Anti-inflammatory and mydriatic intracameral solutions for inhibition of postoperative ocular inflammatory conditions

Abstract

To provide methods for inhibiting postoperative inflammatory conditions following ophthalmologic surgical procedures by administering intraocularly during an ophthalmologic surgical procedure a solution including a nonsteroidal anti-inflammatory drug and an α-1 adrenergic mydriatic agent, such as a liquid irrigation solution of ketorolac and phenylephrine.SOLUTION: In one aspect, there is provided a method for inhibiting a postoperative inflammatory condition following an ophthalmologic surgical procedure, including: identifying a subject with an elevated risk of suffering from a postoperative inflammatory condition; and administering intraocularly to the subject during the ophthalmologic surgical procedure a solution including a nonsteroidal anti-inflammatory drug (NSAID) and an α-1 adrenergic receptor agonist mydriatic agent in an intraocular irrigation carrier.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to methods of using a liquid pharmaceutical composition comprising a nonsteroidal anti-inflammatory agent and an alpha-adrenergic mydriatic for intraocular administration during an ophthalmic surgical procedure to inhibit a post-operative inflammatory condition. [Background technology]

[0002] Ophthalmic surgery inevitably causes trauma to delicate intraocular structures, which induces prostaglandin synthesis and the inflammatory cascade. The resulting inflammation can lead to the development of excessive inflammation and the associated postoperative inflammatory state, especially in subjects with preoperative conditions that place them at high risk for postoperative inflammatory states, or in subjects who may experience high levels of surgical trauma.

[0003] Ocular surgery often requires the use of physiological irrigation solutions to facilitate the procedure and to protect and maintain the physiological integrity of intraocular tissues. Examples of ophthalmic surgical procedures that typically require irrigation solutions include cataract extraction and lens replacement, refractive lens exchange procedures, corneal transplant procedures, and vitreoretinal surgery, as well as trabeculectomy procedures for glaucoma. Throughout intraocular surgery, the patient's pupils must be sufficiently dilated to allow for a clear surgical field and to limit any trauma that may be associated with the procedure. Pupil dilation (mydriasis) is typically achieved by dilating the eye preoperatively with the topical administration of a mydriatic drug.

[0004] During surgery, as the tip of the surgical tool is inserted into the anterior chamber and surgical trauma is introduced, the iris sphincter muscle tends to contract (miosis), reducing the window defined by the pupil. If pupil diameter is not adequately maintained throughout the procedure, the risk of damaging intraocular structures increases and often prolongs the required surgical time. Clinically significant reductions in pupil diameter are associated with increased procedure-related complications, including posterior capsule tears, retained lens fragments, and vitreous leaks.

[0005] Many ophthalmic surgeons incorporate epinephrine into intraocular irrigation solutions to help maintain pupil dilation. Epinephrine is an α- and β-adrenergic agonist, while phenylephrine is an α-1 agonist that is sometimes administered topically before surgery to promote mydriasis, although phenylephrine is not approved in the United States in a preservative- and bisulfite-free form for intraocular administration.

[0006] It is also desirable to reduce postoperative pain and irritation for the patient's comfort. For this reason, patients may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) preoperatively and / or postoperatively. Ketorolac is available in a preservative form for ophthalmic use. Allergan's Acular® is a ketorolac tromethamine solution (available in 3 mL and 6 mL dropper bottles) containing 0.01% benzalkonium chloride as a preservative. Bedford Laboratories also supplies concentrated forms of ketorolac tromethamine (15 mg or 30 mg in 1 mL, or 60 mg or 300 mg in 10 mL) for intravenous or intramuscular injection. Allergan also supplies a preservative-free 0.45% ketorolac tromethamine ophthalmic solution (which is sold in individual use vials under the trade name Acuvail®) containing sodium carboxymethylcellulose, sodium chloride, sodium citrate dihydrate. Some ophthalmic surgeons also use topical NSAIDs preoperatively in an attempt to prevent intraoperative miosis. This approach to preventing miosis is suboptimal because the intraoperative irrigation solution washes out the preoperatively delivered medication from areas of the eye bathed in the irrigation solution.

[0007] OMIDRIA™ (phenylephrine and ketorolac injection) 1% / 0.3%) (Omeros Corporation), approved by the FDA in 2014, is an alpha-1-adrenergic receptor agonist and nonselective cyclooxygenase inhibitor indicated for maintaining pupil size by preventing intraoperative miosis and for reducing postoperative pain. OMIDRIA™ is added to standard irrigation solutions used during cataract surgery or intraocular lens replacement. OMIDRIA™ is not currently indicated for reducing postoperative inflammation. Summary of the Invention [Means for solving the problem]

[0008] The present invention provides a method for inhibiting a postoperative inflammatory condition following an ophthalmic surgical procedure. The method includes identifying a subject at high risk for developing a postoperative inflammatory condition, which may be performed preoperatively based on pre-existing physiological conditions or characteristics, previous medical history, or pharmacological history, and administering to the subject during the ophthalmic surgical procedure a solution containing a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier. The NSAID and mydriatic are present in the solution in an amount sufficient to promote mydriasis and inhibit miosis, thereby maintaining an intraoperative pupillary diameter of at least 6.0 mm during the procedure, and the solution is administered in an amount sufficient to achieve ocular tissue uptake of the NSAID in an amount sufficient to inhibit cyclooxygenase for a period of at least 6 hours postoperatively, thereby inhibiting the postoperative inflammatory condition. In another embodiment of the present invention, the identification of a high risk for postoperative inflammation can be performed during the procedure based on the nature of trauma incurred during the procedure. In yet other embodiments, identification of a high risk of a post-operative inflammatory condition can be performed intraoperatively and / or preoperatively.

[0009] Suitable NSAIDs for use in the solution administered according to the present invention include flurbiprofen, suprofen, diclofenac, ketoprofen, ketorolac, indomethacin, nepafenac, and bromfenac, and suitable alpha-1 adrenergic receptor agonists include phenylephrine, epinephrine, oxymetazoline, and naphazoline. In a preferred embodiment of the present invention, the NSAID is ketorolac and the mydriatic is phenylephrine. In another embodiment, the solution contains phenylephrine at a concentration of 240-720 μM and ketorolac at a concentration of 44-134 μM. Phenylephrine and ketorolac may suitably be present in a molar ratio of 3:1 to 10:1 phenylephrine:ketorolac.

[0010] In one embodiment of the present invention, administration of the solution inhibits baseline cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) activity in ocular tissue by at least 85%, preferably at least 90%, for a period of at least 6 hours postoperatively. In another embodiment of the present invention, administration of the solution inhibits baseline COX-1 and COX-2 activity in ocular tissue by at least 85%, preferably at least 90%, for a period of at least 7 hours postoperatively. In another embodiment of the present invention, administration of the solution inhibits baseline COX-1 and COX-2 activity in ocular tissue by at least 85% for a period of at least 8 hours postoperatively. In another embodiment of the present invention, administration of the solution inhibits baseline COX-1 and COX-2 activity in ocular tissue by at least 90% for a period of at least 8 hours postoperatively. In yet another embodiment, administration of the solution inhibits baseline COX-1 and COX-2 activity in ocular tissue by at least 85% for a period of at least 10 hours postoperatively.

[0011] The methods of the present invention may be used in any ophthalmic surgical procedure that requires pupil dilation and is associated with a risk of postoperative inflammation, including procedures that require pupil dilation and are associated with postoperative inflammation, such as cataract extraction and lens replacement, refractive lens exchange, vitrectomy, retinal photocoagulation, retinal detachment repair, macular hole repair, removal of a posterior iris tumor or mass, posterior sclerotomy, and optic neurotomy, or in intravitreal procedures. The present invention may be used in connection with the inhibition of inflammatory conditions resulting from intraocular injection. In some embodiments, the solution of the present invention is administered to irrigate intraocular tissues during a procedure, for example, continuously throughout the procedure. In other embodiments, the solution of the present invention is administered by intraocular injection as part of a procedure. In yet other embodiments, the solution of the present invention is administered by irrigation of intraocular tissues during a procedure, followed by an intraocular bolus injection of the solution at the end of the procedure. In yet another embodiment, the solution of the present invention is administered by a postoperative bolus injection of the solution at the end of the procedure, after identifying a patient at risk for a postoperative inflammatory condition, for example, due to trauma sustained during surgery. In yet another embodiment, the solution is administered by intraocular injection before, during, and / or after surgery.

[0012] In another aspect of the invention, the method is used in a procedure selected from vitrectomy, retinal photocoagulation, retinal detachment repair, macular hole repair, removal of a posterior iris tumor or mass, posterior sclerotomy, and optic nerve resection, or in connection with inhibiting an inflammatory condition resulting from an intravitreal injection.

[0013] Postoperative inflammatory conditions inhibited by the methods of the invention include, for example, toxic anterior segment syndrome, cystoid macular edema, including non-pseudophakic cystoid macular edema and pseudophakic (Irvine-Gass) cystoid macular edema, acute endophthalmitis, posterior capsule opacification, anterior capsule contraction, herpes simplex virus keratitis after cataract surgery, postoperative hypotony, nylon suture toxicity, chronic corneal endothelial cell loss after cataract surgery, corneal edema, iris abrasion, corneal-retinal inflammatory syndrome, scleritis, episcleritis, vitreous incarceration syndrome, postoperative acute iridocyclitis, uveitis, retinal deposits after cataract extraction, reiterative membranous proliferation with giant cell deposits, toxic vitritis, posterior iris synechiae, postoperative intraocular fibrin formation, incisional fibrosis, complications of macular hole surgery, choroidal effusion, and anterior chamber hypopyon.

[0014] In another embodiment, the subject has been identified as being at high risk for a postoperative inflammatory condition due to a preoperative physiological condition or characteristic selected from small pupil diameter (e.g., a preoperative dilated pupil diameter of less than 6 mm), floppy iris syndrome, uveitis, retinal vein occlusion, epiretinal membrane, advanced age (e.g., over 65 years old, elderly, or geriatric), diabetes mellitus, diabetic macular edema, diabetic retinopathy, macular degeneration, or systemic hypertension; a history of preoperative treatments including previous ocular surgery or pharmacological treatment with an alpha-1 adrenergic receptor agonist or latanoprost; surgical trauma including posterior capsule rupture, secondary capsulotomy, iris incarceration, retained lens substance, or vitreous loss; and surgical placement of a nylon suture, iris-fixated intraocular lens, or anterior chamber intraocular lens.

[0015] In further aspects of the invention, the subject has been identified as being at high risk for a postoperative inflammatory condition due to preoperative physiological conditions or characteristics including small pupil diameter (e.g., a preoperative dilated pupil diameter of less than 6 mm), iris hypotony syndrome, uveitis, retinal vein occlusion, preretinal membrane, diabetic macular edema, diabetic retinopathy, macular degeneration, or systemic hypertension; a history of preoperative treatment including previous ocular surgery or pharmacological treatment with an alpha-1 adrenergic receptor agonist or latanoprost; surgical trauma including posterior capsule rupture, secondary capsulotomy, iris incarceration, retained lens substance, or vitreous loss; and surgical placement of nylon sutures, an iris-fixated intraocular lens, or an anterior chamber intraocular lens.

[0016] The present invention also provides a method for inhibiting a postoperative inflammatory condition following an ophthalmic surgical procedure by identifying a subject at physiological risk of suffering from a postoperative inflammatory condition and intraocularly administering to the subject a solution comprising a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier during the ophthalmic surgical procedure, wherein the NSAID and mydriatic are contained in the solution in an amount sufficient to maintain intraoperative pupillary diameter due to the promotion of intraoperative mydriatic and the inhibition of intraoperative miosis due to the NSAID, thereby reducing intraoperative trauma, and to inhibit the postoperative inflammatory condition due to the intraoperative and postoperative anti-inflammatory effects of the NSAID.

[0017] The present invention provides a method for inhibiting a postoperative inflammatory state following an ophthalmic surgical procedure by intraocular administration of a solution containing a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier during an ophthalmic surgical procedure to a subject at risk for the postoperative inflammatory state, wherein the NSAID and the mydriatic are present in the solution in amounts sufficient to promote mydriasis and inhibit miosis, thereby maintaining intraoperative pupillary diameter, and the solution is administered in an amount sufficient to achieve postoperative uptake of the NSAID in ocular tissues in an amount sufficient to inhibit cyclooxygenase, thereby inhibiting the postoperative inflammatory state, for a period of at least six hours. In an embodiment of the present invention, for example, the following items are provided: (Item 1) 1. A method for inhibiting a post-operative inflammatory state following an ophthalmic surgical procedure, comprising: Identifying a subject at high risk for suffering from a post-operative inflammatory condition; administering to the subject intraocularly during an ophthalmic surgical procedure a solution comprising a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier, wherein the NSAID and the mydriatic are present in the solution in amounts sufficient to promote mydriasis and inhibit miosis, thereby maintaining pupillary diameter during surgery, and wherein a sufficient amount of the solution is administered to achieve postoperative uptake of the NSAID in ocular tissues in an amount sufficient to inhibit cyclooxygenase for a period of at least six hours, thereby inhibiting the postoperative inflammatory state; A method comprising: (Item 2) 2. The method of claim 1, wherein the NSAID is selected from the group consisting of flurbiprofen, suprofen, diclofenac, ketoprofen, ketorolac, indomethacin, nepafenac, and bromfenac. (Item 3) 2. The method of claim 1, wherein the alpha-1 adrenergic receptor agonist is selected from the group consisting of phenylephrine, epinephrine, oxymetazoline, and naphazoline. (Item 4) 2. The method of claim 1, wherein the NSAID is ketorolac and the mydriatic is phenylephrine. (Item 5) 5. The method according to item 4, wherein the solution contains phenylephrine at a concentration of 240 to 720 μM and the ketorolac is present at a concentration of 44 to 134 μM. (Item 6) 2. The method of claim 1, wherein the subject is identified prior to the treatment as having a high risk of suffering from a postoperative inflammatory condition. (Item 7) 2. The method of claim 1, wherein the subject is identified during the treatment as having a high risk of suffering from a postoperative inflammatory condition. (Item 8) 10. The method of claim 1, wherein the NSAID and the mydriatic are contained in the solution in amounts sufficient to maintain an intraoperative pupil diameter of at least 6.0 mm during the procedure. (Item 9) 10. The method of claim 1, wherein the solution results in at least 90% inhibition of baseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in ocular tissue for a period of at least 6 hours postoperatively. (Item 10) 10. The method of claim 1, wherein the solution results in at least 90% inhibition of baseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in ocular tissue for a period of at least 8 hours postoperatively. (Item 11) 10. The method of claim 1, wherein the solution results in at least 85% inhibition of baseline cyclooxygenase-1 and cyclooxygenase-2 activity levels in ocular tissue for a period of at least 10 hours postoperatively. (Item 12) 2. The method of claim 1, wherein the postoperative inflammatory condition is selected from the group consisting of toxic anterior segment syndrome, cystoid macular edema, acute endophthalmitis, posterior capsule opacification, anterior capsule contraction, herpes simplex virus keratitis after cataract surgery, postoperative hypotony, nylon suture toxicity, prolonged corneal endothelial cell loss after cataract surgery, corneal edema, iris abrasion, corneal-retinal inflammatory syndrome, scleritis, episcleritis, vitreous incarceration syndrome, postoperative acute iridocyclitis, uveitis, retinal deposits after cataract extraction, recurrent membraneous proliferation with giant cell deposits, toxic vitritis, posterior iris synechiae, postoperative intraocular fibrin formation, incisional fibrosis, complications of macular hole surgery, choroidal effusion, and hypopyon. (Item 13) 2. The method of claim 1, wherein the subject has a high risk of a postoperative inflammatory condition due to preoperative physiological conditions or characteristics, preoperative treatment history, surgical trauma, or surgical placement of a device associated with a high incidence of postoperative inflammation. (Item 14) 14. The method of claim 13, wherein the subject has a preoperative physiological condition or characteristic including a dilated pupil diameter of less than 6 mm, iris hypotony syndrome, uveitis, retinal vein occlusion, epiretinal membrane, age greater than 65 years, diabetes mellitus, diabetic macular edema, diabetic retinopathy, macular degeneration, or systemic hypertension; a history of preoperative treatment including previous ocular surgery or pharmacological treatment with an alpha-1 adrenergic receptor agonist or latanoprost; surgical trauma including posterior capsule rupture, secondary capsulotomy, iris incarceration, retained lens substance, or vitreous loss; and surgical placement of a nylon suture, an iris-fixated intraocular lens, or an anterior chamber intraocular lens, which puts the subject at high risk for a postoperative inflammatory condition. (Item 15) 10. The method of claim 1, wherein the solution is administered by continuous intraocular irrigation during the treatment. (Item 16) 16. The method of claim 15, wherein the solution is administered by continuous intraocular irrigation during the treatment, followed by a bolus injection of the solution at the end of the treatment. (Item 17) 10. The method of claim 1, wherein the solution is administered by intraocular injection during a procedure in which another therapeutic agent is injected intraocularly. (Item 18) 10. The method of claim 1, wherein the solution is administered by intraocular injection before, during, and / or after surgery. (Item 19) 1. A method for inhibiting a post-operative inflammatory state following an ophthalmic surgical procedure, comprising: Identifying a subject at high risk for suffering from a post-operative inflammatory condition; administering to the subject intraocularly during an ophthalmic surgical procedure a solution comprising a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier, wherein the NSAID and the mydriatic are present in the solution in amounts sufficient to maintain pupil diameter intraoperatively and inhibit the postoperative inflammatory state; A method comprising: (Item 20) A method for inhibiting a postoperative inflammatory state after an ophthalmic surgical procedure, comprising intraocularly administering to a subject at risk of a postoperative inflammatory state a solution comprising a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier during the ophthalmic surgical procedure, wherein the NSAID and the mydriatic are contained in the solution in amounts sufficient to promote mydriasis and inhibit miosis, thereby maintaining pupil diameter during surgery, and the solution is administered in an amount sufficient to cause ocular tissue to take up an amount of the NSAID sufficient to inhibit cyclooxygenase for a period of at least 6 hours after surgery, thereby inhibiting the postoperative inflammatory state. (Item 21) 1. A method for reducing the incidence or severity of cystoid macular edema following an ophthalmic surgical procedure, comprising: Identifying a subject at high risk for cystoid macular edema; administering to the subject intraocularly during an ophthalmic surgical procedure a solution comprising a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier, wherein the NSAID and the mydriatic are included in the solution in amounts sufficient to maintain pupil diameter intraoperatively and reduce the incidence or severity of postoperative cystoid macular edema; A method comprising: [Brief explanation of the drawings]

[0018] IV. Brief Description of the Drawings The invention will now be described in more detail, by way of example, with reference to the accompanying drawings, in which:

[0019] [Figure 1] Figures 1-3 show the results of the clinical study of Example 1. Figure 1 shows the mean (±SEM) change over time in mean pupil diameter (PD) from baseline to the end of surgery. From video recordings of the subjects' surgeries, pupil diameter was measured at 1-minute intervals from baseline to the end of the procedure and at the end of cortical clearing. [Figure 2]Figures 1-3 show the results of the clinical study of Example 1. Figure 2 shows the maximum intraoperative pupil constriction at any time during surgery obtained from the study. [Figure 3] Figures 1-3 show the results of the clinical study of Example 1. Figure 3 shows the mean ocular pain visual analog scale (VAS) scores during the early postoperative period (full analysis set population).

[0020] [Figure 4] Figures 4-7 show the results of the dog intracameral study of Example 2, showing the mean ketorolac concentrations in ocular tissues of female dogs at specific time points after intracameral administration of a 1.0% phenylephrine / 0.3% ketorolac injection in balanced salt solution. Figure 4 shows the ketorolac concentrations in the cornea, lens capsule, iris-ciliary body (ICB), aqueous humor, and anterior sclera. [Figure 5] Figures 4-7 show the results of the dog intracameral study of Example 2, showing the mean ketorolac concentrations in ocular tissues of female dogs at specific time points after intracameral administration of a 1.0% phenylephrine / 0.3% ketorolac injection in balanced salt solution. Figure 5 shows the ketorolac concentrations in the bulbar and palpebral conjunctiva. [Figure 6] Figures 4-7 show the results of the dog intracameral study of Example 2, showing the mean ketorolac concentrations in ocular tissues of female dogs at specific time points after intracameral administration of a 1.0% phenylephrine / 0.3% ketorolac injection in balanced salt solution. Figure 6 shows the ketorolac concentrations in the vitreous humor, retina, choroid-RPE (peripheral), choroid-RPE (lamina lucida), and posterior sclera. [Figure 7] Figures 4-7 show the results of the dog intracameral study of Example 2, showing the mean ketorolac concentrations in ocular tissues of female dogs at specific time points after intracameral administration of a 1.0% phenylephrine / 0.3% ketorolac injection in balanced salt solution. Figure 7 shows the mean percent inhibition of COX-1 and COX-2 in retinal tissue from t=0 to t=10 hours. DETAILED DESCRIPTION OF THE INVENTION

[0021] The present invention provides a method for inhibiting a postoperative inflammatory state after an ophthalmic surgical procedure by intraocular administration of a solution containing a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier to a subject at risk for a postoperative inflammatory state. The NSAID and the mydriatic are included in the solution in amounts sufficient to promote mydriasis and inhibit miosis, thereby maintaining pupil diameter during surgery, thereby reducing the likelihood of inflammation-induced trauma to intraocular structures. A sufficient amount of the solution is administered to ocular tissues to achieve uptake of the NSAID in an amount sufficient to inhibit cyclooxygenase for a period of at least six hours after surgery, thereby inhibiting or reducing the likelihood or severity of the postoperative inflammatory state.

[0022] Ophthalmic surgical procedures The present invention can be utilized in various ophthalmic surgical procedures associated with the development of postoperative inflammatory conditions, including anterior segment procedures performed in the anterior or posterior chamber of the eye, and procedures performed in the posterior segment of the eye, such as retinal procedures. In many cases, the procedures are intracameral procedures. Suitably, the ophthalmic surgical procedures in which the methods of the present invention are used are those requiring pupil dilation or mydriasis, so that the dilated pupil allows the surgeon to visualize the surgical field and intraocular structures. In accordance with the present invention, the solution is administered intraocularly by irrigation and / or injection during the procedure to promote mydriasis and inhibit miosis, thereby maintaining pupil diameter and reducing surgical trauma to the iris and intraocular structures manipulated through the iris. The solution of the present invention can be administered to the anterior segment of the eye, particularly the anterior or posterior chamber of the eye, or to the posterior segment of the eye.

[0023] Examples of procedures requiring pupil dilation and associated with postoperative inflammation that are suitable for the practice of the present invention include cataract extraction and lens replacement (CELR), refractive lens exchange (RLE), vitrectomy, retinal photocoagulation, retinal detachment repair, macular hole repair, removal of posterior iris tumors or masses, posterior sclerotomy, and optic nerve resection. CELR and RLE may include femtosecond or scalpel incisions, phacoemulsification for lens removal, and intraocular lens (IOL) replacement. The present invention may also be used in conjunction with the inhibition of inflammatory conditions resulting from intravitreal injection by injecting the solution of the present invention with, simultaneously with, or immediately before or after the injection of one or more other therapeutic agents, such as anti-vascular endothelial growth factor (anti-VEGF), such as ranibizumab.

[0024] Ophthalmic surgeons typically use preoperative treatment with mydriatic medications to dilate the pupil before surgery. Behndig, A. et al., "Intracameral mydriatics incataract surgery," Cataract Surgery, Zaidi F. (ed.), Rijeka, Croatia: InTech, 2013: pp. 149-172. The larger the pupil remains and the longer it remains dilated with one or more mydriatic medications, the easier and less risky the procedure. Pupillary constriction during surgery makes the procedure more difficult and increases the risk of additional complications. (Behndig, 2013).

[0025] Postoperative inflammation Most cataract procedures are routine and uncomplicated. Patalano, VJ, "The risks and benefits of cataract surgery," Digital Journal of Ophthalmology, http: / / www.djo.harvard.edu / site.php?url= / patients / pi / 408, accessed June 26, 2014. ADAM, Inc., "Cataracts In-depth Report," The New York Times, http: / / www.nytimes.com / health / guides / disease / cataract / print.html, June 2, 2014. Accessed on the 6th. However, the occurrence of intraoperative complications is often unpredictable and is estimated to be associated with 3.8% of cataract procedures in the United States (Patalano, 2014); Greenberg, PB et al., "Prevalence and predictors of ocular complications associated with cataract surgery in United States veterans," Ophthalmology, Vol. 118 ( 3): pp. 507-514 (2011).

[0026] Intraoperative miosis makes cataract surgery more difficult by reducing the surgeon's visual field and working space (Behndig, 2013). Intraoperatively, a small pupil increases the risk of posterior capsule rupture and It is associated with an increased risk of intraoperative complications, including vitreous loss. Artzen, D. et al., "Capsule complication during cataract surgery: Case-control study of preoperative and intraoperative risk factors: Swedish Capsule Rupture Study Group report 2," J Cataract Refract Surg, Vol. 35(10): pp. 1688-1693 (2009); Zare, M. et al., "Riskfactors for posterior capsule rupture and vitreous loss during phacoemulsification," J Ophthalmic Vis Res., Vol. 4(4): pp. 208-212 (2009). Also, The reduced visibility and space for surgical manipulation may increase the chance of losing part or the entire vitreous nucleus into the vitreous chamber (dropping the nucleus) or causing injury to the iris (Behndig, 2013).

[0027] Intraoperative miosis is often accompanied by intraoperative floppy iris syndrome (IFIS). Eyes with IFIS have loose, swirling iris tissue, increasing the risk of prolapse and pupil constriction during surgery. Chang, DF, Campbell, JR, "Intraoperative floppy iris syndrome associated with tamsulosin," J Cataract Refract Surg, Vol. 31(4): 664-673.22 (2005); Chang, DF et al., "Prospective multicenter evaluation of cataract surgery in patients taking tamsulosin (Flomax)," Ophthalmology, Vol. 114(5): 957-964 (2007). The incidence of IFIS is known to be particularly high in patients treated with alpha-1 adrenergic receptor agonists, such as tamsulosin (Flomax). (Chang, 2005); Haridas, A. et al., "Intraoperative floppy iris syndrome (IFIS) in patients receiving tamsulosinor doxazosin - a UK-based comparison of incidence and complication rates," GraefesArch Clin Exp Ophthalmol, Vol. 251(No. 6): pp. 1541-1545 (2013). Tamsulosin is used to treat patients with benign prostatic hyperplasia (non-cancerous enlargement of the prostate). Significant intraoperative miosis has been shown to occur in over 70% of these high-risk patients, even when surgery is performed by highly experienced cataract surgeons. (Chang, 2007).

[0028] Even when the procedure is routine and uncomplicated, surgical trauma can result in intraocular inflammation. Lobo, C., "Pseudophakic cystoid macular edema," Ophthalmologica, Vol. 227 (No. 2): pp. 61-67 (2012); Miyake, K., and Ibaraki, N., "Prostaglandins and cystoid macular edema," Surv Ophthalmol, Vol. 2 (Suppl. 1): S203-S18 (2002). Inflammation usually begins in the anterior chamber at the surgical entry site or due to direct mechanical irritation of intraocular structures, such as the iris or ciliary body. The initial inflammatory pathway is self-perpetuating, meaning that inflammation initially increases in intensity and then spreads from the anterior chamber to the vitreous and retina. (Lobo, 2012), (Miyake, 2002).

[0029] Inflammation is associated with dilation of the vessels and vascular leakage. When the eye is inflamed after surgery, retinal blood vessels leak and excess fluid buildup leads to retinal swelling or edema. (Lobo, 2012), (Miyake, 2002). The swelling may involve the macula, a specialized area of the central retina that provides the sharp, detailed vision used in tasks like reading or driving. Retinal swelling involving the macula is called macular edema. Cystoid macular edema (CME) is defined by the presence of anatomically evident fluid pockets or cysts. Ismail, R., Sallam, A., "Complications associated with cataract surgery," Cataract Surgery, Zaidi F. (eds.), Rijeka, Croatia: InTech, 2013: pp. 221-244. Inflammation and Intraocular Proliferation After Cataract Surgery Increased prostaglandin levels have been identified as a cause of CME, and there is a relationship between severe anterior segment inflammation and postoperative CME. Rossetti, L., Autelitano, A., "Cystoid macular edema following cataract surgery," Opin Ophthalmol, Vol. 11: pp. 65-72. 2000).

[0030] Cystoid macular edema (CME) is a major cause of vision loss after cataract and successful vitreoretinal surgery. Loewenstein, A., Zur, D., "Postsurgical Cystoid Macular Edema," in Macular Edema, Dev Ophthalmol., Coscas, G. (ed.), Basel, Karger, 2010: pp. 148-159. CME also remains a problem after capsulotomy, penetrating keratoplasty, scleral cerclage, filtration surgery, and panretinal photocoagulation. (Loewenstein, 2010); Shimura, M. et al., "Panretinal photocoagulation induces pro-inflammatory cytokines and macular thickening." in high-risk proliferative diabetic retinopathy,” Graefes Arch Clin Exp Ophthalmol, 11:65-72 (2000). Estimates of the incidence of postoperative CME depend on the definition and detection method. Studies estimate the prevalence of CME after cataract surgery to be between 4% and 20%. Wielders, L. et al., “Prevention of CME after cataract surgery,” Cataract Refract Surg Today Eur., 53-55 (2013). CME is a common condition in all cases. In some cases, macular edema does not result in vision loss, or the loss of vision may be mild and minimal for the patient. Clinically significant macular edema is associated with visual impairment and is estimated to occur in up to 5.8% of eyes after cataract surgery (Lobo, 2012), (Wielders, 2013).

[0031] An in vivo study evaluated prostaglandin accumulation in aqueous humor after paracentesis in rabbits as a model of ocular surgical trauma. Aqueous humor PGE2 concentrations peaked 1 hour after paracentesis, remained substantially elevated for 7 hours after paracentesis, and approached baseline levels 48 hours after surgical injury. Graff, G. et al., "Transient loss of prostaglandinsynthetic capacity in rabbit iris-ciliary body following anterior chamber paracentesis," Ocular Immunology and Inflammation, Vol. 6(4): pp. 227-238 (1998). Studies have shown that once the inflammatory cascade is initiated during ocular surgical trauma, prostaglandin levels remain elevated for extended periods, potentially leading to an undesirable postoperative state associated with excessive inflammation.

[0032] Postoperative inflammatory state Excessive inflammation induced by ocular surgery can lead to several undesirable postoperative conditions, and the methods and compositions of the present invention can be used to inhibit or reduce the severity or incidence of these conditions. Toxic anterior segment syndrome (TASS) is an acute postoperative inflammatory response in which noninfectious agents enter the anterior segment and induce toxic damage to intraocular tissues. Almost all cases occur after uncomplicated cataract surgery, and more recently, it has been reported after phakic intraocular lens implantation. This syndrome was previously defined by other names, such as sterile endophthalmitis of unknown etiology or postoperative uveitis. Additionally, a condition called toxic endothelial cell destruction (TECD) syndrome has been described and is considered a variant of TASS. Nonsteroidal anti-inflammatory eye drops have been shown to be a useful adjunct in some cases of TASS, supporting the idea that TASS is mediated by inflammation. Al-Ghouri, AR, MD, “Toxic Anterior Segment Syndrome,” http: / / emedicine.medscape.com / article / 1190343-overview, accessed November 23, 2014.

[0033] Cystoid macular edema (CME) is a painless condition characterized by swelling or thickening of the central retina (macula), usually accompanied by blurred or distorted central vision. Less common symptoms include metamorphopsia, micropsia, scotoma, and photophobia. CME is relatively common and is often associated with various ocular conditions, such as age-related macular degeneration (AMD), uveitis, preretinal membranes, vitreomacular traction, diabetes, retinal vein occlusion, medication-related conditions, or post-ocular surgery. When CME develops after cataract surgery and its cause is thought to be directly related to the surgery, it is called Irvine-Gass syndrome or pseudophakic CME. Medical treatments for Irvine-Gass syndrome include NSAIDs, corticosteroids, and carbonic anhydrase inhibitors. Recent advances in cataract surgery, such as phacoemulsification, small-incision surgery, and foldable intraocular lenses, have reduced the physical trauma associated with cataract surgery. Reduction of physical surgical trauma reduces the release of prostaglandins, which play a major role in postoperative ocular inflammation. However, postoperative inflammation continues to cause patient discomfort, delayed recovery, and in some cases suboptimal visual outcomes. If left untreated, this inflammation can interfere with patient rehabilitation and / or contribute to the development of other complications, such as cystoid macular edema. Topically applied NSAIDs are commonly used in the management and prevention of noninfectious ocular inflammation and cystoid macular edema after cataract surgery. Colin, J., "The Role of NSAIDs in the Management of Postoperative Ophthalmic Inflammation," Drugs, Vol. 67(9): pp. 1291-308, (2007).

[0034] The most common cause of cystoid macular edema (CME) is Irvine-Gas syndrome, a condition characterized by CME after cataract extraction or other intraocular surgery (i.e., pseudophakic cystoid macular edema), although many other conditions involve the clinical appearance of fluid-filled cystoid spaces within the macular region (i.e., non-pseudophakic cystoid macular edema). CME is the final, common pathology of many intraocular diseases and usually involves the retinal vasculature. Its appearance may vary somewhat depending on the etiology; however, CME can present as a nonspecific clinical finding. When the cause of CME is unclear, a detailed fundus examination and, occasionally, ancillary tests, may be necessary to identify the cause. The most common medications used to treat CME include steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetazolamide. Roth, DB, MD, “Nonpseudophakic CystoidMacular Edema,” http: / / emedicine.medscape.com / article / 1225735-overview#showall, accessed November 23, 2014.

[0035] Inflammation also appears to play a role in acute postoperative endophthalmitis, and the inventors believe that the present invention may be suitable for improving this condition. The use of intravitreal dexamethasone in the treatment of acute postoperative endophthalmitis remains controversial. Clinicians have used this short-acting corticosteroid to inhibit the inflammatory effects of bacterial endotoxins, host factors, and antibiotics. In a rabbit model of toxic infectious endophthalmitis, dexamethasone has been shown to reduce the efflux of intraocular vancomycin through the trabecular meshwork, suggesting a potential new benefit to steroid administration. Clark, WL, MD, "Postoperative Endophthalmitis Treatment & Management," http: / / emedicine.medscape.com / article / 1201260-treatment, accessed November 23, 2014. Nonsteroidal anti-inflammatory drugs are typically They can provide comparable anti-inflammatory efficacy (for both postoperative inflammation and cystoid macular edema) without the adverse events associated with corticosteroids. Rowen, S., "Preoperative and Postoperative Medications Used for Cataract Surgery," Curr Opin Ophthalmol., 10(1):29-35 (1999).

[0036] The present invention may also be suitably used to inhibit postoperative posterior capsule opacification or anterior capsule contraction. In approximately 20% of patients, the posterior portion of the capsule becomes opaque sometime during cataract surgery recovery, or even several months later, resulting in posterior capsule opacification. Posterior capsule opacification occurs due to proliferation of lens epithelial cells on the capsule that remain after cataract surgery. Knobbe, CA, MD, "Cataract Surgery Complications," http: / / www.allaboutvision.com / conditions / cataract-complications.htm, 2014 Accessed November 23. Sustained-release celecoxib (an NSAID) from incubated acrylic intraocular lenses has been shown to suppress lens epithelial cell proliferation in an ex vivo model of posterior capsule opacity. Davis, JL et al., "Sustained-release Celecoxib From Incubated Acrylic Intraocular Lenses Suppresses Lens Epithelial Cell Growth in an Ex Vivo Model of Posterior Capsule Opacity," J Ocul Pharmacol Ther., 28(4):359-68 (2012).

[0037] The present invention can also be suitably used to inhibit herpes simplex virus keratitis after cataract surgery. Ocular infection with herpes simplex virus (HSV) leads to blinding immunoinflammatory stromal keratitis (SK) lesions. Early preclinical events include polymorphonuclear neutrophil (PMN) infiltration and angiogenesis in the corneal stroma. HSV infection of the cornea has been shown to result in upregulation of the cyclooxygenase 2 (COX-2) enzyme. Inhibition of COX-2 with selective inhibitors has been shown to reduce corneal angiogenesis and SK severity, so induction of COX-2 by HSV infection is an important event. Administration of COX-2 inhibitors has been shown to reduce PMN infiltration into the cornea and attenuate corneal vascular endothelial growth factor levels, likely responsible for the reduced angiogenic response. Biswas, PS et al., “Role of Inflammatory Cytokine-induced Cyclooxygenase 2 in the Ocular Immunopathologic DiseaseHerpetic Stromal Keratitis,” J Virol, vol. 79(16): 10589~ 600 pages (2005).

[0038] The nonsteroidal anti-inflammatory drug ketorolac can prevent postoperative hypotension due to cyclooxygenase products released during cataract surgery and other procedures, demonstrating further utility of the present invention. A study evaluating the inhibition of PGE2 production by ketorolac, bromfenac, and nepafenac in patients undergoing phacoemulsification showed that ketorolac 0.45% achieved the highest PGE2 inhibition compared with nepafenac 0.1% and bromfenac 0.09%. Bucci, FA, Jr. et al., "Prostaglandin E2 Inhibition of Ketorolac 0.45%, Bromfenac 0.09%, and Nepafenac 0.1% in Patients Undergoing Phacoemulsification," Adv Ther, 28(12):1089-95 (2011). The possibility of acute increases in intraocular pressure (IOP) after laser iridotomy is well known. Studies have shown that laser irradiation of the iris itself can also cause hypotony in the eye, so this phenomenon may be another explanation for the IOP response after peripheral iridoplasty. Kim, YY et al., "Biphasic Intraocular Pressure Response to Laser Irradiation of the Irisin Rabbits," Ophthalmic Res, 27(4):243-8 (1995).

[0039] Nylon suture toxicity also results in postoperative inflammation and may be adequately inhibited by the use of the present invention. A cluster of symptoms and signs that developed in 10 of 105 consecutive patients (9.5%) who underwent uncomplicated planned extracapsular cataract extraction (ECCE) with a posterior chamber intraocular lens (PC IOL) implant appeared to be related to wound closure. These signs and symptoms included a foreign body sensation, focal conjunctival hyperemia and infiltrate around the scleral wound, and scleral cupping beneath the continuous 10-0 nylon suture, likely resulting from focal scleral edema. The duration of clinical symptoms ranged from 1 to 6 weeks. Conjunctival staining showed eosinophils and polymorphonuclear leukocytes in some cases. Results of Gram stain, conjunctival culture, and suture toxicology studies were negative. Balyeat, HD et al., "Nylon Suture Toxicity After Cataract Surgery," Ophthalmology, Vol. 95(11): pp. 1509-14 (1988).

[0040] Cataract surgery may, in some cases, result in long-term corneal endothelial cell loss, while vitrectomy may result in corneal edema, both of which can be inhibited by the present invention. Three-day and one-day administration of ketorolac has been shown to reduce surgical time, phacoemulsification time and energy, and endothelial cell loss, and improved visual acuity in the immediate postoperative period compared with one-hour pre-administration or the use of a placebo. Donnenfeld, E.D. et al., "Preoperative Ketorolac Tromethamine 0.4% in Phacoemulsification Outcomes: Pharmacokinetic-Response Curve," J. Cataract Refract Surg., 32(9):1474-82 (2006); Hiraoka, M. et al., "Factors Contributing to Corneal Complications after Vitrectomy in Diabetic Patients," J. J. Ophthalmol., 45(5):492-5 (2001). Ketorolac tromethamine 0.5% ophthalmic solution has been shown to be effective and well tolerated in controlling postoperative inflammation. Simone, JN, "Comparison of the Efficacy and Safety of Ketorolac Tromethamine 0.5% and Prednisolone Acetate 1% after Cataract Surgery," J Cataract Refract Surg., Vol. 25 (No. 5) ): pp. 699-704 (1999).

[0041] Intraocular lens implantation can be associated with corneal-retinal inflammatory syndrome, which causes corneal decompensation and cystoid macular edema. The inflammatory lesions often appear unremarkable and manifest as mild ciliary injection, mild redness, moderate anterior chamber cytosis, and moderate vitritis. The cornea decompensates in the presence of an endothelial cell count sufficient to maintain corneal transparency in non-inflamed eyes. Metal-ring lenses and poorly polished lenses can cause iris abrasion and capillary leakage, which increase the severity of this syndrome. It is hypothesized that intraocular surgery initiates an inflammatory response, which is amplified by certain components of the intraocular lens. Mediating this increased inflammatory response can be inhibited by both steroidal and nonsteroidal anti-inflammatory drugs. The presence of leukocytes and their products, such as lysosomal enzymes, can be sufficient to perpetuate the inflammatory response, resulting in damage to abnormal and normal cells. The presence of proteins and their immune components, as well as complement, may be associated with this syndrome. Obstbaum, SA et al., "Cystoid Macular Oedema and Ocular Inflammation. The Corneo-Retinal Inflammatory Syndrome," Trans Ophthalmol Soc U K., 99(1):187-91 (1979).

[0042] In addition, postoperative scleritis and episcleritis can be inhibited by the use of the present invention. Several cases of necrotizing sclerokeratitis after ocular surgery have been reported in recently published literature. The condition was probably induced by surgical inflammation and caused by focal occlusive vasculitis: one case showed immune complex deposits in the blood vessel walls. Clinical examination showed loss of blood vessels along with tissue necrosis in the affected sclera. Gregersen, E. et al., "Necrotizing Sclerokeratitis: Following Cataract Extraction," Klin Monbl Augenheilkd., 193(6):642-4 (1988). A report of 21 cases of surgically induced diffuse scleritis (SIDS) after planned extracapsular cataract extraction with intraocular lens implantation among 682 cataract patients found that the mean age was significantly lower in patients with SIDS (mean 62.5 years, SD 13.68) compared with the non-scleritis group (mean 73.6 years, SD 10.2; Mann-Whitney U test, p=0.0003). There was an association between SIDS and general anesthesia (chi-square test, p=0.0008). Twenty of the 21 patients with SIDS responded to oral nonsteroidal anti-inflammatory drugs and had excellent visual outcomes. Scott, J.A. et al., "Surgically Induced Diffuse Scleritis Following Cataract Surgery," Eye (London), 8(Pt3):292-7 (1994).

[0043] Vitreous incarceration syndrome occurs after ocular surgery and consists of microscopic wound breakage, followed by vitreous prolapse, which progresses to vitreous wicking, which can also be appropriately inhibited by the practice of the present invention. Vitreous incarceration syndrome develops against the background of trauma, either iatrogenic or non-iatrogenic. Vitreous incarceration syndrome of iatrogenic origin usually occurs as a result of anterior segment surgery, but can also occur as a result of sub-Tenon injections and muscle surgery. Corneal wound healing has been described to be slower on the endothelial side (inner layer). Poor suturing technique has been implicated as a major cause of wound breakage. Tightly compressed corneal wound edges may exhibit puckering. This may also cause enlargement of the suture area and promote tissue necrosis within the suture loop. If communication between the posterior wound gap and the anterior wound defect occurs (following tissue necrosis from tight sutures), anterior aqueous humor may be released and vitreous impaction may occur, creating a vitreous wick. Occasionally, complete dissection of the trapped tissue within the suture loop may occur. Sloughing may occur. Rogue, MR, MD, MBA, FPAO, "Vitreous Wick Syndrome." http: / / emedicine.medscape.com / article / 1230457-overview#a0101, accessed November 23, 2014. A study comparing the force required to separate corneal wounds after topical application of nonsteroidal anti-inflammatory drugs or corticosteroids found that steroid treatment resulted in weaker corneal wound scars than NSAIDs. McCarey, BE et al., "Corneal Wound Healing Strength with Topical Antiinflammatory Drugs," Cornea, 14(3):290-4 (1995).

[0044] Additionally, postoperative acute iridocyclitis, or postoperative inflammation of the iris and ciliary body, offers a therapeutic opportunity for the present invention. Evaluation of the adjunctive use of nonsteroidal anti-inflammatory drugs for the treatment of chronic iridocyclitis in 14 patients reported that 8 of these patients had juvenile rheumatoid arthritis and 6 had idiopathic iridocyclitis. In all patients, the activity of iridocyclitis improved with the addition of an NSAID to the treatment regimen, allowing for a reduction in the dose of corticosteroids. These data suggest that NSAID therapy may have an adjunctive role in the treatment of chronic iridocyclitis in childhood. Olson, NY et al., "Nonsteroidal anti-inflammatory drug therapy in chronic childhood iridocyclitis," Am J Dis Child, Vol. 142 (No. 12): 1289-92 (1988). Cataracts are a common juvenile condition. Idiopathic arthritis-associated uveitis is an early complication of juvenile idiopathic arthritis-associated uveitis. Under strict control of uveitis, IOL implantation is an important option for visual rehabilitation in this type of patient. Control of uveitis with NSAIDs before, during, and after cataract surgery demonstrates further utility of the present invention. Kotaniemi, K. et al., "Intraocular Lens Implantation in Patients with Juvenile Idiopathic Arthritis-Associated Uveitis," Ophthalmic Res., Vol. 38(6): 318-23 (2006).

[0045] The present invention may further be used to inhibit inflammation due to retinal deposits after cataract extraction. In a report of two patients identified with retinal deposits after cataract extraction in which the posterior capsular barrier was breached, the inflammation was found to be confined to the posterior segment, and investigations for infectious causes were negative. Behera, UC, "Epiretinal Deposits Postcataract Extraction" Extraction,” RetinCases Brief Rep., Vol. 7(No. 4): pp. 359-61 (2013) ).

[0046] Recurrent membrane proliferation with giant cell deposits may result in some cases of cataract surgery. One report addresses the outcomes of a 72-year-old Japanese woman and a 67-year-old Japanese man (both eyes in the first case and the left eye in the second case) who underwent AcrySof IOL (SA60AT) implantation for the treatment of cataract and vitreous opacification associated with uveitis. Although the intraocular inflammation appeared to be well controlled, the number of giant cell deposits on the posterior surface of the posterior capsule gradually increased, leading to the development of posterior capsular opacification at 5 and 9 months, respectively, requiring neodymium-doped yttrium-aluminum-garnet (Nd:YAG) laser capsulotomy. Iwase, T. , "ReiterativeMembranousProliferation With Giant-Cell Deposits on Hydrophobic Acrylic Intraocular Lenses After Triple Procedures in Eyes with Cataracts and Uveitis", CutanOcul Toxicol., vol. 29(4): pp. 306-11 (2010).

[0047] A report of 11 cases of intraocular inflammation after intravitreal injection demonstrates another suitable use of the present invention. Only one of these cases had infectious endophthalmitis with retinal abscess; all others had toxic vitreitis. Seven eyes had hypopyon, and five eyes had retinal hemorrhage. The toxic reaction occurred within 48 hours after injection, whereas in the endophthalmitis case, the toxic reaction occurred 72 hours later. The authors attributed this reaction to the specific syringe brand used. After switching to a different syringe brand, no further cases of toxic vitreitis occurred over the next 6 months. Ness, T. et al., "Toxic Vitreitis Outbreak After Intravitreal Injection," Retina., 30(2):332-8 (2010).

[0048] Synechia is an ocular condition in which the iris adheres to either the cornea (i.e., anterior synechia) or the lens (i.e., posterior synechia), and instances of this condition following surgical procedures can be inhibited by the present invention. Synechia can be caused by ocular trauma, iritis, or iridocyclitis, and can lead to certain types of glaucoma. Topical corticosteroids have traditionally been used to suppress the inflammation. Wikipedia contributors, "Synechia (eye)," Wikipedia, The Free Encyclopedia, http: / / en.wikipedia.org / wiki / Synechia_(eye), accessed November 23, 2014.

[0049] The present invention can also be used to inhibit postoperative intraocular fibrin formation. The anti-inflammatory effect of 0.1% diclofenac sodium on anterior segment inflammation after cataract surgery has been reported. Postoperative fibrin deposition in patients without systemic or ocular disease was significantly reduced when diclofenac sodium ophthalmic solution was used in combination with topical corticosteroids. There was also a reduction in fibrin deposition in other patients, particularly those with diabetes mellitus, primary angle-closure glaucoma, and exfoliation syndrome. Matsuo, K. et al., "Clinical Efficacy of Diclofenac Sodium on Postsurgical Inflammation After Intraocular Lens Implantation," Refract Surg., Vol. 21 (No. 3): pp. 309-12 (1999). 995).

[0050] Four cases of incisional complications after pars plana vitrectomy demonstrate the utility of the present invention for inhibiting incisional fibrosis. As reported, in each case, excessive fibrosis occurred at the wound site. In one patient, the damage was mild and did not result in clinical difficulties during life; however, in three severe cases, the eye lost secondary intraocular structures (fibrotic changes) and had pneumophthalmos. Possible contributing factors include diabetes mellitus, excessive trauma and necrosis at the wound site, postoperative inflammation, and vitreous involvement in the wound. Kreiger, A.E. , “IncisionalComplications inPars Plana Vitrectomy”, Mod Probl Ophthalmol. 18:210-23 (1977).

[0051] The present invention may be useful for treating choroidal neovascularization and other complications after surgical treatment for macular holes. In a study of complications of vitrectomy surgery for full-thickness macular holes, posterior segment complications were noted in 39 eyes (41%). The incidence of retinal pigment epithelial changes and retinal detachment was 33% and 11%, respectively. One case of retinal detachment due to a giant retinal break resulted in optic flaps. Other complications included reopening of the macular hole in two eyes (2%), cystoid macular edema in one eye (1%), choroidal neovascular membrane in one eye (1%), and endophthalmitis in one eye (1%). Banker, AS, "Vision-Threatening Complications of Surgery for Full-Thickness Macular Holes. Vitrectomy for Macular Hole Study Group," Ophthalmology, Vol. 104(9): pp. 1442-52 (1997). Preliminary studies have suggested that topical ketorolac may complement the activity of intravitreal ranibizumab in reducing the 6-month mean change in central macular thickness in choroidal neovascularization. Russo, A. et al., "A Randomized Controlled Trial of Ranibizumab With and Without Ketorolac Eyedrops for Exudative Age-Related Macular Degeneration," Br J Ophthalmol., 97(10):1273-6 (2013).

[0052] Choroidal effusion, the accumulation of abnormal fluid in the suprachoroidal space, is a common complication of glaucoma surgery and can be successfully inhibited by the practice of the present invention. Choroidal effusion can also result from several conditions, including other intraocular surgical procedures, inflammatory and infectious diseases, trauma, neoplasms, drug reactions, and venous congestion. Idiopathic causes fall under the umbrella of uveal effusion syndromes, rare conditions that are usually considered diagnoses of exclusion. Reddy, AC, MD, "Diagnosis and Management of Choroidal Effusions," http: / / www.aao.org / publications / eyenet / 201211 / pearls.cfm?RenderForPrint=1&, accessed November 23, 2014.

[0053] Hypopyon, seen as a yellowish exudate in the lower anterior chamber of the eye, is composed of inflammatory cells. It is a leukocytic exudate and is a sign of iritis, an inflammation of the anterior uvea and iris, a form of anterior uveitis. Hypopyon has been reported in patients with rheumatoid arthritis who underwent phacoemulsification. This 70-year-old woman received a maintenance dose of systemic methylprednisolone during an uncomplicated phacoemulsification of her left eye. She developed a sterile hypopyon on the first postoperative day and was treated aggressively with topical and systemic therapy, leading to gradual resolution of the inflammatory response. The patient subsequently underwent phacoemulsification of her right eye. The only notable difference in preoperative management this time was that the patient received topical ofloxacin and ketorolac for 4 days before surgery. The postoperative inflammatory response was much better controlled. The patient continued ketorolac and prednisolone acetate, resulting in a normal postoperative inflammatory response. Caronia, RM, "Antiinflammatory Effect of Preoperative Ketorolac in Phacoemulsification", JCataract Refract Surg., Vol. 28 (Issue 10): pp. 1880-1 (200 2 years). This report suggests that the present invention may have utility for inhibiting hypopyon following ocular surgery.

[0054] Predisposing conditions The present invention also provides a method for inhibiting a postoperative inflammatory condition following an ophthalmic surgical procedure by identifying a subject at physiological risk of suffering from a postoperative inflammatory condition and intraocularly administering to the subject during the ophthalmic surgical procedure a solution comprising a nonsteroidal anti-inflammatory drug (NSAID) and an alpha-1 adrenergic receptor agonist mydriatic in an intraocular irrigation carrier, wherein the NSAID and mydriatic are contained in the solution in an amount sufficient to inhibit the postoperative inflammatory condition.

[0055] Also, small pupil size during surgery has been associated with a higher risk of intraoperative complications (Artzen, 2009), (Zare, 2009). Studies have identified risk factors that help surgeons predict which patients may be at risk for complications during surgery. Older age, previous eye surgery, and diabetes with ocular manifestations are among the patient-related factors that have been associated with a higher risk of intraoperative complications (Greenberg, 2011). Having diabetes mellitus (DM) Individuals with diabetes are often prone to developing cataracts, and it is estimated that over 25% of patients with cataracts also have concomitant DM. National Diabetes Clearing House, diabetes.niddk.nih.gov, accessed September 30, 2012; Ostri C. et al., "Phacoemulsification cataract surgery in a large cohort of diabetes patients: visual acuity outcomes and prognostic factors," J Cataract Refract Surg, 37(11):2006-2012. pp. 012 (2011). Individuals with DM undergoing cataract surgery have a greater tendency to have intraoperative miosis than individuals without DM. This may lead to more postoperative complications, such as the development of postoperative cystoid macular edema, worsening of diabetic macular edema, progression to proliferative diabetic retinopathy, and the development of rubeosis iridis. Oetting, T., "Complicated cataract cases. Cataract surgery and diabetes,” ASCRS EyeWorld, http: / / www.eyeworld.org / article-cataract-surgery-and-diabetes, accessed November 25, 2014.

[0056] Systemic diseases, intraoperative complications, and pre-existing ocular conditions are risk factors that influence the development of CME (Loewenstein, 2010). Systemic risk factors for postoperative CME include diabetes mellitus, This includes diabetic retinopathy, which promotes the development of CME even in the absence of diabetic retinopathy. Schmier J. et al., "Evaluation of costs for cystoid macular edema refractory to topical medications," Ophthalmology, 104:2003-2008 (1997). High blood pressure significantly increases the incidence of postoperative CME. Flach, A., "The incidence, pathogenesis, and treatment of cystoid macular edema following cataract surgery," Trans Am Ophthalmol Soc, 96:557-634 (1998). Systemic hypertension is also a risk factor for retinal vein occlusion, which itself increases CME. (Loewenstein, 2010)

[0057] Certain surgical complications also increase the risk of CME. Posterior capsule rupture and secondary capsulorhexis, including YAG capsulorhexis, are associated with higher rates of CME. Vitreous loss increases the prevalence of CME by 10-20%. Iris incarceration is an additional risk factor for CME, as are certain types of intraocular lenses, particularly iris-fixated IOLs and anterior chamber IOLs (Loewenstein, 2010). Pars plana vitreous for retained lens fragments A review of patients with CME after cataract extraction showed that 8% of eyes with sulcus-fixated posterior chamber IOLs and 46% of eyes with aphakic or anterior chamber IOLs developed CME. Cohen, S., et al., "Cystoid macular edema after parsplana vitrectomy forretained lens fragments," JCataract Surg, 32:1521. 1526 pages (2006).

[0058] Certain pre-existing conditions also increase the risk of postoperative CME. These conditions can compromise the integrity of the blood-retinal barrier and accelerate inflammatory activity. These include uveitis, in which CME is the most important cause of poor visual outcomes after cataract surgery (Loewenstein, 2010). As noted above, preoperative diabetic retinopathy , significantly increasing the risk of onset and persistence of CME (Iliff, W., "Aphakic cystoid "Macular edema and the operating microscope: is there a connection?" TransAm Ophthalmol Soc 83:476-500 (1985)), while a history of retinal vein occlusion and preretinal membrane (ERM) also predicts the development of CME. Henderson, B. et al., "Clinical pseudophakiccystoid macular edema. Risk factors for development and duration." of treatment,” J Cataract Refract Surg, 33:1550-1558 (2007). Topical use of latanoprost in patients with glaucoma has been reported to be associated with pseudophakic CME. Warwar, R. et al., “Cystoid macular edema and anterior uveitis associated with latanoprost use. Experience and incidence in an antrospective review of 94 Ophthalmology, vol. 105: 263-268 (1998).

[0059] According to aspects of the present invention, subjects treated with the NSAID and alpha-1 adrenergic receptor agonist solution of the present invention have been identified as being at high risk for a postoperative inflammatory condition due to preoperative physiological conditions or characteristics including small pupil diameter (e.g., a preoperative dilated pupil diameter of less than 6 mm), iris hypotony syndrome, uveitis, retinal vein occlusion, preretinal membrane, advanced age (e.g., over 65 years old, elderly, or geriatric), diabetes mellitus, diabetic macular edema, diabetic retinopathy, macular degeneration, or systemic hypertension; a history of preoperative treatments including previous ocular surgery or pharmacological treatment with an alpha-1 adrenergic receptor agonist or latanoprost; surgical trauma including posterior capsule rupture, secondary capsulotomy, iris incarceration, retained lens material, or vitreous loss; and surgical placement of nylon sutures, an iris-fixated intraocular lens, or an anterior chamber intraocular lens. As used herein, "high risk" of a postoperative inflammatory condition refers to a subject whose risk of experiencing a postoperative inflammatory condition after an ophthalmic procedure is higher than the average incidence of the same postoperative inflammatory condition in healthy subjects without any predisposing risk characteristics undergoing the same procedure.

[0060] Subjects at high risk for postoperative inflammation can be identified by surgeons prior to surgery based on the patient's preoperative physiological condition or characteristics or preoperative treatment history, or the planned placement of sutures or intraocular devices associated with a high incidence of postoperative inflammation. Once identified, the surgeon can administer the solution of the present invention during the surgical procedure to proactively reduce or diminish the incidence or severity of postoperative inflammation. Alternatively, the surgeon can prophylactically administer the solution of the present invention during the surgical procedure to address a high risk of postoperative inflammation that may be identified during the procedure due to the nature of the surgical trauma, such as posterior capsule rupture, secondary capsulotomy, iris incarceration, retained lens material, or vitreous loss, or the use of unplanned sutures or devices associated with a high incidence of postoperative inflammation.

[0061] Pharmacological agents A wide variety of ophthalmic surgical procedures induce intraocular inflammation. As evidenced by the paracentesis study described above, once the inflammatory cascade is initiated, prostaglandin levels remain elevated for up to 7 hours. The method of the present invention provides intraoperative delivery of a combination of an NSAID and an alpha-1 adrenergic receptor agonist mydriatic. In a preferred embodiment of the present invention, the NSAID is ketorolac, and the alpha-1 adrenergic receptor agonist mydriatic is phenylephrine.

[0062] Several studies have shown that the effect of NSAIDs in inhibiting prostaglandin formation by the cyclooxygenase (COX) enzyme has an important impact on the prevention of CME. Wolf, EJ, et al., "Incidence of visually significant pseudophakic macular edema after uneventful phacoemulsification in patients treated with nepafenac," J Cataract Refract Surg, 33:1546-1549 (2007); Cervantes-Coste, G., et al., "Inhibition of surgically induced miosis and prevention of postoperative macular edema with nepafenac," Clin Ophthalmol, 3:219-226 (2007). 2009); Donnenfeld, ED et al., “Preoperative ketorolactromethamine 0.4% in phacoemulsification outcomes:pharmacokinetic-responsecurve”, J Cataract Refract Surg., 32:1474-1482 (2006).

[0063] Nonsteroidal anti-inflammatory drugs (NSAIDs) suitable for use in the present invention include flurbiprofen, suprofen, diclofenac, ketoprofen, ketorolac, indomethacin, nepafenac, and bromfenac.Preferred NSAID is ketorolac.As used herein, "ketorolac" refers to the salt form of ketorolac, such as ketorolac tromethamine [(+ / -)-5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid:2-amino-2(hydroxymethyl)-1,3-propanediol (1:1)].In one formulation of the present invention, ketorolac is included as ketorolac tromethamine salt [(±)-5-benzoyl-2,3-dihydro-1H-pyrrolidine-1-carboxylic acid:2-amino-2(hydroxymethyl)-1,3-propanediol (1:1)]. Ketorolac is a member of the pyrrolo-pyrrole group of nonsteroidal anti-inflammatory drugs. Ketorolac HCl is a racemic mixture of the R-(+) and S-(-) enantiomers, which can exist in three crystalline forms, all of which are equally water-soluble. Ketorolac is a nonsteroidal anti-inflammatory drug that inhibits both cyclooxygenase enzymes (COX-1 and COX-2). When used in accordance with the present invention, it reduces tissue concentrations of prostaglandins, thereby reducing pain due to surgical trauma. Ketorolac also prevents surgically induced miosis by inhibiting prostaglandin synthesis secondary to surgical eye injury or direct mechanical stimulation of the iris.

[0064] Suitable alpha-1 adrenergic receptor agonists for use as mydriatics in the present invention include, for example, phenylephrine, epinephrine, oxymetazoline, and naphazoline. A preferred alpha-1 adrenergic receptor agonist is phenylephrine. As used herein, "phenylephrine" refers to a salt form of phenylephrine, such as phenylephrine HCL [(-)-m-hydroxy-α-[(methylamino)methyl]benzyl alcohol hydrochloride]. Phenylephrine is an alpha-1 adrenergic receptor agonist, and in the eye, it acts as a mydriatic by contracting the radial muscle of the iris.

[0065] In accordance with the present invention, an NSAID and an alpha-1 adrenergic receptor agonist solution are administered intraocularly by irrigation and / or injection during the procedure to promote mydriasis and inhibit miosis, thereby maintaining pupil diameter and thereby reducing surgical trauma to the iris and intraocular structures manipulated through the iris. In this manner, the local presence of both a mydriatic (e.g., phenylephrine) and an anti-miotic (e.g., ketorolac) intraocularly during the surgical procedure provides a complimentary mechanism for proactively limiting trauma-induced inflammation during the procedure. Using a puncture in a rabbit model of surgical trauma as described above (Graff, 1998), In vivo studies have shown that prostaglandin levels remain elevated for periods of up to 7 hours after ocular surgical trauma. In vivo studies in dogs to determine ketorolac concentrations in the retina and other ocular tissues after intracameral administration of a phenylephrine and ketorolac solution, described in Example 2 below, surprisingly show that intraoperative ketorolac uptake by the retina and other ocular tissues is sufficient to inhibit COX-1 and COX-2 levels by at least 90% in ocular tissues for at least 8 hours after drug administration and by at least 85% in ocular tissues for at least 10 hours after drug administration. Thus, the present invention inhibits inflammation during surgical procedures by reducing trauma through complementary mydriatic and antimiotic effects and by proactively inhibiting prostaglandin release, and continues to inhibit inflammation during the period when postoperative cyclooxygenase levels are most elevated.

[0066] formulation NSAID and alpha-1 adrenergic receptor agonist are contained in an aqueous solvent as a carrier to obtain a drug composition or solution.The aqueous carrier is suitably water for injection (WFI), which is a sterile, solute-free preparation of distilled water.Alternatively, other aqueous carriers that are not harmful to intraocular tissues and do not adversely affect the stability of the formulation can be used (for example, deionized water, or saline or balanced salt solutions such as those described below, after first evaluating the potential impact on stability).

[0067] The NSAID and alpha-1 adrenergic receptor agonist solutions of the present invention are suitably adjusted to a pH of 5.8 to 6.8, and preferably about 6.3. Sodium hydroxide and hydrochloric acid can be added as needed to adjust the formulation to this pH. The desired pH is suitably maintained by using a buffer system. One such suitable system is a citrate buffer (containing citric acid monohydrate and sodium citrate dihydrate), and another suitable system is a sodium phosphate buffer (containing dibasic sodium phosphate and monobasic sodium phosphate). Either buffer system can be used at a suitable concentration ranging from 10 mM to 100 mM, suitably 20 mM. As described in Example 1 below, sodium citrate is a preferred buffering agent for use in preservative- and antioxidant-free formulations. Because citric acid in a citrate buffer has the ability to chelate divalent cations, it can also prevent oxidation, providing antioxidant and buffering effects. As used herein, the term "antioxidant-free" excludes the use of other antioxidants, but does not exclude the use of buffering agents (e.g., citric acid) included as part of a buffer system.

[0068] The NSAID and alpha-1 adrenergic receptor agonist solution of the present invention, such as the phenylephrine and ketorolac combination drug solution, is appropriately diluted into an irrigating solution by pouring it into a bag, bottle, or other container before administration by irrigation or injection.Suitable irrigating solutions include saline, lactated Ringer's solution, balanced salt solution, or any other irrigating solution that is compatible with aqueous formulations and is not harmful to ocular tissues.A suitable irrigating carrier contains one or more, and preferably all, of the following auxiliary substances: sufficient electrolytes to provide a physiologically balanced salt solution; a cellular energy source; a buffering agent; and a free radical scavenger. One suitable solution (referred to in the examples below as "balanced salt solution" or "BSS") contains the following: electrolytes at 50-500 millimolar sodium ions, 0.1-50 millimolar potassium ions, 0.1-5 millimolar calcium ions, 0.1-5 millimolar magnesium ions, 50-500 millimolar chloride ions, and 0.1-10 millimolar phosphate ions; bicarbonate as a buffer at 10-50 millimolar; a cellular energy source selected from dextrose and glucose at 1-25 millimolar; and glutathione as a free radical scavenger (i.e., antioxidant) at 0.05-5 millimolar.

[0069] One example of a suitable method for diluting and administering a preferred phenylephrine and ketorolac composition of the present invention utilizes the formulation of the present invention set forth in Table 1 below. A 4.5 mL aliquot of this solution (including 4.0 mL as the intended amount for a single use and a 0.5 mL overfill) is contained in a sterile, closed, single-use vial and intended for mixing with irrigation solution for administration during intraocular surgery. 4 mL is withdrawn from the vial with a syringe and mixed with 500 mL of BSS by injecting into a 500 mL bag or bottle of BSS to provide a final concentration of 483 μM phenylephrine and 89 μM ketorolac in the irrigation solution for topical delivery to the eye.

[0070] In another aspect of the present invention, a sterile liquid pharmaceutical formulation for irrigation can be provided, in which the phenylephrine and ketorolac are diluted to the desired concentration of each active pharmaceutical ingredient for local delivery to intraocular tissues during surgery and pre-mixed in an intraocular irrigation carrier, such that the active pharmaceutical ingredients are contained in a sterile bag, bottle, or other irrigation container. For example, such a formulation for irrigation can contain phenylephrine at a concentration of 30-720 μM and ketorolac at a concentration of 10-270 μM, or preferably, phenylephrine at a concentration of 90-720 μM and ketorolac at a concentration of 44-134 μM.

[0071] As described above, exemplary sterile, stable liquid pharmaceutical formulations of the present invention comprise phenylephrine and ketorolac in a buffered aqueous carrier. Suitable concentrations of phenylephrine in the combination drug compositions of the present invention range from 10 mM to 500 mM, and preferably from 45 mM to 112 mM. Suitable concentrations of ketorolac in the combination drug compositions of the present invention range from 2 mM to 75 mM, and preferably from 8.5 mM to 24 mM. The buffer system (e.g., a sodium citrate buffer system) is suitably included at a concentration of 10 to 100 mM, and preferably about 20 mM. Exemplary formulations for use in accordance with the present invention are shown in Table 1 below. Sodium hydroxide and / or hydrochloric acid may be added, if necessary, to adjust the pH to about 6.3 when preparing the formulation. [Table 1]

[0072] The amount of the pharmaceutically active ingredient contained in the formulation can be expressed as a molar ratio. The molar ratio of phenylephrine to ketorolac can range from 1:1 to 13:1, and more suitably from 3:1 to 10:1. An exemplary molar ratio of phenylephrine and ketorolac as shown in Table 1 above is 5.4:1 phenylephrine:ketorolac.

[0073] After dilution of this exemplary formulation of the present invention into an intraocular irrigation carrier for topical delivery, the dosage concentration of phenylephrine can be 3-7,200 μM, more suitably 30-720 μM, more suitably 90-720 μM, even more suitably 240-720 μM, and most preferably about 483 μM. After dilution of this exemplary formulation of the present invention into an intraocular irrigation carrier for topical delivery, the dosage concentration of ketorolac can be 3-900 μM, more suitably 10-270 μM, more suitably 44-134 μM, even more suitably 30-90 μM, and most preferably about 90 μM.

[0074] It should be noted that as used herein and in the appended claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "an excipient" includes a plurality of such excipients and equivalents thereof known to those skilled in the art, and the like. The term "about," as used herein, is understood to mean that there may be a variation in the stated condition or amount, which may be inclusive of 5%, 10%, 15%, or up to 20% of a given value.

[0075] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein should be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates, which may need to be independently confirmed. All citations are incorporated herein by reference. [Example]

[0076] Example 1 A clinical study evaluating phenylephrine 1% / ketorolac 0.3% in cataract surgery and intraocular lens placement for maintaining pupil dilation and preventing postoperative pain. This example describes two Phase 3 clinical studies conducted to evaluate the efficacy and safety of phenylephrine 1% and ketorolac 0.3% injections, formulated as described in Table 1 above, when used to maintain pupil dilation during cataract surgery and intraocular lens (IOL) placement and to prevent postoperative pain after cataract surgery and IOL placement.

[0077] method Two pivotal, multicenter, randomized, parallel-group, double-blind, placebo-controlled phase 3 studies (Study 1 and Study 2) were conducted to support the use of phenylephrine 1% and ketorolac 0.3% injection (OMS302) for maintaining intraoperative pupillary dilation, preventing intraoperative miosis, and reducing early postoperative ocular pain associated with cataract surgery and IOL placement. Subjects from a total of 20 sites in the United States and the Netherlands were enrolled in these studies.

[0078] Subjects were randomized to receive either OMS302 or placebo. A single dose of the study drug, OMS302 (483 μM phenylephrine and 89 μM ketorolac formulated in 20 mM sodium citrate buffer) or placebo (20 mM sodium citrate buffer) was added to balanced salt solution (BSS, 500 mL) and administered intracamerally as part of the standard irrigation solution during the procedure. Postoperative assessments were performed for up to 14 days (Study 1) or 90 days (Study 2), and the pooled safety analysis was limited to data collected up to 14 days postoperatively. All subjects in the study (OMS302-treated and placebo-treated) received standard medical preoperative topical mydriatics and anesthetics.

[0079] Two co-primary endpoints were prespecified for the pooled analysis: 1) intraoperative pupil diameter during surgery, and 2) ocular pain during the early postoperative period after surgery. Each subject's surgical procedure was videotaped, and a single blinded central reader measured the change in pupil diameter at 1-minute intervals from the time of incision (operative baseline) until wound closure (end of surgery). Postoperative ocular pain was measured using a subject-rated visual analog scale (VAS) at 2, 4, 6, 8, and 10–12 hours after surgery, and at 2, 7, and 14 days.

[0080] Key secondary endpoints included a pupil diameter of less than 6 mm at the end of cortical clearing, a pupil diameter of less than 6 mm at any time during surgery, intraoperative pupil constriction of 2.5 mm or more, moderate to severe ocular pain (VAS ≥ 40) at any time assessed within the first 12 hours after surgery, and absence of ocular pain (VAS = 0) at all time points assessed within the first 12 hours after surgery. Post-hoc secondary analyses included classification of subjects' intraoperative pupil constriction and analgesic use on the day of surgery.

[0081] statistical analysis Each study was conducted independently. The sample size calculations for the two studies were identical: a total of 400 subjects in each study (200 subjects per treatment arm) provided 99% power to detect a 0.6 mm (standard deviation [SD]: 0.7 mm) difference in the mean area under the curve (AUC) pupil diameter change from baseline and 96% power to detect a 5.0 mm (SD: 13.3 mm) difference in the mean AUC of the ocular pain VAS during the first 12 hours after surgery, using a two-tailed t-test with α=0.05.

[0082] The mean AUC pupil diameter change from baseline during surgery was calculated as follows: 1) the trapezoidal rule was used to calculate the AUC of pupil diameter from surgical baseline to wound closure, 2) the result was divided by the time of the last pupil diameter value to obtain the mean AUC, and 3) the baseline pupil diameter was subtracted from the mean AUC. Additionally, the AUC of the ocular pain VAS during the first 10-12 hours after surgery was calculated using the trapezoidal rule, with the mean AUC defined as the AUC divided by the number of hours from the first VAS score to the last VAS score within this time frame. For both primary endpoints, the two treatment arms of the two combined studies were compared using the generalized Cochran-Mantel-Haenszel (CMH) test stratified by randomization strata (LaVange et al., 2005).

[0083] Treatment comparisons for all secondary efficacy analyses shown were performed using the chi-squared test or Fisher's exact test when the frequency within a category was less than 5. All statistical analyses were performed using SAS software (version 9.3, SAS Institute, Inc., Cary NC).

[0084] Results – Effectiveness OMS302 was superior to placebo in maintaining pupil dilation during cataract surgery or IOL replacement procedures. Among 759 subjects with usable video images for pupil diameter determination, the mean AUC change from baseline in pupil diameter was 0.08 mm for the OMS302 group (n=379) compared with -0.50 mm for the placebo group (n=380), with a CMH weighted mean difference (OMS302-placebo) (standard error [SE]) of 0.58 mm (0.04) (95% confidence interval [CI]: 0.51, 0.65; p<0.0001). After the start of surgery, baseline pupil diameter was maintained with OMS302 treatment, whereas progressive miosis was observed with placebo treatment (Figure 1). Additionally, results of secondary efficacy analyses evaluating the incidence of subjects with a pupil diameter of less than 6 mm at the completion of cortical clearance and at any time during surgery favored OMS302 treatment (Table 2). The proportions of subjects with a pupil diameter of less than 6 mm at the completion of cortical clearance, a pupil diameter of less than 6 mm at any time during surgery, and an intraoperative pupillary constriction of 2.5 mm or greater were all significantly lower in OMS302-treated subjects than in placebo-treated subjects (p<0.0001 for each endpoint). Significantly fewer OMS302-treated subjects than placebo subjects experienced intraoperative pupillary constriction of more than 1 mm (Figure 2). [Table 2]

[0085] Treatment with OMS302 was associated with a significant reduction in early postoperative ocular pain compared with placebo. Ocular pain VAS scores during the first 12 hours after surgery were >50% lower in the OMS302 group (mean AUC = 4.16 mm, n = 403) than in the placebo group (mean AUC = 9.06 mm, n = 403). The CMH-weighted mean difference (OMS302 minus placebo) (SE) in AUC for ocular pain scores was -4.89 mm (0.80) (95% CI: -6.46, -3.31; p < 0.001). Mean VAS scores were lower in subjects treated with OMS302 at each postoperative time point (Figure 3). The proportion of subjects with no ocular pain (VAS=0) at all postoperative time points was significantly higher for OMS302 compared with placebo (25.8% vs. 17.1%, respectively, p=0.0027; Table 2), and the proportion of subjects with moderate to severe ocular pain (VAS≧40) at any postoperative time point was significantly lower for OMS302 compared with placebo (7.2% vs. 14.1%, respectively, p=0.0014). Notably, in addition to lower VAS pain scores in the OMS302 group, analgesic use on the day of surgery was also significantly lower in subjects treated with OMS302 compared with placebo (24.6% vs. 35.1%, respectively, p=0.0010).

[0086] Results - Safety Of the 808 subjects included in the pooled safety analysis (403 OMS302, 405 placebo), 513 (63.5%) experienced at least one treatment-emergent adverse event (TEAE). The proportion of subjects reporting a TEAE was slightly lower in subjects receiving OMS302 (242 / 403 [60.0%]) than in those receiving placebo (271 / 405 [66.9%]). The majority of TEAEs were mild or moderate in severity. Only one serious adverse event was reported in both studies. This event (death due to electric shock believed to be unrelated to the study drug) was the only event that resulted in early discontinuation from the study.

[0087] The most frequently reported TEAEs consisted of ocular pain (reported by 35.1% of subjects overall), ocular inflammation (15.5%), anterior chamber inflammation (8.7%), headache (7.9%), increased intraocular pressure (4.1%), posterior capsule opacification (4.1%), ocular discomfort (4.1%), photophobia (4.0%), corneal edema (2.8%), blurred vision (2.7%), conjunctival hyperemia (2.6%), and ocular foreign body sensation (2.2%). These events were reported by similar proportions of subjects in each treatment group, with the exception of ocular pain, headache, ocular discomfort, photophobia, and blurred vision, which were experienced by slightly more OMS302 subjects (30.3%, 6.5%, 3.0%, 3.0%, and 1.2%, respectively) than placebo subjects (40.0%, 9.4%, 5.2%, 4.9%, and 4.2%, respectively) (a difference of more than 1% between treatment groups). Increased intraocular pressure was the only common TEAE that occurred in a slightly higher proportion (a difference of more than 1%) of OMS302-treated subjects (4.7% OMS302 vs. 3.5% placebo).

[0088] A total of 18 subjects experienced severe TEAEs (13 [3.2%] placebo subjects and 5 [1.2%] OMS302 subjects). With the exception of the fatal electrocution event experienced by an OMS302-treated subject, all severe TEAEs consisted of ocular disorders, including ocular inflammation (n=11), anterior chamber inflammation (n=2), and chemosis, corneal edema, conjunctival hyperemia, ocular pain, and photophobia (n=1 each). Of note, all severe TEAEs considered related to study treatment occurred in subjects receiving placebo. These events included two cases of anterior chamber inflammation and events of corneal edema, ocular pain, photophobia, ocular inflammation, and conjunctival hyperemia.

[0089] Increased intraocular pressure was observed in several subjects in both treatment groups after surgery. By day 2, the increase compared to baseline was less significant; however, in some subjects, abnormalities persisted until the end of the study. No significant TEAEs were reported in these subjects, and no differences in the proportion of subjects with increased intraocular pressure were observed between the two treatment groups on each evaluation day. In addition, no differences were observed between the treatment groups for any other serial assessments of safety (i.e., vital signs or ophthalmic examinations).

[0090] conclusion OMS302 was superior to placebo in maintaining pupil dilation during IOL replacement and reducing ocular pain after IOL replacement. The mean area under the curve (AUC) change from baseline in pupil diameter was 0.08 mm for OMS302 compared to -0.50 mm for placebo (p<0.0001). The mean AUC for subjects' ocular pain visual analog scale (VAS) scores within 12 hours postoperatively was more than 50% lower for OMS302 (mean AUC=4.16 mm) than for placebo (mean AUC=9.06 mm) (p<0.001). Results of all secondary efficacy analyses demonstrated significant treatment effects associated with OMS302. Treatment-emergent adverse events were as expected for a population undergoing IOL replacement, and no clinically significant differences in safety measures were observed between treatment groups.

[0091] The combined results of these two pivotal Phase 3 studies demonstrated superiority of OMS302 over placebo in maintaining pupil diameter and preventing miosis during cataract extraction or refractive lens exchange procedures with lens replacement, and in preventing postoperative ocular pain after these procedures, despite all subjects receiving standard preoperative topical mydriatics and anesthetics. Efficacy analyses were robust, and area under the curve (AUC) analysis of the co-primary endpoint of the combined analysis demonstrated a cohesive effect of OMS302 on intraoperative pupil diameter and early postoperative pain. All secondary efficacy analyses were supportive. Furthermore, compared with placebo, OMS302 was not associated with any new or additional toxicities. The usual adverse events and safety findings observed in clinical studies of OMS302 to date (e.g., increased intraocular pressure) were consistent with those typically reported in patients undergoing these procedures, and no clinically significant differences were observed between treatment groups.

[0092] Example 2 Ocular tissue distribution of ketorolac after administration of phenylephrine 1% / ketorolac 0.3% to dogs during intraocular lens placement This example describes the results of an in vivo study in dogs to determine the concentration of ketorolac in the retina and other ocular tissues after intracameral administration of phenylephrine 1% and ketorolac 0.3% injection (OMS302) formulated as described in Table 1 during IOL replacement in dogs.

[0093] method Twenty female beagles underwent IOL replacement via phacoemulsification. During the procedure, OMS302 was administered in BSS solution via irrigation and intracameral injection immediately after the procedure. The target dose level of ketorolac was 5.71 mg / eye, and the target dose volume of OMS302 diluted in BSS solution was 250 mL / eye. Four animals per time point were sacrificed at 0, 2, 6, 8, and 10 hours post-procedure. Blood and aqueous humor samples were collected. Enucleated eyes were frozen and dissected for collection of the retina, retinal pigment epithelium-choroid, cornea, iris-ciliary body, vitreous humor, sclera, and lens capsule. Tissue concentrations of ketorolac were quantified using liquid chromatography / mass spectrometry (LCMS). Percent inhibition estimates were obtained for each time point using published IC50 values for cyclooxygenase (COX) inhibition by ketorolac (Waterbury et al., Curr Med Res Opin, 22(6):1133-40 (2006)).

[0094] result Figures 4-6 show the mean ketorolac concentrations at specific time points after an intracameral dose of OMS302: Figure 4 shows the ketorolac concentrations in the cornea, lens capsule, iris-ciliary body (ICB), aqueous humor, and anterior sclera; Figure 5 shows the ketorolac concentrations in the bulbar and palpebral conjunctiva; and Figure 6 shows the ketorolac concentrations in the vitreous humor, retina, choroid-RPE (peripheral), choroid-RPE (tacupuncture), and posterior sclera. Figure 7 shows the mean percent inhibition of COX-1 and COX-2 in retinal tissue from t=0 to t=10 hours, based on an IC50 of 20 nM and K i of 10 nM for COX-1 and an IC50 of 120 nM and K i of 60 nM for COX-2. Ketorolac concentrations in the retina were 1400 ± 1004 ng / g immediately after IOL placement and 164 ± 39 ng / g 8 hours after treatment, corresponding to estimated COX-1 / COX-2 inhibition of 99.3% / 96.0% at t = 0 and 98.4% / 91.1% at t = 8 hours. The retinal half-life was approximately 3.8 hours. Remarkably, tissue concentrations in the aqueous humor, vitreous humor, and RPE-choroid at t = 8 hours were consistent with greater than 90% inhibition of COX-1 and COX-2. Also striking, at t = 10 hours, retinal tissue concentrations were 97.74% (standard deviation of 0.36%) for COX-1 and 87.82% (standard deviation of 1.75%) for COX-2. The mean plasma level of ketorolac was 4.73±1.46 ng / mL at t=0 and decreased to undetectable levels at t≧2 hours.

[0095] conclusion In this study, the use of OMS302 during IOL replacement surgery resulted in ketorolac uptake by the retina and other ocular tissues at levels sufficient to inhibit COX-1 and COX-2 levels in intraocular tissues by greater than 90% for at least 8 hours and greater than 85% for at least 10 hours after drug administration in the anterior chamber irrigation solution, with an unexpected duration of activity. Systemic exposure was low and transient.

[0096] Example 3 A clinical study evaluating intracameral ketorolac concentrations after topical ketorolac administration before cataract surgery This example describes the results of a clinical study to determine postoperative intracameral ketorolac concentrations in subjects given topical ketorolac prior to cataract surgery.

[0097] method Patients undergoing cataract extraction and lens replacement (CELR) were eligible. Written informed consent was obtained from 14 subjects, each of whom received topical ophthalmic ketorolac, according to the surgeon's usual practice, beginning 1 day before surgery. Immediately prior to the initial surgical incision, the surgeon withdrew a 100 μL sample of aqueous humor from the operative eye with a 30-gauge tuberculin syringe. At the end of CELR, before final anterior chamber reexpansion and wound closure, the surgeon withdrew another 100 μL sample from the anterior chamber. The ketorolac concentration of the anterior chamber fluid samples was analyzed in an analytical laboratory.

[0098] result Thirteen of the 14 subjects received four doses of ketorolac the day before surgery, and one subject received three doses the day before surgery. All 14 subjects received topical ketorolac at the surgery center on the day of surgery. Aqueous humor samples were inadvertently not collected from two subjects. Preoperative ketorolac concentrations ranged from 4.9 to 369 ng / mL for the 12 subjects for whom samples were collected. End-of-procedure samples ranged from less than 1.0 (the lower limit of quantification, or LLOQ) to 6.32 ng / mL; eight of the 12 subjects had ketorolac levels below the LLOQ.

[0099] conclusion Home compliance with topical ketorolac was generally good, with 92.9% of subjects using topical ketorolac as directed. After CELR, ketorolac levels in the aqueous humor at the end of the surgical procedure were low, likely due to irrigation, because 66.7% of subjects had undetectable concentrations of ketorolac.

[0100] The in vivo and clinical studies in Examples 2 and 3 demonstrate that ketorolac delivered intracamerally in a ketorolac / phenylephrine solution during cataract and IOL replacement surgery, respectively, should provide pharmacologically active levels of ketorolac in the eye for a substantially longer postoperative time than results from ketorolac delivered topically preoperatively, thereby providing sustained postoperative inflammation inhibition.

[0101] Although the foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the present invention that certain changes and modifications can be made thereto without departing from the spirit or scope of the appended claims. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

Claims

[Claim 1] A method for inhibiting a postoperative inflammatory state following an ophthalmic surgical procedure as described herein.

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