PHARMACEUTICAL COMPOSITION OF CYCLOOXYGENASE - 2 INHIBITORS

Abstract

Present invention relates to aqueous compositions comprising cyclooxygenase-2 (COX-2) inhibitors, preferably Etoricoxib or Celecoxib or Valdecoxib or Paracoxib or salts thereof at least two solubilizers at 4.2% w/v to 19% w/v, preferably between 4.2% w/v to 18% w/v having viscosity in range of 1.0 cps to 3 cps, wherein the Etoricoxib and Celecoxib or salts thereof are present in amount ranging from 0.14 mg to 4 mg. The composition is suitable for the parenteral route of administration primarily for ready to dilute and ready to infuse which alternatively can be administered as intramuscular, intraarterial, intraocular, intraventricular, intravenous routes; also for subcutaneous, cutaneous delivery. The invention further provides a method for preparing the said composition.

Claims

1. A stable, clear aqueous composition of COX 2 inhibitors or salts thereof comprising 1.4 mg to 4.0 mg/ml of COX 2 inhibitor, having viscosity in range of 1.0 cps to 3 cps, at least two solubilizers between 4.2% w/v to 19% w/v, and at least one excipient selected from a solvent/cosolvent, a surfactant, a preservative, an antioxidants, a buffer, and a tonicity modifier.

2. The composition as claimed in claim 1 wherein the COX 2 inhibitor is Etoricoxib, Celecoxib, Valdecoxib, or Parecoxib.

3. The composition as claimed in claim 1 wherein at least two solubilizers are selected from solid solubilizers, or liquid solubilizers, or mixtures thereof.

4. The composition as claimed in claim 3 wherein the solid solubilizer is selected from Cyclodextrins (CDs), preferably hydroxy propyl beta cyclodextrin (HP-β-CD or HPBCD), sulfobutyl ether beta cyclodextrin (SBE-β-CD), and mixtures thereof.

5. The composition as claimed in claim 4, where the cyclodextrin is hydroxypropylbetacyclodextrin (HPBCD).

6. The composition as claimed in claim 3 wherein the liquid solubilizer is selected from monohydric alcohols, polyhydric alcohols and ethers, esters, Transcutol, Glycofurol, Tweens, and mixtures thereof.

7. The composition as claimed in claim 1 wherein at least two solubilizers are selected from Hydroxyalkyl beta cyclodextrin such as HPBCD, sulfobutyl ether beta cyclodextrin, Transcutol, Ethyl Alcohol, Benzyl Alcohol, Glycerin, Tween, Transcutol, Glycofurol, propylene glycol, and polyethylene glycol.

8. The composition as claimed in claim 1 where in at least two solubilizers are Ethanol and Tween, or Ethanol and Transcutol, or Transcutol and Tween, or HPBCD and Transcutol, or HPBCD and Glycofurol, or HPBCD and benzyl alcohol.

9. The composition as claimed in claim 8 wherein ratio of HPBCD to Transcutol is from 20:1 to 1:1.

10. The composition as claimed in claim 1 wherein the ratio of COX 2 inhibitor to solubilizers is between 1:27.5 to 1:135.71, preferably between 1:27:5 to 1:58.33.

11. The composition as claimed in claim 10 wherein the COX 2 inhibitor is Celecoxib or Etoricoxib.

12. The composition as claimed in claim 11 comprising up to 0.4% Celecoxib or Etoricoxib up to 0.14%.

13. The composition as claimed in claim 3 wherein ratio of solid to liquid solubilizers is between 1:1 to 21.4, preferably 1:20:1.

14. The composition as claimed in claim 1 wherein a solubilizer is Transcutol and the COX 2 inhibitor to Transcutol ratio is between 1:1.66 to 1:25.

15. The composition as claimed in claim 1 wherein solubilizers are present from 4.2% w/v to 19% w/v, preferably from 4.2% w/v to 18% w/v.

16. The composition as claimed in claim 1 wherein a solubilizer is HPBCD and the ratio of COX 2 inhibitor to HPBCD is 1:25 to 1:33.33.

17. The composition as claimed in claim 1 wherein the surfactant is selected from Polysorbates/Tweens, sorbitan mono laurate, lecithin, povidone, and other pharmaceutically acceptable surfactants which may be employed either individually or in combination.

18. The composition as claimed in claim 1 wherein the antioxidant is selected from thioglycerol, acetyl cysteine, butylated hydroxy anisole (BHA) and butylated hydroxy toluene (BHT), ascorbates, ascorbyl palmitate, methyl paraben, propyl paraben, thiomerosal, and mixed Tocopheryl ingredient.

19. The composition as claimed in claim 1 wherein the preservative is selected from benzalkonium chloride, benzyl alcohol, m-cresol, parabens, phenols, thiomerosal. In another embodiment the composition of present invention may also comprise the stabilizers such as polysorbate 80, 1-cysteine, diethanolamine, 1-methionine, sodium gluconate, sodium thioglycolate, triethanolamine, and oleic acid.

20. The composition as claimed in claim 1 wherein the buffer is selected from sodium, potassium or ammonium salt of a weak acid, a tris-(hydroxymethyl)-aminomethane, or Sodium citrate, Sodium phosphate, Sodium Hydroxide, Tris base-65, Tris acetate, Tris HCl-65 or commonly known acetates, citrates, phosphates or a further physiologically active material acting as a buffer such as sodium hydroxide, hydrochloric acid, boric acid, citric acid, acetic acid, phosphoric acid, succinic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, and any combination thereof.

21. The composition as claimed in claim 1 wherein the tonicity modifier is selected from sodium chloride and dextrose anhydrous, Glycerin, Mannitol, and Potassium Chloride, and mixtures thereof.

22. A composition comprising Etoricoxib up to 1.4 mg/ml, having viscosity in range of 1.0 cps to 3 cps, at least two solubilizers between 4.2% w/v to 19% w/v, preferably between 4.2% w/v to 18% w/v, and at least one excipient selected from a solvent/cosolvent, a surfactant, a preservative, an antioxidants, a buffer, and a tonicity modifier.

23. A composition comprising Celecoxib up to 4 mg/ml, having viscosity in range of 1.0 cps to 3 cps, at least two solubilizers between 4.2% w/v to 19% w/v, preferably between 4.2% w/v to 18% w/v, and at least one excipient selected from a solvent/cosolvent, a surfactant, a preservative, an antioxidants, a buffer, and tonicity modifier.

24. The composition as claimed in claim 1 wherein the COX 2 inhibitor is Etoricoxib or Celecoxib and at least one of the solubilizers is Transcutol or Glycofurol or HPBCD.

25. The composition as claimed in claim 1 presented in dosage form for parenteral, topical, oral or any other route of administration.

26. The composition as claimed in claim 22 which is devoid of HPBCD.

27. The composition as claimed in claim 22 wherein HPBCD is one of the solubilizers.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0092] The present invention provides a clear, stable parenteral composition comprising a pharmaceutical active selected from group of Etoricoxib or Celecoxib or other selective COX II inhibitors like Rofecoxib, Parecoxib, Valdecoxib, Firocoxib, Lumiracoxib or salts thereof along with the pharmaceutically acceptable excipients. Ingredients used include but not limited to Diethylene Glycol Monoethyl Ether (Transcutol) or alkyl derivatives thereof, various grades of Glycofurol, conventionally used parenteral grade Monothioglycerol, Glycine, Cyclodextrins, EDTA and alike. Present invention is suitable for administration by multiple routes preferably injectable routes.

[0093] The invention provides therapeutically effective amount of Etoricoxib or Celecoxib or other selective COX II inhibitors or salts thereof in an aqueous composition suitable to be administered by multiple routes mainly intramuscular and intravenous and other viz. oral, dermal, subcutaneous, cutaneous, nasal, ocular drops, rectal suppository, vaginal pessaries, intra-articular and otic delivery.

[0094] Composition of the present invention is ready-to-dilute or ready-to-infuse pharmaceutical preparation of selective COX 2 inhibitors such as Etoricoxib or Celecoxib or salts thereof in management of musculoskeletal and joint disorders like rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, hemophilic arthropathy painful condition such as acute gout, dysmenorrhoea and some surgical procedures, post operative pain, acute postoperative pain, for treatment of inflammation after surgery.

[0095] In particular, the invention provides a composition comprising a pharmaceutical active selected from group of Etoricoxib or Celecoxib or other selective COX II inhibitors or salts thereof in amount ranging from 1.2 mg to 4.0 mg/ml suitable for parenteral routes and using the same liquid with suitable modification for use in ocular preparations.

[0096] There is provided a pharmaceutical composition of selective COX 2 inhibitors such as Etoricoxib or Celecoxib or salts thereof, in parenteral form which would be simple and economical.

[0097] There is provided a Stable, clear composition comprising active agent from class of COX 2 inhibitors preferably or salts thereof 1.2 mg to 4.0 mg/ml having lower viscosity in range of 1.0 cps to 3.0 cps.

[0098] There is provided a stable, clear, transparent composition comprising 1.2 to 4 mg/ml of coxib more specifically Celecoxib or Etoricoxib or Parecoxib or Valdecoxib, having a viscosity of 1.0 cps to 3 cps, at least two solubilizers between 4.2% w/v to 18% w/v and at least one excipient selected from solvent/cosolvent, surfactant, preservative, antioxidants, buffer and tonicity modifier.

[0099] As coxibs are poorly soluble or insoluble in water, presence of water has a deterrent effect on its ability to remain in water or to remain stable. Presence of water imparts a tendency to crystallize to coxibs, being poorly soluble. Mixing coxib with pharmaceutically acceptable solvent in presence of water and to stabilize it, is therefore difficult. Either immediately on addition of water or with lapse of time, coxib crystallizes out or it degrades and assay value is lost. Therefore stabilizing a coxib in solution form in aqueous solution is challenge. It was not known in which solvent system huge quantities of coxibs such as 1.2 mg to 4.0 mg/ml can be solubilized and stabilized. Designing a stable composition is therefore a challenge.

[0100] The composition can be conveniently prepared using various solvents, co-solvents, solubilizers, anti-oxidants, buffers, chelating agents, complexing agents, pH modifiers, preservatives, tonicity adjusting agents as may be necessary.

[0101] Terms Solvents, Cosolvents or solubilizer are used interchangeably. These can be solids or liquids. Solids when present in the form of solution in appropriate solvents also act as solubilizers.

[0102] Commonly used solvents such as water, ethanol can be employed to perform the invention. Various types of alcohols can be employed as solubilizers. Alcohols selected from monohydric alcohol or polyhydric alcohols may be employed. An alcohol other than monohydric alcohol is to be interpreted as polyhydric alcohol. Examples of monohydric alcohol are any pharmaceutically acceptable single chain or branched chain alcohol having only one OH group. Suitable examples being ethyl alcohol or benzyl alcohol. Glycerin is example of polyhydric alcohol. There are many other polyhydric alcohols such as polyethylene glycol. Some ether derivatives also act as good solubilizers.

[0103] Solubilizers may be selected from but not limited to Transcutol 2 to 50%, PEG 300 up to 50%, PEG 400 up to 20.30%, Polysorbates or Tweens such as Tween 80. It may also comprise solvents like Sesame oil and Soybean oil. Alcohols such as Ethanol are good solubilizer. In accordance with non-limiting embodiment, the concentration of Diethylene Glycol Monoethyl Ether or alkyl derivatives thereof is present in between 0.2%-5% (v/v). When used in the range of 0.2 v/v to 4% v/v it gives better results. It also gives good results when used in the range of 0.2 v/v to 3% v/v. Transcutol is not known to cause any toxicity related issues including irritancy or pain for a therapeutic applications. The safety profile of Transcutol in humans for its use has been exhaustively studied. Its' LD50 in rat through IV route is 4 g/kg, intraperitoneal: mouse LD50 is 2300 mg/kg, subcutaneous: mouse 5500 μl/kg, intravenous: mouse 4300 μl/kg, LD50; intravenous: Dog 3 ml/kg LD50; intravenous: rabbit 2500 μl/kg, LD50; eyes: rabbit 500 mg. Transcutol occurs as colorless and transparent liquid well miscible with water. In the present invention, it is preferable to use Diethylene Glycol Monoethyl Ether having a purity of 99% or higher, more preferably 99.7% of higher and most preferably 99.9% or higher. The density of Transcutol is 0.988. Transcutol makes composition of the present invention less viscous. It enhances and offers an advantage of better absorption of drug in mammals when injected and hence has better pharmacological effect for the intended purpose.

[0104] Cyclodextrins (CDs) preferably Beta-cyclodextrins and particularly hydroxyalkyl ether derivatives, preferably hydroxy propyl beta cyclodextrin (HP-β-CD) and sulfobutyl ether beta cyclodextrin (SBE-β-CD) are used in the formulation as solubilizers. As having ability to solubilize the drug in the formulation, cyclodextrins are used in the pharmaceutical formulation to improve drug delivery. Hydroxypropyl Betacylodextrin may comprise in concentration up to 5% w/v and Sulphobutylether Betacylodextrin in concentration up to 5% w/v. When used in the range of 3-4% w/v, good results are produced. They have the ability to form the complex with the active drug; hence the drugs are easily dissolved in the formulation which enhances the drug delivery. Prior art by Hanumegowda U M et al. has reported CDs are shown to improve tolerance and/or reduce local toxicity of several compounds. This protection from local toxicities of compounds likely improves overall tolerability. Betacyclodextrin may be selected from other pharmaceutically acceptable betacyclodextrins. It was surprisingly noticed that when Coxibs, more specifically Etoricoxib, Celecoxib or Paracoxib or Valdecoxib were incorporated in the compositions as taught by the present invention in presence of solubilizers and optionally with other pharmaceutical excipients, result into stable composition and they are able to stabilize 1.2 mg to 4 mg of coxib, more specifically 1.2 mg of Etoricoxib or 4 mg of Celecoxib. These coxibs are not soluble in water other wise.

[0105] Hydroxy propyl beta cyclodextrin is same as Hydroxypropyl beta cyclodextrin or Hydroxy propyl betacyclodextrin HP-β-CD or HPBCD or Hydroxyropylbetacyclodextrin.

[0106] Glycofurol of various grades such as Glycofurol 75 may also be used as solvent or co-solvent or solubilizer. Up to 5%, it gives satisfactory results. Tweens such as Tween 80 acts as surfactant or solubilizer.

[0107] The present invention may also comprise antioxidants selected from but not limited to thioglycerol, acetyl cysteine, butylated hydroxy anisole (BHA) and butylated hydroxy toluene (BHT), ascorbates, ascorbyl palmitate, methyl paraben, propyl paraben, thiomerosal and mixed Tocopheryl ingredient. Further, the invention may also comprise additional excipients like preservatives such as benzalkonium chloride, benzyl alcohol, m-cresol, parabens, phenols, thiomerosal. In another embodiment the composition of present invention may also comprise the stabilizers such as polysorbate 80, 1-cysteine, diethanolamine, 1-methionine, sodium gluconate, sodium thioglycolate, triethanolamine and oleic acid. These are to be incorporated as per guidelines allowing their incorporation with respect to quantity and applicable specifications known to persons skilled in the art.

[0108] The isotony of the composition may be obtained by adding a precisely calculated quantity of isotonicity agent or tonicity adjusting agent selected from sodium chloride, dextrose anhydrous, Glycerin, glucose, mannitol, sorbitol, potassium chloride or calcium chloride, the often preferred isotonic agent being sodium chloride. Present invention enables and provides compositions having osmolality from about less than 80 to about 650 mOsm/kg. The solution isotony is between 270 and 330 mOsm/kg, particularly between 280 and 290 mOsm/kg is desirable. Techniques and processes to adjust the isotonicity or osmolality are known in the art and accordingly isotonicity should be adjusted.

[0109] Chelating agent are used in formulation to chelate traces of metallic impurity. Chelating agents that may be used are but not limited to disodium EDTA, sodium EDTA, Calcium disodium EDTA 0.2%, Versetamide 2.54%, Calteridol Calcium 0.023%, also Diethylenetriaminepenta Acetic Acid and ingredients alike can be used as chelating agent.

[0110] Antimicrobial preservatives may be selected from but not limited to Benzethonium Chloride 0.01%, Benzyl Alcohol up to 2%, Benzalkonium Chloride 0.02%, Chlorobutanol 2.5 to 5%, m-Cresol 0.1% to 0.3%, Parabens like methyl paraben, propyl paraben up to 1%, phenol up to 0.45%. Some more excipients like 2-PhenoxyEthanol, Phenyl Mercuric Nitrate, Thiomersal and excipients alike or mixtures thereof. Benzyl alcohol acts as solvent also. Permissible quantities of Chelating agents and Antimicrobial preservatives can be selected from inactive ingredients database or such other source.

[0111] Suitable surfactants such as Polysorbates/Tweens, sorbitan mono laurate, lecithin, povidone or Other pharmaceutically acceptable surfactants may be used either individually or in combination to prepare compositions of the invention.

[0112] A pH close to the physiological one is recommended to minimize pain, irritation, and tissue damage. Buffers optimize solubility and stability by adjusting the pH; however, their strength should be kept as low as possible to avoid pain upon injection.

[0113] Examples of pH adjustment agents or buffers that may be employed include but not limited to sodium, potassium or ammonium salt of a weak acid, a tris-(hydroxymethyl)-aminomethane, or Sodium citrate, Sodium phosphate, Sodium Hydroxide, Tris base-65, Tris acetate, Tris HCl-65 or commonly known acetates, citrates, phosphates or a further physiologically active material acting as a buffer such as sodium hydroxide, hydrochloric acid, boric acid, citric acid, acetic acid, phosphoric acid, succinic acid, potassium hydroxide, ammonium hydroxide, magnesium oxide, calcium carbonate, magnesium carbonate, malic acid, potassium citrate, sodium phosphate, lactic acid, gluconic acid, tartaric acid, fumaric acid, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate, triethanolamine, or any combination thereof. The stable aqueous injectable solution may comprise one or more pH adjusting agents in an amount to provide pH of the solution between about 5 and about 8 preferred being between 5 to 7. Buffers are used in sufficient quantity to maintain appropriate pH value during storage. Chelating agents, antimicrobial agents, pH modifying agents or buffers and surfactants may be employed in permissible quantities as per pharmaceutical guidelines known to persons skilled in the art.

[0114] Surprisingly it was noticed that poorly soluble or water insoluble Coxibs provide stale compositions if ingredients are present in some definite proportions and these proportions are novel and non-obvious.

[0115] Present invention teaches compositions comprising at least two solubilizers between 4.2% w/v to 19% w/v, preferably between 4.2% to 18% w/v.

[0116] It was observed that particular ratios of actives to solubilizers, between different solubilizers play a critical role in preparation of stable parenteral solution of coxibs more specifically Etoricoxib, Celecoxib, Valdecoxib and Paracoxib. The ratio of active to solubilizers between 1:35 to 1:135.71 gives good solubilization of coxib. Satisfactory compositions can be produced wherein ration of active to solubilizer is between 1:35 to 1:58.33. Etoricoxib 1.4 mg ie 0.14% w/v can be solubilized in Twin 80, 8% w/v and Transcutol 3% w/v. It can also be solubilized in Ethanol and Tween 8% w/v each and Transcutol 3% w/v. One can consider it as 3 solubilizers or 2 solubilizers and one solvent.

[0117] In one embodiment Celecoxib stable solution was prepared wherein ratio of Celecoxib to solubilizers was 1:27.5. In another embodiment it was between 1:45 to 1:47.5. Several Etoricoxib compositions were prepared and tested for their physical and quality test parameters. Satisfactory results were obtained when ratio of Etoricoxib to solubilizers was between 1:35 to 1:58.33. In yet another embodiment the ratio of Etoricoxib to solubilizers was between 1:78.57 to 1:135.71. Thus the invention provides stable coxib compositions wherein ratio of active to solubilizers between 1:27.5 to 1:135.71 both included.

[0118] In another embodiment ratio of solid to liquid solubilizers between 1:1 to 20:1 provided a satisfactory composition. Etoricoxib quantity incorporated was 0.12% w/v.

[0119] Coxib to Transcutol ratios between 1:1.66 to 1:25 provided satisfactory compositions. One embodiment comprised of Celecoxib to Transcutol in the ratio of 1:7.5 whereas other embodiments provided satisfactory compositions wherein Etoricoxib to Transcutol ratios were between 1:1.66 to 1:25.

[0120] Embodiments exemplified indicate that solubilizers are present from 4.2 to 19% w/v.

[0121] Some embodiments wherein ratio of Coxib to HPBCD was 1:25 to 1:33.33 it provided satisfactory stable composition. The ratio of HPBCD can be lowered.

[0122] Some embodiments with HPBCD to Transcutol ratio between 1:1 to 20:1 provided satisfactory and stable compositions.

[0123] Present invention provides a stable, clear aqueous composition of COX 2 inhibitors or salts thereof comprising 1.2 mg to 4.0 mg/ml of COX 2 inhibitor, having viscosity in range of 1.0 cps to 3 cps, at least two solubilizers between 4.2% w/v to 19% w/v and at least one excipient selected from solvent/cosolvent, surfactant, preservative, antioxidants, buffer and tonicity modifier.

[0124] Coxib composition means composition as per present invention comprising COX 2 inhibitor such as Celecoxib, Etoricoxib, Valdecoxib or Parecoxib.

[0125] Glycofurol can be used as solubilizer to provide stable solution of coxibs and is part of the invention.

[0126] Coxibs being poorly soluble or insoluble in aqueous medium, they tend to crystallize out when cooled or over a period of time. Surprisingly it was found that when more than one solubilizer is used, it kept poorly soluble coxibs in solution over a long period of time and avoided its crystallization.

[0127] Further, present invention provides of packaging for the composition comprising pharmaceutical active selected from group of coxibs such as Paracoxib or Celecoxib or Valdecoxib or Etoricoxib or salts thereof ranging equivalent to 1.2 mg to 4.0 mg/ml active moiety which may be available as ready to infuse kit such as bags and glass or plastic bottles preferably of single compartment which may be composed of low density polyethylene (LDPE), high density polyethylene (HDPE), polypropylene (PP) or mixtures of polyethylene and polypropylene. Preferably used glass material may of as cited in USP such as type I glass (borosilicate glass) and type II glass (soda lime glass with chemical surface treatment). In another embodiment, the said composition may be provided in volume of equal or greater than 1 ml to 500 ml of single compartment or ready-to-use injection which can be diluted according to physiological use. Further the kit said herein may be also of flexible bags.

[0128] The present invention provides the composition comprising pharmaceutical active selected from group of coxibs such as Paracoxib or Celecoxib or Etoricoxib or salts thereof ranging from 1.2 mg to 4.0 mg/ml in which rubber stoppers, closures or disc seals, screw-caps or cap-stopper combination seals closures may be used as a component of packaging.

[0129] The pharmaceutical composition comprising a pharmaceutical active selected from group of coxibs such as paracoxib or Etoricoxib and Celecoxib are present in amount ranging from 1.2 mg to 4.0 mg/ml. are subjected to sterilization process to achieve the sterile compositions. The formulation is prepared and filled in article and is terminally sterilized by electron beam irradiation such as γ-irradiation, natural light, microwave heat viz. moist heat sterilization, dry heat sterilization. Autoclave sterilization may be preferred to achieve moist heat sterilization of the drug after final packaging. Typical cycle of autoclave in the pharmaceuticals to attain the sterilization of the final product is 121° C. for 15 minutes.

[0130] Compositions of the present invention can be autoclaved at temperature ranging from 110° C. to 130° C., preferably 115° C. to 125° C. for period of time ranging from 5 minutes to 30 minutes, preferably 10 minutes to 20 minutes. More preferably the autoclaving is done at 120° C. to 122° C. for 15 minutes.

[0131] Compositions of the present invention ie of Etoricoxib and Celecoxib after sterilization were stored at different stability conditions as per the pharmaceutical stability guidelines for stability.

[0132] Both the sterile products are stable at least for the period of six months at accelerated storage conditions.

[0133] The invention provides an accurate dose of pharmaceutical composition comprising a pharmaceutical active selected from group of Etoricoxib and Celecoxib present in amount ranging from 1.2 mg to 4.0 mg/ml suitable for parenteral routes especially ready-to-use or ready-to-infuse and using the same liquid with suitable modification for use in ocular preparations.

[0134] In another embodiment, composition is having pH ranging from 5.00 to 7.00 and viscosity is in between 1.0 cps to 3.0 cps.

[0135] Novelty of the present invention resides in providing stable compositions solubilizing huge amounts of Cox 2 inhibitors which are otherwise not soluble in aqueous media and tend to precipitate in presence of water. Novelty also resides in ability of the compositions to keep the active Cox 2 in solution even when diluted with aqueous media. Novelty also resides in providing stable clear compositions with lower viscosity, causing less pain, fit for parenteral route.

[0136] Nonobviousness of the present invention resides in the fact that clear, stable aqueous compositions comprising 1.2 mg to 4.0 mg/ml of Cox 2 inhibitors were not provided by prior art and were not imagined by the prior art. Non-obviousness and novelty also resides in the fact that present inventions dissolves water insoluble active ingredient like Celecoxib or Etoricoxib in the range of 1.2 mg to 4.0 mg/ml yet resulting into solution of viscosity of about 1.0 cps to 3.0 cps.

[0137] Coxibs means COX 2 inhibitors. Pharmaceutical preparation and pharmaceutical composition or pharmaceutical formulation mean one and the same and are interchangeable. Utility and non-obviousness of the present invention resides in the fact that solution of Cox 2 inhibitor prepared as per present invention can be formulated for administration by injection, oral, topical application route. Novelty and industrial application of the invention also resides in the fact that for the first time there is provided an IV solution that can be administered over a prolonged period. None of the prior arts provides any motivation to prepare the compositions as described by the present invention. Prior art has not provided slightest guidance or hint to prepare an IV composition as taught by the present invention.

[0138] Compositions of the present invention are suitable to be presented in dosage form for parenteral or topical or injectable or oral or nasal or per oral or any other route of administration. The invention is illustrated in the examples stated below.

EXAMPLES

Example 1: Celecoxib 4.00 mg/ml Formula and Manufacturing Procedure

[0139]

TABLE-US-00001 Sr. No. Ingredients Qty/mL 1. Celecoxib 0.4% w/v (4.00 mg) 2. Ethanol 10.0% w/v 3. Tween 80 8.0% w/v 4. Water for Injection q.s to 1 Lit [0140] a. In a 2.0 L beaker poured dispensed quantity of Ethanol and dissolved dispensed quantity of drug. Ensured that solution was clear. [0141] b. Added Tween 80 to solution obtained in step a. under continuous stirring. [0142] c. Made final volume with WFI up to 1.0 L in Volumetric Flask of 1000 mL. [0143] d. Continued Nitrogen Purging with continuous stirring by magnetic stirrer. [0144] e. Filled in USP Type-1 10 mL amber color glass vial and USP Type-1 10 mL clear glass vial and were terminally sterilized in autoclave at 121° C. for 15 minutes.

Example 2: Stability Details of Example 5 at the End of 6 Months

[0145] i. For composition filled in USP type-1 10 mL amber color glass vial:

TABLE-US-00002 40 ± 2° C./ 25 ± 2° C./ 30 ± 2° C./ 30 ± 2° C./ 75% ± 5% 60% ± 5% 65% ± 5% 75% ± 5% RH RH RH RH Test Initial 6 M 6 M 6 M 6 M Description Light Complies Complies Complies Complies yellow color pH 7.0 7.04 7.13 7.05 7.07 Assay 102.1% 98.25%    99.75%    99.50%    98.75%    RS SI ND 0% 0% 0% 0% TI ND 0% 0% 0% 0% [0146] ii. For composition filled in USP type-1 10 mL Clear glass vial:

TABLE-US-00003 40 ± 2° C./ 25 ± 2° C./ 30 ± 2° C./ 30 ± 2° C./ 75% ± 5% RH 60% ± 5% RH 65% ± 5% RH 75% ± 5% RH Test Initial 6 M 6 M 6 M 6 M Description Light Complies Complies Complies Complies yellow color pH 7.0 7.00 7.06 7.03 7.02 Assay 101.87% 98.75%    100.00%    99.50%    99.25%    RS SI ND 0% 0% 0% 0% TI ND 0% 0% 0% 0%

[0147] Above data depicts a stable composition at above mentioned stability conditions.

Example 3: Celecoxib 4.00 mg/ml. Formula and Manufacturing Procedure

[0148]

TABLE-US-00004 Sr. No. Ingredients Qty/mL 1 Celecoxib 0.4% w/v (4.00 mg) 2 Ethanol 8.0% w/v 3 Tween 80 8.0% w/v 4 Transcutol-HP 3.0% w/v 5 Water for Injection q.s to 1 Lit [0149] a. In a 2.0 L beaker poured dispensed quantity of Ethanol, Transcutol-HP and dissolved dispensed quantity of drug. Ensured that solution was clear. [0150] b. Added Tween 80 to solution obtained in step a. under continuous stirring. [0151] c. Made final volume with WFI up to 1.0 L in Volumetric Flask of 1000 mL. [0152] d. Continued Nitrogen Purging with continuous stirring on magnetic stirrer. [0153] e. Filled in USP Type-1 5 mL clear glass vial. [0154] f. Filled samples were terminally sterilized in autoclave at 121° C. for 15 min.

Example 4: Stability Details of Example 3 in Clear 5 ml Glass Vial

[0155]

TABLE-US-00005 40 ± 2° C./ 25 ± 2° C./ 30 ± 2° C./ 30 ± 2° C./ 75% ± 5% RH 60% + 5% RH 65% + 5% RH 75% ± 5% RH Test Initial 6M 12M 12M 12M Description Light Clear yellow Clear yellow Clear yellow Clear yellow yellow liquid solution liquid solution liquid solution liquid solution color pH 6.98 6.76 7.08 7.05 7.02 % Assay 102.96 99.35 101.75 102.75 102.25 Impurities 0 0 0 0 0

Example 5

[0156] Etoricoxib Infusion 1.2 mg/mL, Batch No: EIF-1903, Batch size: 250 mL

TABLE-US-00006 Ingredient Ph. Specs Qty/ml Qty/batch Etoricoxib IH 12 mg or 0.12% w/v 300 mg HPβCD IH 4% w/v 10 gm Transcutol HP BP/EP 0.3% w/v 0.75 mL Monothioglycerol USP 2.5 mg or 0.25% w/v 0.625 g Water for injection IH Qs to 1 mL Qs to 250 ml Primary Packing Details 5 mL clear glass vials with Bromobutyl 50 NOS rubber stopper and Plain Aluminum seal

[0157] Manufacturing Procedure:

[0158] (A) Preparation of Drug, Transcutol & Monothioglycerol Solution

[0159] Taken dispensed quantity of Transcutol HP, Monothioglycerol and added dispensed quantity of drug and mixed well.

[0160] (B) Preparation of HPβCD Solution

[0161] Taken 100 mL of water for Injection and added dispensed quantity of HPβCD, mixed well to form a clear solution

[0162] (C) Addition of A & B

[0163] Added slowly solution B into solution A and mixed well for 30 minutes. Then made up the volume up to 250 ml with continuous stirring with water for injection and stirred about 3 Hour with fast stirring (about 900 rpm). Viscosity: 1.164 (Ostwald Viscometer Type A), Wt/mL: 1.0128, pH: 6.68, Osmolality: 63 mosm/kg.

Example 6

[0164] Stability of Batch No: EIF-1903 produced as per example 5 was studied at different temp and humidity conditions ie 40° C. and 75% RH, 30° C. and 75% RH and 25° C. and 60% RH. Data on Stability conditions of 40° C. and 75% RH, 30° C. and 75% RH is listed below. These are more corrosive and harsh conditions than 25° C. and 60% RH. The product was found stable in all three conditions. RS were within the limits. Above stated results depict a stable clear colourless liquid composition of Etoricoxib. Etoricoxib Infusion 1.2 mg/mL.

TABLE-US-00007 40° C./75% 30° C./65% 25° C./30% RH RH RH Tests Initial 6M 9M 9M Description Clear Complies Complies Complies colorless solution pH pH 5.0-7.0 6.68 5.88 5.69 6.51 Assay: Each ml 99.16% 98.38% 98.34% 98.60% contains: 1.2 mg/mL (90.0% to 110.0%)

Example 7

[0165] Batch No: EIF-1904; Batch size: 250 mL; Each ml contains: Etoricoxib—1.2 mg

TABLE-US-00008 Ingredient Ph. Specs Qty/ml Qty/batch Etori coxib IH 12 mg or 0.12% w/v 300 mg HPβCD IH 4% w/v 10 gm Transcutol HP BP/EP 2% v/v 5 mL Monothioglycerol USP 2.5 mg w/v or 0.25% w/v 0.625 g Water for injection IH Qs to 1 mL Qs to 250 ml 5 mL clear glass vials with Bromobutyl rubber stopper and Plain 50 NOS Aluminum seal

Example 8

[0166] Stability testing results of Etoricoxib Infusion 1.2 mg/mL, Batch No: EIF-1904

TABLE-US-00009 40° C./75% 30° C./65 25° C./30% RH % RH RH Tests Initial 6M 9M 9M Description Clear colorless Complies Complies Complies solution pH 5.0-7.0 6.52 5.74 5.96 6.13 Assay: Each ml contains: 98.34% 98.70% 98.48% 97.84% 1.2 mg/mL (90.0% to 110.0%)

[0167] RS were within limits.

Example 9

[0168] Batch No: EIF-1906; Batch size: 250 mL, Each ml contains: Etoricoxib—1.2 mg

TABLE-US-00010 Ingredient Ph. Specs Qty/ml Qty/batch Etori coxib IH 12 mg or 0.12% w/v 300 mg HPβCD IH 4% w/v 10 gm Transcutol HP BP/EP 0.2% v/v 0.5 mL Monothioglycerol USP 2.5 mg or 0.25% w/v 0.625 g Water for injection IP/BP/USP Qs to 1 mL Qs to 250 ml 5 mL clear glass vials with Bromobutyl rubber stopper and 50 NOS Plain Aluminum seal

Example 10

[0169] Stability of composition in Example 9 Etoricoxib Infusion 1.2 mg/mL, Batch No: EIF-1906

TABLE-US-00011 40° C./75% 30° C./65% 25° C./ RH RH 60% RH Tests Initial 6M 9M 9M Description Clear Complies Complies Complies colorless solution pH 5.0-7.0 6.60 5.90 5.88 6.25 Assay: 97.45% 97.99% 97.27% 97.56% Each ml contains: 1.2 mg/mL (90.0% to 110.0%)

[0170] RS were within limits.

Example: 11

[0171] Batch No: EIF-2001; Batch size: 50 mL; Each ml contains: Etoricoxib—1.2 mg

TABLE-US-00012 Ingredient Ph. Specs Qty/ml Qty/batch Etoricoxib IH 1.2 mg or 0.12% w/v 60 mg HPβCD IH   4% w/v 2 gm Transcutol HP BP/EP 0.3% v/v 0.15 Ml Sodium Chloride IP 0.6% w/v 0.3 g Monothioglycerol USP 2.5 mg or 0.25% w/v 0.125 g Water for injection IH Qs to 1 mL Qs to 50 ml 10 mL clear glass vials with Bromobutyl rubber 5 NOS stopper and Plain Aluminum seal

[0172] Manufacturing Procedure:

[0173] (A) Preparation of Drug, Transcutol & Monothioglycerol Solution [0174] Taken dispensed quantity of Transcutol HP, Monothioglycerol and add dispensed quantity of drug and mixed well.

[0175] (B) Preparation of HPβCD and Sodium Chloride Solution

[0176] Taken approx 20 mL water for injection and added dispensed quantity of sodium chloride, mixed well to form a clear solution then added dispensed quantity of HPβCD in above solution, mixed well to form a clear solution

[0177] (D) Addition of A & B

[0178] Added slowly solution B into solution A and mixed well for 30 minutes. Then made up the volume up to 50 ml with continuous stirring with water for injection and stirred for about 3 Hours with fast stirring (approx 900 rpm).

[0179] Initial pH: 6.52; Osmolality: 299 mosm/kg

Example 12

[0180] Batch No: ETS-1716; Batch size: 250 ml

[0181] Each ml contains: Etoricoxib—1.20 mg

TABLE-US-00013 Ingredient Qty/ml Qty/batch Etoricoxib 1.20 mg or 0.12% w/v 300.8 mg Hydroxypropyl 3% w/v 7.5 g Betacylodextrin (HPBCD) Transcutol HP 3% v/v 7.5 ml Sodium chloride   9 mg or 0.9% w/v 2.25 g Monothiglycerol  2.5 mg or 0.25% w/v 0.625 g Water for injection Qs to 1 ml Qs to 250 ml (approx 97.0%)

[0182] Assay of Etoricoxib raw material: 100% & LOD 0.27%

[0183] Manufacturing Procedure:

[0184] (A) Preparation of Sodium Chloride & Hydroxy Propyl Beta Cyclodextrin Solution [0185] Taken 50 ml water for injection in glass beaker. Added slowly dispensed quantity of Sodium chloride under stirring to get a clear solution and added hydroxyl propyl betacyclodextrin (HPBCD) in above solution under continuous stirring to get a clear solution. Checked the clarity of solution.

[0186] (B) Preparation of Drug Solution:

[0187] Taken a 7.5 ml transcutol HP in another glass beaker. Slowly added dispensed quantity of monothioglcerol. Mixed well. Slowly added dispensed quantity of Etoricoxib under continuous stirring to get a clear solution. Checked the clarity of solution.

[0188] (C) Addition of Sodium Chloride & Hydroxy Propyl Beta Cyclodextrin Solution in Drug Solution. [0189] Added sodium chloride and hydroxyl propyl betacyclodextrin (HPBCD) solution in drug solution with continuous stirring and nitrogen bubbling to make complex with each other for 10 minutes. A clear solution is obtained. Checked the clarity of solution.

[0190] (D) Make Up the Final Volume

[0191] Made up the final volume with water for injection up to 250 ml & stirred for 20-25 minutes under nitrogen purging. Checked the clarity of solution. Filtered and filled in 5.0 ml clear glass vials. usp type I, Bromobutyl rubber stopper & aluminum seal.

[0192] Ostwald viscometer: Bulb type B (viscosity range 1 to 10 cps)

[0193] Weight per mL=1.011 g/ml, Viscosity; 1.146 cps

Example 13

[0194] Batch No: ETS-1716, Etoricoxib Infusion 1.2 mg/ml; Batch size: 250 ml; Strength: 1.2 mg/ml; Pack size: 5 ml

TABLE-US-00014 40° C./ 25° C./ 30° C./ 75% RH/ 60% RH/ 75% RH/ Tests Initial 6M 6M 6M Description Clear Complies Complies Complies colourless pH 5-7 6.80 6.15 6.60 5.27 Assay Etoricoxib 100.60% 98.33 98.33 99.17 1.2 mg/ml (90% to 110%) Related Substances Impurity-I  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-II  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-III  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-IV  0.10% 0.12% 0.12% 0.12% NMT 1.0% Individual Imp:  0.05% 0.00% 0.00% 0.00% NMT 0.5% Total Impurity  0.15% 0.12% 0.12% 0.12% NMT = 2.0% Viscosity (cps) 1.146 — — —

Example 14

[0195] Batch No: ETS-1717, Batch size: 250 ml; Each ml contains: Etoricoxib—1.20 mg

TABLE-US-00015 Ingredient Qty/ml Qty/batch Etoricoxib 1.20 mg or 0.12% w/v 300.81 mg Hydroxypropyl 3% w/v 7.5 g Betacylodextrin (HPBCD) Transcutol HP 3% v/v 7.5 ml Dextrose anhydrous 50 mg or 5% w/v  12.5 g Monothiglycerol  2.5 mg or 0.25% w/v 0.625 g Water for injection Qs to 1 ml Qs to 250 ml (approx 95.0%)

[0196] Assay of Etoricoxib raw material: 100% & LOD 0.27%

[0197] Manufacturing Procedure:

[0198] (A) Preparation of Dextrose Anhydrous & Hydroxy Propyl Beta Cyclodextrin Solution [0199] Taken 50 ml water for injection in glass beaker. Added slowly dispensed quantity of Dextrose anhydrous under stirring to get a clear solution. Added hydroxyl propyl betacyclodextrin (HPBCD) in above solution under continuous stirring to get a clear solution. Checked the clarity of solution.

[0200] (B) Preparation of Drug Solution: [0201] Taken a 7.5 ml transcutol HP in another glass beaker. Added slowly dispensed quantity of monothioglcerol. Mixed well. Added slowly dispensed quantity of Etoricoxib under continuous stirring to get a clear solution. Checked the clarity of solution.

[0202] (C) Addition of Dextrose Anhydrous and Hydroxy Propyl Beta Cyclodextrin Solution in Drug Solution. [0203] Added Dextrose and hydroxyl propyl betacyclodextrin (HPBCD) solution in drug solution under continuous stirring and nitrogen bubbling to make complex with each other for 10 minutes. A clear solution is obtained. Checked the clarity of solution.

[0204] (D) Make Up the Final Volume [0205] Made up the final volume with water for injection up to 250 ml. Stirred for 20-25 minutes under nitrogen purging. Checked the clarity of solution. Filtered solution. Filled in 5.0 ml clear glass vials. usp type I, bromobutyl rubber stopper & aluminum seal. [0206] Ostwald viscometer: Bulb type B (viscosity range 1 to 10 cps): Viscosity; 1.215 cps [0207] Weight per mL=1.016 g/ml pH: 6.64; Osmolarity Result: 636 mOsmol/kg

Example 15: Stability Testing of Batch ETS-1717

[0208]

TABLE-US-00016 40° C./75% 25° C./60% 30° C./75% Tests Initial RH/6M RH/6M RH/6M Description Clear Complies Complies Complies colourless pH 5-7 6.64 6.63 5.83 6.23 Assay Etoricoxib 100.28% 98.33 99.17 98.33 1.2 mg/ml Related Substances Impurity-I 0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-II 0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-III 0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-IV 0.12% 0.12% 0.12% 0.12% NMT 1.0% Individual Imp: 0.05% 0.00% 0.00% 0.00% NMT 0.5% Total Impurity 0.15% 0.12% 0.12% 0.12% NMT = 2.0% Viscosity (cps) 1.215 — — — indicates data missing or illegible when filed

[0209] Sterile composition can be prepared by aseptic filling or by terminal sterilization as described in the detailed description and by sterilization methods known in art.

Example 16

[0210] Batch No: ETS-1718, Batch size: 250 ml; Each ml contains: Etoricoxib—1.20 mg

TABLE-US-00017 Ingredient Qty/ml Qty/batch Etoricoxib 1.20 mg or 300.81 ,g 0.12% w/v Hydroxypropyl Betacylodextrin 4% w/v 10 g (HPBCD) Transcutol HP 3% v/v 7.5 ml Dextrose anhydrous 50 mg or 5.0 g 5% w/v Monothiglycerol 2.5 mg or 250 mg 0.25% w/v Water for injection Qs to 1 ml Qs to 250 ml (approx 99.5%)

[0211] Assay of Etoricoxib raw material: 100% & LOD 0.27%

[0212] Manufacturing Procedure:

[0213] (A) Preparation of Dextrose Anhydrous & Hydroxy Propyl Beta Cyclodextrin Solution [0214] Taken 50 ml water for injection in glass beaker. Added slowly, dispensed quantity of Dextrose anhydrous under stirring to get a clear solution. Added hydroxyl propyl betacyclodextrin (HPBCD) in above solution under continuous stirring to get a clear solution. Checked the clarity of solution.

[0215] (B) Preparation of Drug Solution: [0216] Taken 7.5 ml transcutol HP in another glass beaker. Added slowly, dispensed quantity of monothioglcerol and mixed well. Slowly added dispensed quantity of Etoricoxib under continuous stirring to get a clear solution. Checked the clarity of solution.

[0217] (C) Addition of Dextrose Anhydrous & Hydroxy Propyl Beta Cyclodextrin Solution in Drug Solution. [0218] Added Dextrose and hydroxyl propyl betacyclodextrin (HPBCD) solution in drug solution under continuous stirring and nitrogen bubbling to make complex with each other for 10 minutes. A clear solution is obtained. Checked the clarity of solution.

[0219] (D) Make Up the Final Volume [0220] Made up the volume with water for injection up to 250 ml. Stirred for 20-25 minutes under nitrogen purging. Checked the clarity of solution. Filtered solution. Filled in 5.0 ml clear glass vials usp type I, bromobutyl rubber stopper and aluminum seal. [0221] Ostwald viscometer: Bulb type B (viscosity range 1 to 10 cps): Viscosity; 1.158 cps [0222] Weight per mL=1.018 g/ml; pH: 6.80: Osmolarity Result: 684 mOsmol/kg

Example 17

[0223] Batch No: ETS-1718: Strength: 1.2 mg/ml: Batch size: 250 ml (Non sterile batch)

TABLE-US-00018 40° C./75% 25° C./60% 30° C./75% Tests Initial RH/6M RH/6M RH/6M Description Clear Complies Complies Complies colourless solution pH 5-7 6.80 6.21 6.19 5.95 Assay Etoricoxib 101.65% 98.33 99.17 98.33 1.2 mg/ml (90% to 110%) Related Substances (As per kekule API method) Impurity-I  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-II  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-III  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-IV  0.10% 0.13% 0.12% 0.12% NMT 1.0% Individual Imp:  0.05% 0.00% 0.00% 0.00% NMT 0.5% Total Impurity  0.15% 0.13% 0.12% 0.12% NMT = 2.0% Viscosity in cps 1.158 — — —

Example 18

[0224] Batch No: ETS-1719; Batch size: 250 ml; Each ml contains: Etoricoxib—1.20 mg

TABLE-US-00019 Ingredient Qty/ml Qty/batch Etoricoxib 1.20 mg or 300.81 mg 0.12% w/v Hydroxypropyl Betacylodextrin 4% w/v 10 g (HPBCD) Transcutol HP 3% w/v 7.5 ml Sodium chloride 9 mg or 2.25 g 0.9% w/v. Monothiglycerol 2.5 mg or 0.625 g 0.25% w/v Water for injection Qs to 1 ml Qs to 250 ml (approx 95.0%)

[0225] Assay of Etoricoxib raw material: 100% & LOD 0.27%

[0226] Manufacturing Procedure:

[0227] (A) Preparation of Sodium Chloride and Hydroxy Propyl Beta Cyclodextrin Solution

[0228] Taken 50 ml water for injection in glass beaker. Slowly added dispensed quantity of Sodium chloride under stirring to get a clear solution. Added hydroxyl propyl betacyclodextrin (HPBCD) in above solution under continuous stirring to get a clear solution. Checked the clarity of solution.

[0229] (B) Preparation of Drug Solution: [0230] Taken 7.5 ml Transcutol HP in another glass beaker. Slowly added dispensed quantity of Monothioglycerol. Mixed well. Slowly added dispensed quantity of Etoricoxib under continuous stirring to get a clear solution. Checked the clarity of solution.

[0231] (C) Addition of Sodium Chloride & Hydroxy Propyl Beta Cyclodextrin Solution in Drug Solution. [0232] Added sodium chloride and hydroxyl propyl betacyclodextrin (HPBCD) solution in drug solution under continuous stirring and nitrogen bubbling to make complex with for 10 minutes. A clear solution is obtained. Checked the clarity of solution.

[0233] (D) Make Up the Final Volume [0234] Made up the final volume with water for injection up to 250 ml. Stirred for 20-25 minutes under nitrogen purging. Checked the clarity of solution. Filtered and filled in 5.0 ml clear glass vials. usp type I, bromobutyl rubber stopper & aluminum seal. [0235] Ostwald viscometer: Bulb type B (viscosity range 1 to 10 cps): Viscosity; 1.176 cps [0236] Weight per mL=1.012 g/ml; pH: 6.36: Osmolarity Result: 620 mOsmol/kg

Example 19: Stability of Composition Exemplified in Example 19. (Non Sterile Batch)

[0237]

TABLE-US-00020 40° C./75% 25° C./60% 30° C./75% Tests Initial RH/6M RH/6M RH/6M Description Clear Complies Complies Complies colourless pH 5-7 6.36 6.38 5.96 6.18 Assay Etoricoxib 101.60% 99.17 100.00 99.17 1.2 mg/ml (90% to 110%) Related Substances Impurity-I  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-II  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-III  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-IV  0.10% 0.12% 0.12% 0.12% NMT 1.0% Individual Imp:  0.04% 0.00% 0.00% 0.00% NMT 0.5% Total Impurity  0.14% 0.12% 0.12% 0.12% NMT = 2.0% Viscosity 1.176 cps — — —

Example 20

[0238] Batch No: ETS-1720; Batch size: 250 ml; Each ml contains: Etoricoxib—1.20 mg

TABLE-US-00021 Ingredient Qty/ml Qty/batch Etoricoxib 1.20 mg or 300.81 mg 0.12% w/v Hydroxypropyl Betacylodextrin 4% w/v 10 g (HPBCD) Transcutol HP 3% w/v 7.5 ml Monothiglycerol 2.5 mg or 0.625 g 0.25% w/v Water for injection Qs to 1 ml Qs to 250 ml

[0239] Assay of Etoricoxib raw material 100% & LOD 0.27%

[0240] Manufacturing Procedure:

[0241] (A) Preparation of Hydroxy Propyl Beta Cyclodextrin Solution [0242] Taken 25 ml water for injection in glass beaker. Slowly added dispensed quantity of hydroxyl propyl betacyclodextrin (HPBCD) under continuous stirring to get a clear solution. Checked the clarity of solution.

[0243] (B) Preparation of Drug Solution: [0244] Taken 7.5 ml Transcutol HP in another glass beaker. Slowly added dispensed quantity of Etoricoxib under continuous stirring to get a clear solution. Checked the clarity of solution.

[0245] (C) Addition of Hydroxypropyl Betacyclodextrin Solution in Drug Solution. [0246] Added Hydroxyl propyl betacyclodextrin (HPBCD) solution in drug solution under continuous stirring and nitrogen bubbling to prepare a complex, for 10 minutes. A clear solution is obtained. Checked the clarity of solution.

[0247] (D) Make Up the Final Volume [0248] Made up volume with water for injection up to 250 ml. Stirred for 20-25 minutes under nitrogen purging. Checked the clarity of solution. Filtered and filled in 5.0 ml clear glass vials. usp type I, bromobutyl rubber stopper & aluminum seal. [0249] Ostwald viscometer: Bulb type B (viscosity range 1 to 10 cps) Viscosity; 1.176 cps [0250] Weight per mL=1.012 g/ml. pH: 6.36. Osmolarity Result: 286 mOsmol/kg

Example 21: Stability of Composition in Example 21, Batch No: ETS-1720; Etoricoxib Infusion 1.2 mg/ml; (Non Sterile Batch)

[0251]

TABLE-US-00022 40° C./75% 25° C./60 30° C./75% Tests Initial RH/6M % RH/6M RH/6M Description Clear Complies Complies Complies colourless pH 5-7 6.36 6.43 6.47 6.25 Assay Etoricoxib 99.38% 98.33 100.00 99.17 1.2 mg/ml (90% to 110%) Related Substances Impurity-I  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-II  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-III  0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-IV  0.10% 0.12% 0.14% 0.14% NMT 1.0% Individual Imp:  0.04% 0.00% 0.00% 0.00% NMT 0.5% Total Impurity  0.15% 0.12% 0.14% 0.14% NMT = 2.0% Viscosity 1.176 cps — — — indicates data missing or illegible when filed

Example 22

[0252] Batch No: ETS-1802; Batch size: 250 ml; Each ml contains: Etoricoxib—1.20 mg

TABLE-US-00023 Ingredient Qty/ml Qty/batch Etoricoxib 1.20 mg or 300.81 mg 0.12% w/v Hydroxypropyl Betacylodextrin 3% w/v 7.5 g (HPBCD) Transcutol HP 3% w/v 7.5 ml Monothiglycerol 2.5 mg or 0.625 g 0.25% w/v Water for injection Qs to 1 ml Qs to 250 ml (approx 95.0%)

[0253] Assay of Etoricoxib raw material 100% & LOD 0.27%

[0254] Manufacturing Procedure:

[0255] (A) Preparation of Hydroxy Propyl Beta Cyclodextrin Solution [0256] Taken 25 ml water for injection in glass beaker. Slowly added dispensed quantity of hydroxyl propyl betacyclodextrin (HPBCD) under continuous stirring to get a clear solution. Checked the clarity of solution.

[0257] (B) Preparation of Drug Solution: [0258] Taken a 7.5 ml transcutol HP in another glass beaker. Slowly added dispensed quantity of Etoricoxib under continuous stirring to get a clear solution. Checked the clarity of solution.

[0259] (C) Addition of Hydroxypropyl Betacyclodextrin Solution in Drug Solution. [0260] Added Hydroxyl propyl betacyclodextrin (HPBCD) solution in drug solution with under continuous stirring and nitrogen bubbling to make complex, for 10 minutes. A clear solution is obtained. Checked the clarity of solution.

[0261] (D) Make Up the Final Volume [0262] Made up the final volume with water for injection up to 250 ml. Stirred for 20-25 minutes under nitrogen purging. Checked the clarity of solution. Filtered and filled in 5.0 ml clear glass vials. usp type I, bromobutyl rubber stopper & aluminum seal. [0263] Ostwald viscometer: Bulb type B (viscosity range 1 to 10 cps); Viscosity; 1.176 cps [0264] Weight per mL=1.012 g/ml; pH: 6.14

Example 23

[0265] Batch No: ETS-1802; Etoricoxib Infusion 1.2 mg/ml; (Non sterile batch);

TABLE-US-00024 40° C./75% 25° C./60% 25° C./60% 30° C./65% Tests Initial RH/6M RH/9M RH/9M Description Clear and Clear and Clear and Clear and Clear and colourless colourless colourless colourless colourless solution solution solution solution solution pH 5-7 6.14 6.45 5.56 5.62 5.41 Assay Etoricoxib 98.19 97.50 98.33 95.44 95.48 1.2 mg/ml (90% to 110%) Related Substances Impurity-I 0.00 0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-II 0.00 0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-III 0.00 0.00% 0.00% 0.00% 0.00% NMT 1.0% Impurity-IV 0.14 0.19% 0.16% 0.15% 0.15% NMT 1.0% Individual Imp: 0.00 0.00% 0.00% 0.00% 0.00% NMT 0 5% Total Impurity 0.14 0.169 0.16% 0.15% 0.15% NMT = 2.0% Viscosity 9 cps) 1.176 — — indicates data missing or illegible when filed

Example 24

[0266] Batch No.: Trial-01; Batch size: 50 mL

TABLE-US-00025 No. Ingredients Qty/mL Qty/Batch 1 Etoricoxib 1.4 mg 70 mg 2 Ethanol 8.0% v/v 4 ml 3 Tween 80 8.0% w/v 4.00 g 4 Transcutol HP 3.0% v/v 1.50 mL 5 Water for Injection q.s q.s. to 50 mL

[0267] Procedure: [0268] 1) In a 100 mL beaker poured dispensed quantity of Ethanol and dissolved dispensed quantity of drug. Ensured that solution is clear. [0269] 2) Added Tween 80 to above solution under continuous stirring. [0270] 3) Added to Transcutol HP above solution under continuous stirring. [0271] 4) Made final volume with WFI up to 50 mL in Volumetric Flask of 50 mL. [0272] 5) Continued stirring on magnetic stirrer for 30 minutes.

Example 25

[0273] Batch No.: Trial-04; Batch size: 50 mL

TABLE-US-00026 No. Ingredients Qty/mL Qty/Batch 1 Etoricoxib 1.4 mg 70 mg 2 Transcutol HP 3.0% v/v 1.50 mL 3 Tween 80 8.0% w/v 4.00 g 4 Water for Injection q.s q.s. to 50 mL

[0274] Procedure: [0275] 1) In a 100 mL beaker poured dispensed quantity of Transcutol HP and dissolved dispensed quantity of drug. Ensured that the solution is clear. [0276] 2) Add Tween 80 to above solution under continuous stirring. [0277] 3) Made final volume with WFI up to 50 mL in Volumetric Flask of 50 mL. [0278] 4) Continued stirring on magnetic stirrer for 30 minutes.