FIELD OF THE INVENTION

The present invention relates to topical ophthalmic compositions of non-steroidal anti-inflammatory drug (NSAID). Particularly, the present invention relates to topical ophthalmic compositions of nepafenac. The present invention also relates to processes for preparation of topical ophthalmic compositions of nepafenac. The present invention also relates to method for the treatment of pain and inflammation associated with cataract surgery using topical ophthalmic compositions of nepafenac.

BACKGROUND OF THE INVENTION

Although improved surgical methods, such as micro-incisions, have lessened the occurrence of inflammation, it nevertheless remains a risk with any surgery. Inflammation after cataract surgery begins with tissue injury when the surgical incisión is made. Even a small degree of surgical trauma can alter the blood-aqueous barrier, resulting in protein leakage, cellular reaction and inflammation in the aqueous humor. Uncontrolled inflammation, even low-grade, can lead to conditions such as cystoid macular edema and permanent visión loss.

The complications añer cataract surgery are much less common, but can include inflammation (swelling and redness) in the eye, swelling of the retina, swelling of the comea, retinal detachment and infection in the eye, such as endophthalmitis. Patients undergoing cataract surgery when pretreated with topical NSAIDs have a larger pupil size during surgery which allows for safer and more effícient cataract procedures and reduces postoperative pain and inflammation. Topical NSAIDs also help reduce the risk of postoperative cystoid macular edema.

For the past few years, surgeons have had a number of topical NSAID options, including Acular®, Acular PF®, and Acular LS® (ketorolac tromethamine, Allergan), Ocufen® (flurbipTofen sodium, Allergan), and Voltaren® (diclofenac sodium, Novartis). The choices of topical NSAIDs have been expanded with approval by the Food and Drug Administration of Xibrom (bromfenac ophthalmic solution, Ista Pharmaceuticals) and Nevanac (nepafenac, Alcon) for use with cataract surgery.

Nepafenac, also known as 2-amino-3-benzoyíphenylacetic acid is first disclosed in US 5,475,034 for the treatment of ophthalmic inflammation and pain. According to the '034 patent, compositions containing nepafenac and its derivatives can be formulated into a variety of topically administrable ophthalmic compositions, such as solutions, suspensions, gels or ointments.

Following patents/patent publications discloses various ophthalmic compositions of nepafenac.

US 7834059, US 8071468 & US 8324281 discloses ophthalmic composition comprising 0.1% w/v nepafenac, 0.5% w/v carbomer, 0.001-0.05% w/v tyloxapol, 0.3-0.5% w/v sodium chlonde, 2-3%» w/v mannitol, a pH-adjusting agent in an amount sufficient to cause the composition to have a pH from 7.3-7.7, 0.001-0.01% w/v benzalkonium chlonde, 0.001-0.1% w/v edetate disodium; and water. US '059 further discloses that unexpected results were obtained with compositions containing 0.1% nepafenac and 0.5% carbomer, but there was no effect on the rate of corneal penetration with 0.5% carbomer on 0.3% nepafenac and 0.35% carbomer on 0.1% nepafenac.

US 2006/0257486 Al discloses ophthalmic suspensión composition comprising drug, poloxamine nonionic surfactants, glycol tonicity-adjusting agents, buffering agents, pH-adjusting agents, chelating agents and preservatives.

US 2006/0257487 Al discloses ophthalmic suspensión composition comprising drug, poloxamer nonionic surfactants, glycol tonicity-adjusting agents, buffering agents, pH-adjusting agents, chelating agents and preservatives,

US 2007/0254939 Al discloses ophthalmic suspensión composition comprising drug, sulfite salt and ophthalmically acceptable vehicle comprising edetate disodium and preservative.

US 2010/0076045 Al discloses ophthalmic submicron suspensión composition comprising nepafenac, sodium carboxymethyl cellulose, carbopol, sodium chlonde, propyiene glycol, benzalkonium chloride, disodium edetate, NaOH, HCl and purified water.

US 2011/0135743 Al discloses ophthalmic suspensión composition comprising 0.3 w/v % nepafenac having a particle size of 50 to 700 nm, 0.4 w/v % carbomer, 0.2 w/v % guar, 0.5 w/v % boric acid, 0.06 w/v % sodium carboxymethylcellulose, 0.4 w/v % sodium chloride, 0.5 w/v % propyiene glycol, a pH-adjusting agent to adjust pH to 7.0, 0.005 w/v % benzalkonium chloride, 0.01 w/v % edetate disodium; and purified water.

WO 02/074281 Al discloses ophthalmic composition comprising non-steroidal anti-inflammatory drug in sub-therapeutical concentration, zwitterionic phospholipid, neutral lipid, ophthalmic carrier and optionally preservative.

US 2002/0037929 Al discloses topical composition for treating angiogenesis-related disorder comprising nepafenac 0.1+6% excess, carbopol 974P 0.08%, tyloxapoi 0.01%, glycerin 2.4%, disodium EDTA 0.01%, benzalkonium chloride 0.01%, pH adjusting agents and water.

Penn et al., Journal of Investigative ophthalmology and visual science (2002), 43, discloses ophthalmic composition comprising 0.1% nepafenac, 0.5% carbopol, 0.1% tyloxapoi and 2.4% mannitol.

The above-discussed prior arts discloses various topical ophthalmic compositions of nepafenac. However, the inventors of present invention have endeavored to develop a stable, non-irritating and cost-effective composition comprising nepafenac.

OBJECTIVE OF THE INVENTION

The objective of the present invention is to provide topical ophthalmic compositions comprising at least one Non Steroidal Anti-inflammatory Drug (NSAID) and one or more other pharmaceutically acceptable excipient(s).

Another objective of the present invention is to provide sterile topical ophthalmic compositions comprising Non Steroidal Anti-inflammatory Drug and one or more other pharmaceutically acceptable excipient(s).

Yet another objective of the present invention is to provide processes for preparation of ophthalmic compositions comprising Non Steroidal Anti-inflammatory Drug.

Yet another objective of the present invention is to provide methods of using the ophthalmic compositions comprising Non Steroidal Anti-inflammatory drug.

SUMMARY OF THE INVENTION

An aspect of the present invention is to provide topical ophthalmic compositions comprising Non Steroidal Anti-inflammatory Drug such as nepafenac, and one or more other pharmaceutically acceptable excipient(s).

A further aspect of the present invention is to provide topical ophthalmic compositions comprising Non Steroidal Anti-inflammatory Drug, surfactant, water and one or more other pharmaceutically acceptable excipient(s).

One embodiment of the present invention relates to topical ophthalmic compositions comprising nepafenac, surfactant, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to topical ophthalmic compositions comprising nepafenac, surfactant, tonicity adjusting agent, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to topical ophthalmic compositions comprising nepafenac, more than about 0.05% to about 3% w/v of surfactant, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac, surfactant, more than about 3.5% to about 25% w/v of tonicity adjusting agent, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac, more than about 0.05% to about 3% w/v of surfactant, more than about 3.5% to about 25% w/v of tonicity adjusting agent, water and one or more other pharmaceutically acceptable excipient(s).

One of the particular embodiments of the present invention relates to an ophthalmic composition comprising about 0.1% w/v nepafenac, about 0.5% w/v of polymer, about 0.05 - 3% w/v of surfactant, about 3.5 - 25% w/v of tonicity adjusting agent, pH-adjusting agent in an amount sufficient to cause the composition to have a pH between about 7.3 to about 7.7, about 0.001-0.01% w/v of preservative, about 0.001-0.1% w/v chelating agent and water.

One of the particular embodiments of the present invention relates to process of preparing a composition of nepafenac ophthalmic composition 0.1% w/v.

Another aspect of the present invention is to provide method of using the ophthalmic composition comprising nepafenac which comprises administration of an effective amount of said composition to a subject in need thereof.

A further aspect of the present invention is to provide method for the treatment of pain and inflammation associated with cataract surgery by administering to a subject in need thereof a topical ophthalmic composition of nepafenac and one or more other pharmaceutically acceptable excipient(s).

DETAILED DESCRIPTION OF THE INVENTION

An aspect of the present invention is to provide a topical ophthalmic composition comprising Non Steroidal Anti-inflammatory drug, surfactant, water and one or more other pharmaceutically acceptable excipient(s).

One embodiment of the present invention relates to a topical ophthalmic composition comprising nepafenac, surfactant, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac, surfactant, tonicity adjusting agent, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac, more than about 0.05% to about 3% w/v of surfactant, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac, surfactant, more than about 3.5% to about 25% w/v of tonicity adjusting agent, water and one or more other pharmaceutically acceptable excipient(s).

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac, more than about 0.05% to about 3% w/v of surfactant, more than about 3.5% to about 25% w/v of tonicity adjusting agent, water and one or more other pharmaceutically acceptable excipients.

In one of the particular embodiments, the present invention relates to an ophthalmic composition comprising about 0.1% w/v nepafenac, about 0.5% w/v of polymer, about 0.05 - 3% w/v of surfactant, about 3.5 - 25% w/v of tonicity adjusting agent, pH-adjusting agent in an amount sufficient to cause the composition to nave a pH between about 7.3 to about 7.7, about 0.001-0.01% w/v of preservative, about 0.001-0.1% w/v chelating agent and water.

In one of the particular embodiments, the present invention relates to an ophthalmic composition comprising 0.1% w/v nepafenac, 0.5% w/v of carbomer, 0.05 -3% w/v of tyloxapol, 0.5-5% w/v sodium chloride, 3-20% w/v mannitol, a pH-adjusting agent in an amount sufficient to cause the composition to have a pH between 7.3 to 7.7, 0.001-0.01% w/v benzalkonium chloride, 0.001-0.1% w/v edetate disodium and water.

In the specification, singular forms, including the singular forms "a," "an" and "the", specifícally also encompass the plural referents of the terms to which they refer unless the context clearly dictates otherwise. In addition, as used herein, unless specifícally indicated otherwise, the word "or" is used in the "inclusive" sense of "and/or" and not the "exclusive" sense of "either/or".

The term "about" used in the specification normally covers a variation of + 10% of the stated valué.

As used in this specification, whether in a transitional phrase or in the body of a claim, the terms "comprise(s)" and "comprising" are to be interpreted as having an open-ended meaning. That is, the terms are to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

The term "composition" refers to liquid having solid particles homogeneously dissolved or dispersed in a pharmaceutically acceptable solvent or carrier system with or without additional ophthalmic excipients.

As used herein, "NSAID" refers to a group of Non steroidal anti inflammatory drugs (including salts, polymorphs, hydrates, solvates, enantiomers, derivatives, synthetic analogs, and pro-drugs) selected from the group comprising Nepafenac, Bromfenac, Ketorolac, Flurbiprofen and Diclofenac. In an embodiment, the compositions of the present invention contain about 0.09 to about 0.5% w/v of NSAID. Therefore the drug nepafenac wherever mentioned covers the drug including salts, polymorphs, hydrates, solvates, enantiomers, derivatives, synthetic analogs, and pro-drugs thereof.

In an embodiment of the present invention, the pharmaceutically acceptable excipients are selected from but not limited to a group comprising tonicity adjusting agents, buffers, preservatives, polymers or thickening agents or viscosity agents, chelating agents and pH adjusting agents.

In an embodiment, the pharmaceutical ophthalmic composition comprises a pharmaceutically acceptable solvent or carrier system in which an active ingredient is dispersed in said solvent or carrier system. The pharmaceutically acceptable solvent may be an aqueous solvent such as water, physiological saline and buffer, in which the active is dispersed.

To obtain an efficient dispersión of the nepafenac particles in the composition, a surfactant is used. The surfactants may also function as stabilizing agents in the compositions. Examples of suitable surfactants include but not limited to tyloxapol-a polymer of 4-(l,l,3,3-tetramethylbutyl)phenol with ethylene oxide and formaldehyde sorbitan derivatives, e.g. polyoxyethylene sorbitan fatty acid esters, preferably of the polysorbate groups, more preferably polysorbate 80 or polysorbate 20, polyoxyethylene ethers, especially polyoxyethylene alkyl ethers, poloxamers, polyoxyethylene castor oil derivatives, polyvinyl alcohol and block copolymers of polyethyleneoxides, polypropyleneoxides, polybutyleneoxides and polyethyleneglycols (PEGs), polyethylene glycol derivatives, especially polyethylene glycol 660 hydroxystearate or Solutol™ HS 15 and the like or mixtures thereof. The surfactant may be present at about 0.05% to about 3%, or about 0.05% to about 0.3% w/v of the composition.

Suspensions that are isotonic with the lachrymal secretions cause minimal discomfort to the corneal tissue. Henee, the tonicity of the suspensión has to be adjusted to maintain the composition at an osmolality of about 280-300 mOsmol/kg. Suitable tonicity adjusting agents are selected from the group comprising mannitol, sorbitol, dextrose, dextran, glucose, glycerin, potassium chloride, sodium chloride and the like, and mixtures thereof. The tonicity adjusting agent may be present at about 3.5% to about 25%, or at about 3.5% to about 10% w/v of the composition.

In order to form a stable suspensión with a minimal tendeney to agglomerate or to form sediment, a viscosity agent may be included in the composition. Examples of suitable viscosity agents are selected from the group comprising polyacrylic acids (e.g. carbomer), microcrystalline cellulose, ethylcellulose, ethylmethyl cellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxyethylethylcelíulose, methylcellulose, hydroxymethyl cellulose hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, cyclodextrin, dextrin, xanthan gum, guar gum, povidone, polyvinylpyrrolidone (PVP) and poiyethyleneglycols (PEGs) and the like, and mixtures thereof. The amount of viscosity agent may be present at about 0.05% to about 15%, or about 0.1% to about 0.5% w/v of the composition.

To stabilize or to maintain the ophthalmic composition at the desired pH, an effective minor amount of at least one buffer component has to be incorporated into the ophthalmic composition. Suitable buffer is selected from but not limited to a group comprising phosphate buffer, acétate buffer, borate buffer, citrate buffer, and the like, and mixtures thereof.

Ophthalmic compositions are typically packed in multidose form. In order to inhibit the growth of microbial contaminants and suppress biodegradation, preservatives are added. Suitable preservative is selected from but not limited to a group comprising benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, p-hydroxybenzoate, and the like, and mixtures thereof. The amount of preservatives may range from about 0.001% to about 5.0%, or about 0.005% to about 2.0% (w/v) of the composition.

Suitable chelating agent is selected from but not limited to edetic acid, edetic acid salts like disodium edetate, sodium edetate, edetate calcium disodium, trisodium edetate and the like, and mixtures thereof. The amount of chelating agent may range from about 0.001% to about 25.0%, or about 0.005% to 10.0% (w/v) of the composition.

The compositions of the present invention have a pH of about 3 to about 9, or about 6.5 to about 8.5. Suitable pH-adjusting agent is selected from but not limited to a group comprising hydrochloric acid, sodium hydroxide, acetic acid, phosphoric acid, and mixtures thereof.

In an embodiment the present invention provides processes for prepanng sterile ophthalmic compositions comprising nepafenac.

In another embodiment the present invention provides process for prepanng stable ophthalmic compositions of nepafenac comprising:

1. Prepanng a slurry comprising polymer and water,

2. Preparing an aqueous solution or slurry comprising tonicity adjusting agent, chelating agent, preservative and water,
3. Combining the slurry of step (1) and solution of step (2),

4. Autoclaving the solution of step (3),

5. Preparing a slurry comprising nepafenac and surfactant,

6. Homogenizing the slurry of step (5), and

7. Aseptically combining the slurry of step (6) and solution of step (4) to form a suspensión and adjusting the pH.

In another embodiment the present invention provides process for preparing stable ophthalmic compositions of nepafenac comprising:

1. Preparing a sluny comprising polymer and water,

2. Preparing a solution comprising tonicity adjusting agent, chelating agent, preservative and water,

3. Combining the slurry of step (1) and solution of step (2),

4. Bulk sterilizing the solution of step (3),

5. Preparing a slurry comprising nepafenac and surfactant,

6. Homogenizing the slurry of step (5), and

7. Aseptically combining the slurry of step (6) and the solution of step (4) to form a suspensión and adjusting the pH.
In yet another embodiment the present invention provides an altérnate process for preparing sterile ophthalmic compositions of nepafenac comprising:

1. Preparing a slurry comprising polymer and water,

2. Autoclaving the slurry of step (1),

3. Preparing a soiution comprising tonicity adjusting agent, chelating agent, preservative and water,

4. Combining the slurry of step (2) and soiution of step (3),

5. Preparing a slurry comprising nepafenac and surfactant,

6. Homogenizing the slurry of step (5), and

7. Aseptically combining the slurry of step (6) and soiution of step (4) to form a suspensión and adjusting the pH.

In yet another embodiment the present invention provides a process for preparing sterile ophthalmic compositions of nepafenac comprising:

1. Preparing a slurry comprising polymer and water,

2. Bulk sterilizing the slurry of step (1),

3. Preparing a soiution comprising tonicity adjusting agent, chelating agent, preservative and water,

4. Combining the slurry of step (2) and soiution of step (3),

5. Preparing a slurry comprising nepafenac and surfactant,

6. Homogenizing the slurry of step (5), and

7. Aseptically combining the slurry of step (6) and soiution of step (4) to form a suspensión and adjusting the pH.

In another embodiment homogenization is done using ball mili, colloidal mili or micro fluídízer for sizing of particles in the composition.

The pharmaceutical compositions of present invention are packaged in plástic containers, preferred container being a low density polyethylene container that is sterilized using gamma radiation or ethylene oxide.

In another embodiment, the present invention relates to a topical ophthalmic composition comprising nepafenac; more than about 0.05% to about 3% w/v of surfactant selected from tyloxapol, polysorbate and the like; more than about 3.5% to about 25% w/v of tonicity adjusting agent selected from mannitol, sodium chloride or combination thereof; water and one or more other pharmaceutically acceptable excipient(s) selected from viscosity agents, chelating agents and pH adjusting agents.

In another embodiment the composition is in the form of suspensión.

In another embodiment the present invention also relates to a method of treatment of pain and inflammation associated with cataract surgery using topical ophthalmic compositions of nepafenac prepared according to the present invention.

In another embodiment, the composition of the present invention is used for the management of a disease condition or a disorder, which includes prophylaxis, amelioration and/or treatment of the said disease condition or a disorder.

The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

EXAMPLES

The processing steps involved in manufacturing nepafenac ophíhalmic suspensión of Examples 1-6 are given below:

1. A slurry compnsing carbomer and water was prepared.

2. A solution comprising mannitol, sodium chloride, edetate disodium, benzalkonium chloride and water was prepared.

3. The slurry of step (1) and solution of step (2) were combined.

4. The solution of step (3) was autoclaved.

5. A slurry comprising nepafenac and tyloxapol was prepared.

6. The slurry of step (5) was homogenized.

7. The slurry of step (6) and solution of step (4) were aseptically combined to form a suspensión, and the pH was adjusted.

Another process used for preparing nepafenac ophthalmic suspensión of Examples 1-6 is given below:

1. A slurry comprising carbomer and water was prepared.

2. A solution comprising mannitol, sodium chloride, edetate disodium, benzalkonium chloride and water was prepared.

3. The slurry of step (1) and solution of step (2) were combined.

4. The solution of step (3) was bulk sterilized.

5. A slurry comprising nepafenac and tyloxapol was prepared.

6. The slurry of step (5) was homogenized.

7. The slurry of step (6) and solution of step (4) were aseptically combined to form a suspensión, and the pH was adjusted.

Yet another process for preparing nepafenac ophthalmic suspensión of Examples 1-6 is given below:

1. A slurry comprising carbomer and water was prepared.

2. The slurry of step (1) was autoclaved.

3. A solution comprising mannitol, sodium chloride, edetate disodium, benzalkonium chloride and water was prepared.

4. The slurry of step (2) and solution of step (3) were combined.

5. A slurry comprising nepafenac and surfactant was prepared.

6. The slurry of step (5) was homogenized.

7. The slurry of step (6) and solution of step (4) were aseptically combined to form a suspensión, and the pH was adjusted.

Yet another process for preparing nepafenac ophthalmic suspensión of Examples 1-6 is given below:

1. A slurry comprising carbomer and water was prepared.

2. The slurry of step (1) was bulk sterilized.

3. A solution comprising mannitol, sodium chloride, edetate disodium, benzalkonium chloride and water was prepared.

4. The slurry of step (2) and solution of step (3) were combined.

5. A slurry comprising nepafenac and surfactant was prepared.

6. The slurry of step (5) was homogenized.

7. The slurry of step (6) and solution of step (4) were aseptically combined to form a suspensión, and the pH was adjusted.

Claims:

1. An ophthalmic composition comprising about 0.1% w/v nepafenac, about 0.5% w/v of polymer, about 0.05 - 3% w/v of surfactant, about 3.5 - 25% w/v of tonicity adjusting agent, pH-adjusting agent in an amount sufficient to cause the composition to nave a pH between about 7.3 to about 7.7, about 0.001-0.01% w/v of preservative, about 0.001-0.1% w/v chelating agent, and water.

2. The composition according to claim 1, wherein the polymer is selected from a group comprising carbomers, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, povidone, xanthan gum, guar gum, and mixtures thereof.

3. The composition according to claim 1, wherein the surfactant is selected from a group comprising tyloxapol, polysorbate, polyvinylalcohol, polyethyleneglycols, poloxamers, and mixtures thereof.

4. The composition according to claim 1, wherein the tonicity adjusting agent is selected from a group comprising mannitol, sorbitol, dextrose, dextran, glucose, glycerin, potassium chloride, sodium chloride, and mixtures thereof.

5. The composition according to claim 1, wherein the preservative is selected from a group comprising benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, p-hydroxybenzoate, and mixtures thereof.

6. The composition according to claim 1, wherein the chelating agent is selected from a group comprising edetic acid and edetic acid salts selected from disodium edetate, sodium edetate, edetate calcium disodium, trisodium edentate, and mixtures thereof.

7. The composition according to claim 1, wherein the pH-adjusting agent is selected from a group comprising hydrochloric acid, sodium hydroxíde, acetic acid, phosphoric acid and mixtures thereof.

8. The composition according to claim 1, which comprises 0.1% w/v nepafenac, 0.5% w/v of carbomer, 0.05 -3% w/v of tyloxapol, 0.5-5% w/v sodium chloride, 3-20% w/v mannitol, a pH-adjusting agent in an amount suffícient to cause the composition to have a pH between 7.3 to 7.7, 0.001-0.01% w/v benzalkonium chloride, 0.001-0.1% w/v edetate disodium, and water.

9. The process of preparing a composition of nepafenac according to claim 1, wherein the said process comprises the following steps:

(i) Preparing polymer solution or slurry in a solvent,

(ii) Preparing an aqueous solution or slurry comprising tonicity adjusting agents, chelating agents and preservatives,

(iii) Mixing the material of Step (i) to Step (ii),

(iv) Autoclaving the material of Step (iii),

(v) Adding surfactant to water under continuous stirring to get clear solution,

(vi) Adding Nepafenac to the solution of step (v),

(vii) Homogenizing the slurry of Step (vi); and

(viii) Mixing the slurry of Step (vii) to the material of Step (iv).

10. The composition of nepafenac according to claim 1, which is useful for the treatment of pain and inflammation associated with cataract surgery.