observed.

Test Condition 2-8° C 25°C/60%RH 40°C/75%RH
Initial 3M 6M 3M 6M 3M 6M
Description Clear colorless solution
pH 7.89 Not performed
Colour index
(AU) NP 0.023 NP 0.036 NP 0.033 NP
Assay
(%) 98.8 99.8 97.3 99.3 97.9 97.5 96.9
Related Substances
Celecoxib Impurity-D(%) ND ND ND ND ND ND ND
Desoxyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Celecoxib Impurity-4 (%) ND ND 0.01 ND 0.006 ND 0.005
2-Methyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Celecoxib Related comp-A(%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
Celecoxib Related Comp-B(%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
2,4-DiMethyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Single max. impurity (%) <0.1 0.009 0.013 0.013 0.016 <0.1 <0.1
Total Impurity (%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
ND- Not detected; NP: Not performed

Example 3:
Ingredients Quantity in mg/vial Quantity in %w/v
Celecoxib 200 4
Polyoxyethylene sorbitan monooleate 2000 40
Ethanol 1500 30
Water for injection q.s. 5ml q.s.100%

Manufacturing process:
1. Celecoxib was dissolved in a mixture of Polyoxyethylene sorbitan monooleate and ethanol till a clear solution was obtained.
2. Volume was made up with water for injection.
3. Filter the solution of step 2 using 0.22 micron filter.
4. Fill the solution of step 3 in vials.

The composition of Example 3 was subjected to stability studies at conditions laid down by ICH guidelines and the below data represents the results observed.
Test Condition 2-8° C 25°C/60%RH 40°C/75%RH
Initial 3M 6M 3M 6M 3M 6M
Description Clear pale yellow solution
pH 7.52 7.41 7.30 7.43 7.49 7.43 7.45
Colour index
(AU) 0.242 0.219 0.198 0.215 0.204 0.228 0.213
Assay
(%) 95.3 95.2 95.0 95.4 95.5 96.2 94.5
Related Substances
Celecoxib Impurity-D(%) ND ND ND ND ND ND ND
Desoxyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Celecoxib Impurity-4(%) ND ND ND ND ND ND ND
2-Methyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Celecoxib Related comp-A(%) <0.1 <0.1 0.035 <0.1 0.033 <0.1 0.038
Celecoxib Related Comp-B(%) ND <0.1 0.036 <0.1 0.05 <0.1 0.037
2,4-DiMethyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Total Impurity (%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
ND- Not detected; NP: Not performed

Example 4:
Ingredients Quantity in mg/vial Quantity in %w/v
Celecoxib 150 3
Polyoxyethylene sorbitan monooleate 2000 40
Ethanol 1500 30
Water for injection q.s. 5ml q.s.100%

Manufacturing process:
1. Celecoxib was dissolved in a mixture of Polyoxyethylene sorbitan monooleate and ethanol till a clear solution was obtained.
2. Volume was made up with water for injection.
3. Filter the solution of step 2 using 0.22 micron filter.
4. Fill the solution of step 3 in vials.

The composition of Example 4 was subjected to stability studies at conditions laid down by ICH guidelines and the below data represents the results observed.
Test Condition 2-8° C 25°C/60%RH 40°C/75%RH
Initial 1 M 3M 1M 3M 1M 3M
pH 7.47 6.81 7.63 6.5 6.64 6.53 7.36
Colour index
(AU) 0.169 NP 0.181 NP 0.213 NP 0.216
Assay
(%) 100.1 99.1 96.3 98.1 96.6 97.4 95.7
Related substances
Celecoxib Impurity-D(%) ND ND ND ND ND ND ND
Desoxyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Celecoxib Impurity-4(%) ND ND ND ND ND ND ND
2-Methyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Celecoxib Related comp-A(%) <0.1 <0.1 0.034 <0.1 0.031 <0.1 0.035
Celecoxib Related Comp-B(%) <0.1 ND 0.059 ND 0.029 ND 0.059
2,4-DiMethyl Celecoxib Impurity(%) ND ND ND ND ND ND ND
Single maximum impurity (%) - - - - - - 0.009
Total Impurity (%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
ND- Not detected; NP: Not performed

Example 5:
Ingredients Quantity in mg/vial Quantity in %w/v
Celecoxib 100 2
Polyoxyethylene sorbitan monooleate 2000 40
Ethanol 1500 30
Water for injection q.s. 5ml q.s.100%

Manufacturing process:
1. Celecoxib was dissolved in a mixture of Polyoxyethylene sorbitan monooleate and ethanol till a clear solution was obtained.
2. Volume was made up with water for injection.
3. Filter the solution of step 2 using 0.22 micron filter.
4. Fill the solution of step 3 in vials.

The composition of Example 5 was subjected to stability studies at conditions laid down by ICH guidelines and the below data represents the results observed.
Test Condition 2-8° C 25°C/60%RH 40°C/75%RH
Initial 1 M 3M 1M 3M 1M 3M
Description Clear pale-yellow solution
pH 6.06 6.86 6.54 6.84 6.49 6.78 6.33
Colour index
(AU) 0.028 NP 0.003 NP 0.006 NP 0.016
Assay
(%) 95.5 95.0 95.5 94.7 95.80 94.6 94.9
Related substances
Celecoxib Impurity-D% ND ND ND ND ND ND ND
Desoxyl Celecoxib Impurity% ND ND ND ND ND ND ND
Celecoxib Impurity-4(%) ND ND ND ND ND ND ND
2-Methyl Celecoxib Impurity% ND ND ND ND ND ND ND
Celecoxib Related comp-A% <0.1 <0.1 0.041 <0.1 0.043 <0.1 0.047
Celecoxib Related Comp-B% ND 0.009 0.019 0.018 0.023 ND 0.021
2,4-DiMethyl Celecoxib Impurity % ND ND ND ND ND ND ND
Single maximum impurity % ND ND ND ND ND ND ND
Total Impurity (%) <0.1 <0.1 <0.1 <0.1 <0.1 <0.1 <0.1
ND- Not detected; NP: Not performed

Although the invention herein has been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.
,CLAIMS:1. An aqueous injectable composition comprising (a) celecoxib or its pharmaceutically acceptable salts thereof, and (b) atleast one solubility enhancing agent, wherein the composition comprises greater than about 65% w/v of a solubility enhancing agent.
2. The injectable composition according to claim 1, wherein the composition comprises about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof.
3. The injectable composition according to claim 1, wherein the composition comprises about 0.1% w/v to about 1% w/v celecoxib or its pharmaceutically acceptable salts thereof.
4. The injectable composition according to claim 1, wherein the composition comprises about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate.
5. The injectable composition according to claim 1, wherein the composition comprises about 20% w/v to about 40% w/v propylene glycol.
6. The injectable composition according to claim 1, wherein the composition comprises about 20% w/v to about 40% w/v ethanol.
7. The injectable composition according to claim 1, wherein the composition comprises about 30% w/v to about 50% w/v polyoxyl-35 castor oil.
8. The injectable composition according to claim 1, wherein the composition has a volume of about 1 ml to about 10 ml.
9. The injectable composition according to claim 1, comprising (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v propylene glycol and (d) water.
10. The injectable composition according to claim 1, comprising (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 20% w/v to about 40% w/v ethanol, (c) about 30% w/v to about 50% w/v polyoxyl-35 castor oil and (d) water.
11. The injectable composition according to claim 1, comprising (a) about 1% w/v to about 8% w/v celecoxib or its pharmaceutically acceptable salts thereof, (b) about 30% w/v to about 50% w/v polyoxyethylene sorbitan monooleate, (c) about 20% w/v to about 40% w/v ethanol and (d) water.
12. The injectable composition according to claim 1, wherein the composition is free of polyethylene glycol.