US 20080O85922A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0085922 A1 Raja et al. (43) Pub. Date: Apr. 10, 2008

(54) METHODS AND OPHTHALMIC DEVICES (22) Filed: Mar. 16, 2007 USED IN THE TREATMENT OF OCULAR ALLERGES Related U.S. Application Data (76) Inventors: Ranganath R. Raj a, Jacksonville, FL (60) Provisional application No. 60/848,332, filed on Sep. (US); Shivkumar Mahadevan, Orange 29, 2006. Park, FL (US); Azaam Alti, Jacksonville, FL (US); Frank F. Publication Classification Molock, Orange Park, FL (US); Brain Pall, Jacksonville, FL (US) (51) Int. Cl. A6II 3/44 (2006.01) Correspondence Address: A6IP 27/02 (2006.01) PHILIP S. JOHNSON (52) U.S. Cl...... 514/324 JOHNSON & JOHNSON ONE JOHNSON & JOHNSON PLAZA (57) ABSTRACT NEW BRUNSWICK, NJ 08933-7003 (US) Ophthalmic devices and methods of treating allergic con (21) Appl. No.: 11/686,979 junctivitis are disclosed herein.

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METHODS AND OPHTHALMIC DEVICES USED limited to chemical substances that inhibit the release of IN THE TREATMENT OF OCULAR ALLERGES histamine, that block the binding of histamine to its recep tors, inhibit mast cell production. Additional anti-allergic RELATED APPLICATIONS agents include but are not limited to decongestants, non 0001. This application claims priority from a non-provi steroidal anti-inflammatory compound, and steroidal com sional filing, U.S. application patent Ser. No. 60/848,332 pounds. Particularly, examples of anti-allergic agents which was filed on Sep. 29, 2006. include but are not limited to acetmetacin, acrivastine, aldosterone, antazoline, astemizole, azatadine, azelastine, FIELD OF THE INVENTION beclometaSone, betamethasone, bromfenac, buclizine, car profen, cetirizine, chloropyriline, chloropheniramine, clem 0002 This invention related to devices and treatments for astine, cromolyn, cyclizine, cyproheptadine, dexametha allergic conjunctivitis. Sone, diazoline, diclofenac, diphenhydramine, ebastine, emedastine, epinastine, etodolac, fenbufen, fenoprofen, fex BACKGROUND ofenadine, fludrocortisone, flurbiprofen, flurometalone, 0003 Allergic conjunctivitis is a disease of the eye that hydroxy Zine, ibuprofen, indometacin, ketoprofen, ketorolac affects millions of people. The symptoms of this disease tromethamine, ketotifen, levocabastine, levoceterizine, include itchiness, tearing, and Swelling of the eyes. Some lodoxamide, loratadine, loteprednol, loxoprofen, times this disease is seasonally associated with the spring medrysone, mepivacaine, meduitazine, methdilazine, meth and Summer hay fever seasons, but many people experience apyrilene, nabumetone, naphazoline, naproxen, nedocromil. symptoms of this disease throughout the year. The Symp norastemizole, norebastine, olopatadine, phenidamine, phe toms of allergic conjunctivitis are caused and mediated by nylephrine, Oxatamide, oxymetazoline, pemirolast, phe the binding of histamine to its receptor. Antihistamines are niramine, picumast, prednisilone, promethazine, rimexa a class of pharmaceutical agent known to either or both lone, repirinast, Sulindac, Suprofen, tetrahydoZoline, Suppress the release of histamine from associated mast cells terfenadine, tiaprofenic acid, tometim, tranilast, triamcino and prevent the binding of histamine to its associated lone, trimeprazine, triprolidine, and pharmaceutically receptors. These agents have been used to treat the Symp acceptable salts and mixtures thereof. Preferred anti-allergic toms of allergic conjunctivitis and one such agent is keto agent include acrivatine, antazoline, astemizole, azatadine, tifen fumarate. Topical solutions of ketotifen fumarate are aZelastine, clemastine, cyproheptadine, ebastine, emedas currently sold in the United States. The concentration keto tine, fexofenadine, hydroxyzine, ketotifen, levocabastine, tifen in of the U.S. approved ketotifen fumarate formulation levoceterizine, meduitazine, methdialazine, methapyrilene, is 0.025% (0.25 mg/mL). At that concentration, the recom norastemizole, norebastine, picumast, promethazine, ter mended dosing regimen is twice daily. It is known that the fenadine, trimeprazine, triprolidine, and pharmaceutically recommended dosing can be reduced if the amount of acceptable salts and mixtures thereof. The class of sub ketotifen fumarate is increased, but it is also known that stances known as antihistamines are the particularly pre higher concentrations of ketotifen fumarate sting and burn ferred anti- allergic agents. The particularly preferred anti upon initial administration to the eye. histamines include, azelastine, epinastine, ketotifen, 0004 Further it is known that they symptoms of allergic ketotifen fumarate, nor-ketotifen fumarate, olopatadine and conjunctivitis have a greater impact on the wearers of mixtures thereof. More particularly preferred antihistamines contact lenses. Many contact lens wearers stop using their include ketotifen, its pharmaceutically acceptable salts and lenses during the spring and Summer hay fever seasons and mixtures thereof. other peak allergen seasons. Contact lens wearers can 0007. The term “minimum effective amount” refers to the administer topical ketotifen Solutions to reduce the Symp weight of anti-allergic agent contained in an ophthalmic toms of allergic conjunctivitis. However, if the inconve device prior to its use by a patient wherein Such minimum nience of carrying a bottle of Solution can be avoided, it effective amount alleviates the symptoms of allergic con would be beneficial. In addition, since it is known that higher junctivitis. The minimum effective amount may vary concentrations of the ketotifen fumarate can cause stinging depending upon the efficacy of a particular anti-allergic and burning, it would be beneficial if the symptoms of agent. For example, if the anti-allergic agent is ketotifen allergic conjunctivitis were alleviated by administering an fumarate, the minimum effective amount is between greater amount of ketotifen fumarate to patients that did not cause than about 9 ug and about less than 90 jug, more particularly stinging in a dose that lasts longer than 6 hours. These between about 40 ug and greater than about 9 ug, most benefits are provided by the following invention. preferably about for 20 ug. It is preferred that minimum effective amount of anti-allergic agent other than ketotifen BRIEF DESCRIPTION OF THE DRAWING fumarate is an amount that exhibits an efficacy equivalent to 0005 FIG. 1 illustrates the ex-vivo release of ketotifen. or more efficacious greater than about 9 ug and about less than 90 ug, more particularly between about 40 ug and about DETAILED DESCRIPTION OF THE 9 ug of ketotifen fumarate. INVENTION 0008. It is preferred that the minimum effective amount 0006. This invention includes an ophthalmic device com of anti-allergic agent alleviates the symptoms of allergic prising about a minimum effective amount of an anti-allergic conjunctivitis for between about 5 minutes, and about 24 agent. As used herein “anti-allergic agent” refers to chemical hours from insertion of the ophthalmic device into the eye of Substances that alleviate the symptoms of allergic conjunc a user, more preferably between about 5 minutes and about tivitis. While not wishing to be bound by any particular 16 hours, most preferably between about 5 minutes and mechanism of action, anti-allergic agents include but are not about 12 hours. US 2008/0085922 A1 Apr. 10, 2008

0009. As used herein, “ophthalmic device” refers to an within the eye or on the ocular adnexa, such as a punctual object that resides in or on the eye. These devices can plug or an ocular insert, it is preferred that the device remain provide optical correction or may be cosmetic. Ophthalmic in contact with the eye for at least 24 hours. devices include but are not limited to soft contact lenses, intraocular lenses, overlay lenses, ocular inserts, punctual 0.011) Still further the invention includes a method of plugs, and optical inserts. The preferred ophthalmic devices making an ophthalmic device comprising about a minimum of the invention are soft contact lenses made from silicone effective amount of an anti-allergic agent comprising the elastomers or hydrogels, which include but are not limited to step of treating an ophthalmic device with a solution com silicone hydrogels, and fluorohydrogels and excludes oph prising said anti-allergic agent, wherein the amount of said thalmic devices that contain phosphate group-containing anti-allergic agent in said solution exceeds the minimum methacrylates (i.e. CH C(CH) C(O)-(CH), O effective amount. It is preferred that the minimum effective P(O)(OH), where n is 1-4: CHC C(CH) C(O)— amount is exceeded by between about 1.0% and about (CH), O-P(O)(OH)—O-(CH), O C(O)— 1000%, in a volume of solution that is between about 500 uL C(CH) CH) or pre-polymers as such defined by US Pat. and about 5000 uL preferably between about 50% and about Application Publication No. US 2006/0100408. Soft contact 500%, in a volume of solution that is between about 500 uL lens formulations are disclosed in U.S. Pat. No. 5,710,302, and about 3000 uL most preferably about 50% in a volume WO 9421698, EP 406161, JP 2000016905, U.S. Pat. No. of solution that is about 1000 uL. 5,998,498, U.S. Pat. No. 6,087,415, U.S. Pat. No. 5,760,100, 0012. As used herein treating means physical methods of U.S. Pat. No.5,776, 999, U.S. Pat. No. 5,789,461, U.S. Pat. contacting the solution containing an anti-allergic agent and No. 5,849,811, and U.S. Pat. No. 5,965,631. The foregoing the ophthalmic device. Preferably treating refers to physical references are hereby incorporated by reference in their methods of contacting the anti-allergic agent with the oph entirety. The particularly preferred ophthalmic devices of the thalmic devices prior to selling or otherwise delivering the inventions are prepared from formulations known by the ophthalmic devices to a patient. The ophthalmic devices United States Approved Names of acofilcon A, alofilcon A, may be treated with the anti-allergic agent anytime after they alphafilcon A, amifilcon A, astifilcon A. atalafilcon A, bala are polymerized. Polymerization refers to the process in filcon A, bisfilcon A, bufilcon A, comfilcon, crofilcon A, which components of an ophthalmic device including but cyclofilcon A, darfilcon A, deltafilcon A, deltafilcon B. not limited to monomers, pre-polymers, diluents, catalysts, dimefilcon A, drooxifilcon A, epsifilcon A, esterifilcon A, initiators, tints, UV blockers, antibacterial agents, polymer etafilcon A, focofilcon A, galyfilcon A, genfilcon A, gova ization inhibitors, and the like are reacted by thermal, filcon A, hefilcon A, hefilcon B, hefilcon D. hilafilcon A, chemical, and light initiated curing techniques to produce a hilafilcon B, hioxifilcon B, hioxifilcon C, hixoi?ilcon A, formed polymer. The preferred methods of polymerization hydrofilcon A, lenefilcon A, licryfilcon A, licryfilcon B, are the light initiated techniques disclosed in U.S. Pat. No. lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilcon B. mafil 6.822,016 which is hereby incorporated by reference in its con A, mesifilcon A, methafilcon B, mipafilcon A, nelfilcon entirety. It is preferred that the polymerized ophthalmic A. netrafilcon A, ocufilcon A, ocufilcon B. ocufilcon C. devices be treated with anti-allergic agent at temperature of ocufilcon D. ocufilcon E, ofilcon A, omafilcon A, oxyfilcon greater than about 50° C. For example in some processes to A, pentafilcon A, perfilcon A, pevafilcon A. phemfilcon A, manufacture contact lenses, an un-polymerized, or partially polymacon, senofilcon A, silafilcon A, siloxyfilcon A, tefil polymerized formulation is placed between two mold con A, tetrafilcon A, trifilcon A. Vasurfilcon, Vi?ilcon, and halves, spincasted, or static casted and polymerized. See, Xylofilcon A. More particularly preferred ophthalmic U.S. Pat. Nos. 4,495,313; 4,680,336; 4,889,664, 3,408.429: devices of the invention are genfilcon A, lenefilcon A, 3,660,545; 4,113,224; and 4,197,266, all of which are incor comfilcon, lotrafilcon A, lotrailfilcon B, and balafilcon A. porated by reference in their entirety. In the case of hydro More preferred lenses include comfilcon, etafilcon A, gally gels, the ophthalmic device formulation is a hardened disc filcon A, senofilcon A, nelfilcon A, hilafilcon, tetrafilcon A, that is subjected to a number of different processing steps vasurfilcon, vifilcon, and polymacon. The most preferred including treating the polymerized ophthalmic device with lenses include etafilcon A. liquids (such as water, inorganic salts, or organic solutions) to swell, or otherwise equilibrate this polymerized oph 0010) Further the invention includes a method of allevi thalmic device prior to enclosing the polymerized oph ating the symptoms of allergic conjunctivitis comprising thalmic device in its final packaging. Polymerized oph administering to a patient an ophthalmic device comprising thalmic devices that have not been swelled or otherwise about a minimum effective amount of an anti-allergic agent. equilibrated are known as un-hydrated polymerized oph The terms ophthalmic device, minimum effective amount thalmic devices. The addition of the anti-allergic agent to and anti-allergic agent all have their aforementioned mean any of the liquids of this “swelling” or “equilibrating” step ings and preferred ranges. As used herein, the term "admin at room temperature or below is considered "treating” the istering means placing the ophthalmic device of the inven lenses with anti-allergic agent as contemplated by this tion onto the surface of the eye, or in the eye, of a patient. invention. In addition, the polymerized un-hydrated oph If the device is in contact with the anterior surface of the thalmic devices may be heated above room temperature with patient’s eye, such as a soft contact lens, it is preferred that the anti-allergic agent during swelling or equilibrating steps. the ophthalmic device remain in contact with that surface for between about 5 minutes, and about 24 hours from insertion The preferred temperature range is from about 50° C. for of the ophthalmic device into the eye of a user, more about 15 minutes to about sterilization conditions as preferably between about 5 minutes and about 16 hours, described below, more preferably from about 50° C. to about more preferably between about 5 minutes and about 12 85° C. for about 5 minutes. hours, most preferably between about 5 minutes and greater 0013 Examples of blister packages and sterilization tech than about 12 hours. If the ophthalmic device is contained niques are disclosed in the following references which are US 2008/0085922 A1 Apr. 10, 2008 hereby incorporated by reference in their entirety, U.S. Pat. thiodipropionate, dioctadecyl-3,3'-thiodipropionate, Nos. D435,966; 4,691,820; 5,467,868; 5,704,468; 5,823, butylhydroxytoluene, ethylene bis3.3-di3-(1,1-dimethyl 327; 6,050,398, 5,696,686; 6,018.931: 5,577,367; and ethyl)-4-hydroxyphenylbutyrate and mixtures thereof. The 5.488,815. This portion of the manufacturing process pre preferred oxidative stabilization agents are diethylenetri sents another method of treating the ophthalmic devices with aminepentaacetic acid (“DTPA), or salts of DTPA such as anti-allergic agent, namely adding anti-allergic agents to a CaNa, DTPA, ZnNaDTPA, and CalDTPA. See, U.S. appli Solution prior to sealing the package, and Subsequently cation patent No. 60/783,557 filed on, Mar. 17, 2006, sterilizing the package. This is the preferred method of entitled “Methods for Stabilizing Oxidatively Unstable treating ophthalmic devices with anti-allergic agents. Pharmaceutical Compositions' and its corresponding non provisional filing which are hereby incorporated by refer 0014 Sterilization can take place at different tempera ence in their entirety. Therefore, the invention includes a tures and periods of time. The preferred sterilization condi method of preventing oxidation of an ophthalmic device tions range from about 100° C. for about 8 hours to about comprising an anti-allergic agent, wherein the method 150° C. for about 0.5 minute. More preferred sterilization includes treating said ophthalmic device with a solution conditions range from about 115° C. for about 2.5 hours to comprising an oxidative stabilization agent. It is preferred about 130° C. for about 5.0 minutes. The most preferred that at the concentration of oxidative stabilization agents in sterilization conditions are about 124° C. for about 18 the solution be from about 2.5 umoles/liter to about, 5000 minutes. umoles/liter more preferably from about 20 Lumoles/liter to 0015 The “solutions” that are used in methods of this about 1000 umoles/liter, more preferably from about 100 invention may be water-based solutions. Typical Solutions umoles/liter to about 1000 umoles/liter, most preferably include, without limitation, saline solutions, other buffered from about 100 umoles/liter to about 500 umoles/liter. Solutions, and deionized water. The preferred aqueous solu tion is deionized water or saline Solution containing salts 0017. Yet still further the invention includes an oph including, without limitation, Sodium chloride, sodium thalmic device comprising about a localized amount of an borate, Sodium phosphate, Sodium hydrogenphosphate, anti-allergic agent. As used herein the terms anti-allergic Sodium dihydrogenphosphate, or the corresponding potas agent and ophthalmic device have their afore mentioned sium salts of the same. These ingredients are generally preferred identities and preferred ranges. combined to form buffered solutions that include an acid and 0018. As used herein, the term “localized amount” refers its conjugate base, so that addition of acids and bases cause to an amount of anti-allergic agent that located in discrete only a relatively small change in pH. The buffered solutions portions of the ophthalmic device. For example, the local may additionally include 2-(N-morpholino)ethanesulfonic ized amount may be on the front or back Surface (using those acid (MES), sodium hydroxide, 2.2-bis(hydroxymethyl)-2, terms as applied to contact lenses) of the device, or in any 2.2"-nitrilotriethanol, n-tris(hydroxymethyl)methyl-2-ami other area or surface. It is preferred that the localized amount noethanesulfonic acid, citric acid, sodium citrate, sodium remain in contact with the conjunctiva of the eye when carbonate, sodium bicarbonate, acetic acid, Sodium acetate, placed in the eye of a user. It is preferred that the localized ethylenediamine tetraacetic acid and the like and combina amount of anti-allergic agent is between about 1 lug and tions thereof. Preferably, the solution is aborate buffered or about 200 ug, preferably between about 1 lug and about 90 phosphate buffered saline solution or deionized water. The ug, more preferably between about 1 lug and about 50 ug, particularly preferred solution contains about 500 ppm to most preferably between about 2 ug and about 20 ug. The about 18,500 ppm sodium borate, most particularly pre anti-effective agent may be adding to a discrete area of the ferred about 1000 ppm of sodium borate. device by including the anti-allergic agent in coatings or 0016. If the anti-allergic agents are subject to oxidative pigments that may be added to the devices. See, U.S. Pat. degradation, agents that stabilize solutions containing Such Nos. 7,172.286; and 6,767,097, WO 02/057837, WO anti-allergic agents may be added. Such “oxidative stabili 03/057837 U.S. Pat. App. Nos. US 2002/0133889, and US Zation agents' include but are not limited to chelants such as 2003/0000028 coatings and pigments that may be applied to EDTA, Dequest, Desferal, silica, chitin derivatives such as ophthalmic devices as well methods of applying the same to chitosan, cellulose and its derivatives, and N.N.N',N',N', Such devices N"-hexa(2-pyridyl)-1,3,5-tris(aminomethyl)benzene, and 0019. Yet further still the invention includes a method of certain macrocyclic ligands such as crown ethers, ligand alleviating the symptoms of allergic conjunctivitis compris containing knots and catenands. See, David A. Leigh et al ing administering to a patient an ophthalmic device com Angew. Chem Int. Ed., 2001, 40, No. 8, pgs. 1538-1542 and prising about a localized amount of an anti-allergic agent. As Jean-Claude Chambron et al. Pure & Appl. Chem., 1990, used herein the terms anti-allergic agent, localized amount, Vol. 62, No. 6, pgs. 1027-1034. Oxidative stabilization and ophthalmic device have their afore mentioned preferred agents may include other compounds that inhibit oxidations identities and preferred ranges. Such as those selected from the group consisting of 2.2.2". 6,6'6"-Hexa-(1,1-dimethylethyl)4,4',4'-(2,4,6-trimethyl-1, 0020 Still further, the invention includes a method alle 3,5-benzenetriyl)-trismethylene-triphenol (Irganox 1330), viating the symptoms of allergic conjunctivitis in a patient 1.3.5tris(3,5-di(1,1-dimethylethyl)4-hydroxybenzyl)-1H, for an extended period of time, wherein said method com 3H,5H-1,3,5-triazine-2,4,6-trione, pentaerythrity1 tetrakis3 prises administering to the eye of said patient an adminis 3,5-di(1,1-dimethylethyl)-4-hydroxyphenyl-propionate). tration system comprising said anti-allergic agent, wherein octadecyl-3-3,5-di(1,1-dimethylethyl)-4-hydroxyphenyl said administration system releases to said patient a dosing propionate, tris(2,4-di(1,1-dimethylethyl)-phenyl-phos effective amount of an anti-allergic agent. The term anti phite, 2,2'-dicoctadecyloxy)-5.5'-spirobi (1,3,2-dioxaphos allergic agent has its aforementioned meaning. The phorinane), dioctadecyl disulphide, didodecyl-3,3'- “extended period of time' is from about 5 minutes to about US 2008/0085922 A1 Apr. 10, 2008 greater than 24 hours depending upon the administration 0026 4.0.10 g of Ca2DTPA system. The term administration system refers to a physical object that contains an anti-allergic agent that releases the 0027 5.981.49 g of deionized water contained anti-allergic to the eye of a patient over time. The 0028 6. 0.01 g of ketotifen fumarate preferred administration systems are ophthalmic devices that are exposed to the anterior Surface of the eye, in the eye, 0029. The system is maintained at room temperature or on the ocular adnexa. Such preferred administrative throughout the solution making process. All components 1-6 systems include soft contact lenses, punctual plugs or ocular are added in any order and stirred using a magnetic or inserts, most particularly, the soft contact lenses of this mechanical stirrer until the Solution is homogeneous. Keto invention. If the administration system is a soft contact lens tifen fumarate is added last and the mixture is stirred for an the preferred extended period of time is greater than about additional 30 minutes or as long as it takes to make the 12 hours, more preferably between about 13 hours and about Solution homogeneous. 24 hours, most preferably between about 13 hours and about 0030 The procedure to prepare a 25 ug/mL, ketotifen 18 hours. If the administration system is a punctual plug or fumarate solution is identical to that described above, with an ocular insert, the preferred period of time is greater than the only exceptions being the amount of ketotifen fumarate 24 hours. The term “administering means placing said (0.025 g instead of 0.010 g) and water (981.475 g instead of administration system on or in the eye of a patient. The term 981.49 g). “releases' means separating the anti-allergic agent from its administration system so that said anti-allergic agent is 0031 1-Day AcuVueR Brand Contact Lenses (etafilcon available to eye of a patient. If the ophthalmic device is A) were removed from their packages and repackaged in administered to the anterior surface of the eye, it is preferred glass vials containing 3.0 mL of the 10 ug/mL or the 25 that the administration system release between about 10% ug/mL, ketotifen fumarate solutions described above to pro and about 90% of its contained anti-allergic agent between duce K-Lens 10 and K-Lens 25 respectively. The vials were administering the device to the eye and about 60 minutes, sealed with PTFE coated rubber stoppers and heated for 18 more preferably between 10% and about 70% in about 30 minutes at 124° C. minutes. If the administration system does not contact the exterior Surface of the eye and is placed in another portion Example 2 of the eye, it is preferred that such administration system release its contained anti-allergic agent over a period of time Clinical Evaluation of Ophthalmic Devices of equal to or greater than 24 hours. The term “dosing effective Example 1 amount refers to an amount of anti-allergic agent Sufficient 0032. This was a single-center double-masked, random to alleviate the symptoms of allergic conjunctivitis for an ized, placebo controlled, clinical trial to assess the efficacy extended period of time. This amount may vary depending of the lenses of Example 1 in a conjunctivial allergen upon the potency of the anti-allergic agent. For example if challenge (CAC Model ). See, Netland et al. Emedastine the ophthalmic device contains ketotifen, the preferred dos Ophthalmic Solution 0.05% Versus Levocabastine Oph age effective amount is between about less than 1 Jug and thalmic Suspension 0.05% in the Treatment of Allergic about 20 lug. The preferred dosage effective amount is Conjunctivitis Using the Conjunctival Allergen Challenge between about less than 1 Jug and about 20g. It is preferred Model, American Journal of Ophthalmology VOL. 130, No. that the dosing effective amount of ketotifen released to the 6, page 717-723, 718 for a description of a positive test to eye of a patient from about 1 minute to about 300 minutes. a CAC challenge. At the first visit (Day 28+3), subjects It is particularly preferred that between about 10% and about underwent an allergen titration and a contact lens fitting. 75% of the ketotifen contained within the ophthalmic device During the allergen titration, a CAC was performed bilat is delivered to the eye of a patient within about 60 minutes. erally with animal (cat) allergens, grass, tree, or wood 0021. In order to illustrate the invention the following pollens. Beginning with the lowest dose, one drop (25 uL) examples are included. These examples do not limit the of solubilized allergen was instilled into the conjunctival invention. They are meant only to Suggest a method of cul-de-sac bilaterally. If the subject failed to react within 10 practicing the invention. Those knowledgeable in contact minutes, increasing doses may have been instilled in both lenses as well as other specialties may find other methods of eyes at a minimum often minute intervals until a positive practicing the invention. However, those methods are reaction was elicited. A positive CAC was defined as at least Grade 2.0+ redness in both eyes in 2 of the 3 vessel beds deemed to be within the scope of this invention. (conjunctival, ciliary, and episcleral), and 2.0+ inching in EXAMPLES both eyes, within 10 minutes of receiving that dose of allergen. Subjects were then be given an approved OTC Example 1 antiallergy eye drop after all CAC evaluations were com pleted to relieve any ocular itching or redness. Subjects were Preparation of Ophthalmic Devices Containing 10 then fitted with placebo lenses. Lens fit was evaluated ug and 25 ug of Ketotifen Fumarate approximately 30 minutes after insertion. Subjects were then given a one week Supply of placebo lenses with the instruc 0022. To prepare 1000g of a 10 ug/mL, ketotifen fumarate tions to use on a daily basis. (“K-10: 0033. At the second visit (Study Day—14+3), subjects 0023 1.9.10 g of boric acid underwent an allergentitration with contact lenses. Subjects 0024 2. 1.00 g of sodium borate decahydrate inserted a new set of placebo lenses in each eye. Subjects then underwent a CAC with one drop of allergen dilution 0025) 3. 8.30 g of sodium chloride one dose lower than previously determined at Visit 1 US 2008/0085922 A1 Apr. 10, 2008 instilled into each eye. If after 10 minutes the subject failed 0041 K-Lens 25 in both eyes (N=10) to react positively to the allergen (eGrade 2 redness and 0.042 Placebo lens in both eyes (N=10). eGrade 2 itching OU in 2 of the 3 vessel beds), the subject was re-challenged with a higher dose. Subjects were then Primary Efficacy Measures given another week Supply of daily wear contact lenses. 0043. Three (3), five (5), and seven (7) minute post challenge subject evaluation of ocular itching. Seven (7). 0034. At Visit 3 (Study Day 7+3), an allergen confir fifteen (15), and twenty (20) minutes post challenge inves mation was done. This visit also served as an untreated tigator evaluation of conjunctival redness. The results are comparison visit. Subjects inserted a new set of placebo presented in Table 1. lenses in each eye. Subjects then underwent CAC with one drop of allergen dose previously determined at Visit 2 to Secondary Efficacy Measures have induced an allergic response instilled into each eye. 0044 Seven (7), fifteen (15), and twenty (20) minutes Subjects evaluated ocular itching prior to CAC challenge post challenge investigator evaluation of ciliary and epis and 3, 5, and 7 minutes following the allergen instillation. cleral redness, chemosis and mucous discharge and Subject Investigators evaluated conjunctival, episcleral and ciliary evaluation of lid Swelling and tearing. The results are hyperemia, chemosis and mucous discharge prior to the presented in Table 1. CAC challenge and 7, 15 and 20 minutes following the allergen instillation. Tearing and lid Swelling were evaluated TABLE 1. by the subject prior to CAC challenge and at 7, 15 and 20 minutes post-challenge. Subjects were then given another Duration of Post CAC Mean Itching Score Difference' week Supply of daily wear contact lenses. Action Evaluation K-Lens 10 minus K-Lens 25 minus 0035 Visit 4 evaluated the effectiveness of K-Lens solu (hours) (min) placebo placebo tion instilled 12 hours prior to CAC. Subjects were randomly 12 3 -0.6 -1.1 5 -0.9 -1.3 assigned to one of five treatment groups: K-Lens 10/Pla 7 -0.9 -1.2 cebo, K-Lens 25/Placebo, K-Lens 10/K-Lens 10, K-Lens 8 3 -0.8 -1.1 25/K-Lens 25, and Placebo/Placebo. For the contralateral 5 -0.9 -1.1 eye subjects (K-Lens and placebo), the K-Lens was coun 7 -0.9 -1.1 terbalanced between the OD and OS eye. After inserting the * A clinically significant difference in the mean itching score is considered assigned contact lens with the designated Solution, Subjects to be 1.0 unit or greater (K-Lens minus placebo). A negative value indi waited at the site for 30 minutes for a visual acuity exami cates that the eye wearing K-Lens experienced less severe itching as com nation, slit lamp biomicroscopy, and lens fit evaluation. pared to the eye wearing the placebo lens. Subjects were then allowed to leave the office with instruc tions to return 11 hours later. At 12 hours post lens insertion, 0045 subjects underwent CAC. Subjects evaluated ocular itching prior to CAC challenge and 3, 5, and 7 minutes following the TABLE 2 allergen instillation. Investigators evaluated conjunctival, episcleral and ciliary hyperemia, chemosis, and mucous Duration of Post CAC Mean Redness Score Difference discharge prior to the CAC challenge and 7, 15 and 20 Action Evaluation K-10 minus K-25 minus minutes following the allergen instillation. Tearing and lid (hours) (min) placebo placebo swelling were evaluated by the subject prior to the CAC 12 7 -1.2 -1.5 challenge and at 7, 15 and 20 minutes post-challenge. 15 -O.7 -1.0 Subjects were then given another two week supply of daily 2O -0.9 -1.0 wear contact lenses. 8 7 -0.5 -1.1 15 -O.7 -0.1 0.036 Visit 5 evaluated the effectiveness of K-Lens solu 2O -0.5 O.O tion instilled 8 hours prior to CAC. Subjects received the NOTE: contact lenses in the same solution that they received at Visit Since this is a composite score of redness (redness assessments were made 4. After inserting the assigned contact lens in the designated at 3 different vessel beds), a greater than or equal to -3.0 unit mean score solution, subjects waited at the site for 30 minutes for a difference is required in 2 out of 3 time points to be considered clinically visual acuity examination, slit lamp biomicroscopy and lens significant. fit evaluation. Subjects were then allowed to leave the office 0046 K-Lens 25 showed a clinically and statistically with instructions to return 7 hours later. At 8 hours post lens significant (>1.0 mean unit difference) inhibition of itching insertion, Subjects underwent CAC. The same allergy signs following the conjunctival allergen challenge. and symptoms evaluations done at Visit 4 were repeated at Visit 5. 0047 The mean ocular itching score difference approached 1 unit for K-Lens 10 following the conjunctival 0037. Eighty subject were enrolled and 79 completed the allergen challenge. evaluation. Each enrolled Subject was randomly assigned to 0048 Neither K-Lens 10 nor K-Lens 25 demonstrated a one of five treatment groups: 1 unit or greater mean difference in ocular redness in any of 0038 K-Lens 10 in one eye and a placebo lens in the the 3 different vessel beds. fellow eye (N=30); or Example 3 0039 K-Lens 25 in one eye and a placebo lens in the Release of Ketotifen from K-Lens 25 fellow eye (N=30); or 0049 K-Lens 25 were prepared as in Example 1 and the 0040 K-Lens 10 in both eyes (N=10); or lenses were determined to contain about 19 Jug of ketotifen US 2008/0085922 A1 Apr. 10, 2008

per lens. The lenses were distributed to patients and worn by acrivatine, antazoline, astemizole, azatadine, azelastine, said patients for a period of time, as indicated by FIG. 1. clemastine, cyproheptadine, ebastine, emedastine, epinas Each lens was removed from the patient’s eyes and blotted tine, feXofenadine, hydroxy Zine, ketotifen, levocabastine, with lint-free blotting papers and transferred to a glass levoceterizine, loratadine, meduitazine, methdialazine, Scintillation vial using tweezers. These lenses were stored in methapyrilene, norastemizole, norebastine, picumast, the closed glass vials in this state (dry state) until they were promethazine, terfenadine, trimeprazine, triprolidine, and analyzed by the methods following below. Three milliliters pharmaceutically acceptable salts and mixtures thereof. (3 mL) of Eluent A (Solution of 6.8 g., potassium phosphate, 5. The ophthalmic device of claim 1 wherein the anti monobasic, 1653 mL deionized water, 340 mL acetonitrile, allergic agent is selected from the group consisting of 2.6 mL o-phosphoric acid (85% aqueous)) were added to epinastine, ketotifen, nor ketotifen, olopatadine, and phar each vial. The vials were closed and sonicated for 1 hour at maceutically acceptable salts and mixtures thereof. ambient conditions. The lenses were removed and 0.50 mL 6. The ophthalmic device of claim 1 wherein the oph samples of the remaining lens extract were analyzed by thalmic device is selected from the group consisting of HPLC (Agilent 1100 Series HPLC System, column: Agilent acofilcon A, alofilcon A, alphafilcon A, amifilcon A, astifil Zorbax Eclipse XDB-18, Rapid resolution HT 4.6 mmx50 con A, atalafilcon A, balafilcon A, bisfilcon A, bufilcon A, mmx 1.8L, dector: wavelength: 299 nm, VW detector peak comfilcon, crofilcon A, cyclofilcon A, darfilcon A, deltafil width setting: >0.05 min, flow rate: 1.0 mL/min, needle con A, deltafilcon B, dimefilcon A, drooxifilcon A, epsifilcon wash solvent: Eluent B (solution of 6.8 g., potassium phos A, esterifilcon A. etafilcon A, focofilcon A, galyfilcon A, phate, monobasic, 994 mL deionized water, 1000 mL aceto genfilcon A, govafilcon A, hefilcon A, hefilcon B, hefilcon nitrile, 2.0 mL triethylamine, 2.6 mL o-phosphoric acid D, hilafilcon A, hilafilcon B, hioxifilcon B, hioxifilcon C, (85% aqueous), run time 25 min, injection volume 100 uL) hixoi?ilcon A, hydrofilcon A, lenefilcon A, licryfilcon A, The amount of ketotifen in any lens extract was determined licryfilcon B, lidofilcon A, lidofilcon B, lotrafilcon A, lotra by comparing the peak volume of the sample against a filcon B. mafilcon A, mesifilcon A, methafilcon B, mipafil reference sample containing a known quantity of ketorifen. con A, nelfilcon A, netrafilcon A, ocufilcon A, ocufilcon B. The percentage of ketotifen released from the lenses was ocufilcon C, ocufilcon D, ocufilcon E, ofilcon A, omafilcon calculated and that percentage was plotted versus the A, oxyfilcon A, pentafilcon A, perfilcon A, pevafilcon A, amount of time of lens wear. The results are shown in FIG. phemfilcon A, polymacon, senofilcon A, silafilcon A, siloxy 1 filcon A, tefilcon A, tetrafilcon A, trifilcon A, Vasurfilcon, 1. An ophthalmic device comprising about a minimum vi?ilcon, and Xylofilcon A. effective amount of an anti-allergic agent 7. The ophthalmic device of claim 1 wherein the oph 2. The ophthalmic device of claim 1 wherein the anti thalmic device is selected from the group consisting of allergic agent is selected from the group consisting of genfilcon A, lenefilcon A, comfilcon, lotrafilcon A, lotrailfil acetmetacin, acrivastine, aldosterone, antazoline, astemi con B, and balafilcon A. Zole, azatadine, azelastine, beclometasone, betamethasone, 8. The ophthalmic device of claim 1 wherein the oph bromfenac, buclizine, carprofen, cetirizine, chloropyriline, thalmic device is selected from the group consisting of chloropheniramine, clemastine, cromolyn, cyclizine, cypro comfilcon, etafilcon A, galyfilcon A, senofilcon A, nelfilcon heptadine, dexamethasone, diazoline, diclofenac, diphenhy A, hilafilcon, tetrafilcon A, Vasurfilcon, vifilcon, and poly dramine, ebastine, emedastine, epinastine, etodolac, fen aCO. bufen, fenoprofen, fexofenadine, fludrocortisone, 9. The ophthalmic device of claim 1 wherein the oph flurbiprofen, flurometalone, hydroxyzine, ibuprofen, thalmic device is etafilcon A and the anti-allergic agent is indometacin, ketoprofen, ketorolac tromethamine, ketotifen, selected from the group consisting of ketotifen, nor keto levocabastine, levoceterizine, lodoxamide, loratadine, tifen, olopatadine, and pharmaceutically acceptable salts and loteprednol, loxoprofen, medrysone, mepivacaine, meduita mixtures thereof. Zine, methdilazine, methapyrilene, nabumetone, naphazo 10. The ophthalmic device of claim 1 wherein the oph line, naproxen, nedocromil, norastemizole, norebastine, olo thalmic device is etafilcon A and the anti-allergic agent is patadine, phenidamine, phenylephrine, oxatamide, ketotifen or pharmaceutically acceptable salts and mixtures oxymetazoline, pemirolast, pheniramine, picumast, pred thereof. nisilone, promethazine, rimexalone, repirinast, Sulindac, 11. The ophthalmic device of claim 1 wherein the oph Suprofen, tetrahydoZoline, terfenadine, tiaprofenic acid, thalmic device is etafilcon A, the anti-allergic agent is tometim, tranilast, triamcinolone, trimeprazine, triprolidine, ketotifen or pharmaceutically acceptable salts and mixtures and pharmaceutically acceptable salts and mixtures thereof. thereof, and the minimum effective amount of the anti 3. The ophthalmic device of claim 1 wherein the anti allergic agent is about 8 Lig to about 90 ug. allergic agent is selected from the group consisting of 12. The ophthalmic device of claim 1 wherein the oph acrivastine, antazoline, astemizole, azatadine, azelastine, thalmic device is etafilcon A, the anti-allergic agent is buclizine, cetirizine, clemastine, cromolyn, cyclizine, cypro ketotifen or pharmaceutically acceptable salts and mixtures heptadine, ebastine, emedastine, epinastine, feXofenadine, thereof, and the minimum effective amount of the anti hydroxy Zine, ketorolac tromethamine, ketotifen, levocabas allergic agent is about 10 ug to about 40 ug. tine, levoceterizine, lodoxamide, loratadine, loteprednol, 13. The ophthalmic device of claim 1 wherein the oph mepivacaine, meduitazine, methdilazine, methapyrilene, thalmic device is etafilcon A, the anti-allergic agent is norastemizole, norebastine, olopatadine, picumast, promet ketotifen or pharmaceutically acceptable salts and mixtures hazine, terfenadine, trimeprazine, triprolidine, and pharma thereof, and the minimum effective amount of the anti ceutically acceptable salts and mixtures thereof. allergic agent is about 10 ug to about 25 ug. 4. The ophthalmic device of claim 1 wherein the anti 14. A method of alleviating the symptoms of allergic allergic agent is selected from the group consisting of conjunctivitis comprising administering to a patient an oph US 2008/0085922 A1 Apr. 10, 2008

thalmic device comprising about a minimum effective polymacon, senofilcon A, Silafilcon A, siloxyfilcon A, tefil amount of an anti-allergic agent. con A, tetrafilcon A, trifilcon A, Vasurfilcon, vifilcon, and 15. The method of claim 14 wherein the anti-allergic Xylofilcon A. agent is selected from the group consisting of acetmetacin, 20. The method of claim 14 wherein the ophthalmic device is selected from the group consisting of genfilcon A, acrivastine, aldosterone, antazoline, astemizole, azatadine, lenefilcon A, comfilcon, lotrafilcon A, lotrailfilcon B, and aZelastine, beclometasone, betamethasone, bromfenac, balafilcon A. buclizine, carprofen, cetirizine, chloropyriline, chlorophe 21. The method of claim 14 wherein the ophthalmic niramine, clemastine, cromolyn, cyclizine, cyproheptadine, device is selected from the group consisting of comfilcon, dexamethasone, diazoline, diclofenac, diphenhydramine, comfilcon, etafilcon A, galyfilcon A, senofilcon A, nelfilcon ebastine, emedastine, epinastine, etodolac, fenbufen, feno A, hilafilcon, tetrafilcon A, Vasurfilcon, vifilcon, and poly profen, fexofenadine, fludrocortisone, flurbiprofen, fluro aCO. metalone, hydroxy Zine, ibuprofen, indometacin, ketoprofen, 22. The method of claim 14 wherein the ophthalmic ketorolac tromethamine, ketotifen, levocabastine, levoceter device is etafilcon A and the anti-allergic agent is selected izine, lodoxamide, loratadine, loteprednol, loxoprofen, from the group consisting of ketotifen, nor ketotifen, olo medrysone, mepivacaine, meduitazine, methdilazine, meth patadine, and pharmaceutically acceptable salts and mix apyrilene, nabumetone, naphazoline, naproxen, nedocromil. tures thereof. norastemizole, norebastine, olopatadine, phenidamine, phe 23. The method of claim 14 wherein the ophthalmic nylephrine, Oxatamide, oxymetazoline, pemirolast, phe device is etafilcon A and the anti-allergic agent is ketotifen, niramine, picumast, prednisilone, promethazine, rimexa its pharmaceutically acceptable salts or mixtures thereof. lone, repirinast, Sulindac, Suprofen, tetrahydoZoline, 24. The method of claim 14 wherein the ophthalmic terfenadine, tiaprofenic acid, tometim, tranilast, triamcino device is etafilcon A, the anti-allergic agent is ketotifen its lone, trimeprazine, triprolidine, and pharmaceutically pharmaceutically acceptable salts or mixtures thereof, and acceptable salts and mixtures thereof. the minimum effective amount of the anti-allergic agent is 16. The method of claim 14 wherein the anti-allergic about 8 Lig to about 90 ug. 25. The method of claim 14 wherein the ophthalmic agent is selected from the group consisting of acrivastine, device is etafilcon A, the anti-allergic agent is ketotifen, its antazoline, astemizole, azatadine, azelastine, buclizine, ceti pharmaceutically acceptable salts or mixtures thereof, and rizine, clemastine, cromolyn, cyclizine, cyproheptadine, the minimum effective amount of the anti-allergic agent is ebastine, emedastine, epinastine, fexofenadine, hydrox about 10 ug to about 40 ug. yZine, ketorolac tromethamine, ketotifen, levocabastine, 26. The method of claim 14 wherein the ophthalmic levoceterizine, lodoxamide, loratadine, loteprednol, mepiv device is etafilcon A, the anti-allergic agent is ketotifen, its acaine, meduitazine, methdilazine, methapyrilene, pharmaceutically acceptable salts or mixtures thereof, and norastemizole, norebastine, olopatadine, picumast, promet the minimum effective amount of the anti-allergic agent is hazine, terfenadine, trimeprazine, triprolidine, and pharma about 10 ug to about 25 ug. ceutically acceptable salts and mixtures thereof. 27. A method of making an ophthalmic device comprising 17. The method of claim 14 wherein the anti-allergic about a minimum effective amount of an anti-allergic agent agent is selected from the group consisting of acrivatine, comprising the step of treating an ophthalmic device with a antazoline, astemizole, azatadine, azelastine, clemastine, Solution comprising said anti-allergic agent, wherein the cyproheptadine, ebastine, emedastine, epinastine, fexofena amount of said anti-allergic agent in said solution exceeds dine, hydroxy Zine, ketotifen, levocabastine, levoceterizine, the minimum effective amount. loratadine, meduitazine, methdialazine, methapyrilene, 28. The method of claim 27 wherein the minimum effec norastemizole, norebastine, picumast, promethazine, ter tive amount is exceeded by about 20% and about 1000%, in fenadine, trimeprazine, triprolidine, and pharmaceutically a volume of solution that is between about 500 uL and about acceptable salts and mixtures thereof. 5000 uL. 18. The method of claim 14 wherein the anti-allergic 29. The method of claim 27 wherein the minimum effec agent is selected from the group consisting of epinastine, tive amount is exceeded by between about 50% and about ketotifen, nor ketotifen, olopatadine, and pharmaceutically 500%, in a volume of solution that is between about 500 uL acceptable salts and mixtures thereof. and about 3000 uL. 19. The method of claim 14 wherein the ophthalmic 30. The method of claim 27 wherein the minimum effec device is selected from the group consisting of acofilcon A, tive amount is exceeded by about 50% in a volume of alofilcon A, alphafilcon A, amifilcon A, astifilcon A, atala solution that is about 1000 uL. filcon A, balafilcon A, bisfilcon A, bufilcon A, comfilcon, 31. A method of preventing oxidation of an ophthalmic crofilcon A, cyclofilcon A, darfilcon A, deltafilcon A, delta device comprising an anti-allergic agent, wherein the filcon B, dimefilcon A, drooxifilcon A, epsifilcon A, esteri method includes treating said ophthalmic device with a filcon A, etafilcon A, focofilcon A, galyfilcon A, genfilcon A, Solution comprising an oxidative stabilization agent. govafilcon A, hefilcon A, hefilcon B, hefilcon D. hilafilcon 32. The method of claim 31 wherein the oxidative stabi A, hilafilcon B, hioxifilcon B, hioxifilcon C, hixoi filcon A, lization agent is selected from the group consisting of DTPA, hydrofilcon A, lenefilcon A, licryfilcon A, licryfilcon B. EDTA, Dequest, Desferal, silica, chitosan, cellulose, N.N. lidofilcon A, lidofilcon B, lotrafilcon A, lotrafilcon B, mafil N',N',N', N"-hexa(2-pyridyl)-1,3,5-tris(aminomethyl)ben con A, mesifilcon A, methafilcon B, mipafilcon A, nelfilcon Zene, crown ethers, ligand containing knots, catenands, and A, netrafilcon A, ocufilcon A, ocufilcon B, ocufilcon C, mixtures thereof. ocufilcon D. ocufilcon E, ofilcon A, omafilcon A, oxyfilcon 33. The method of claim 31 wherein the oxidative stabi A, pentafilcon A, perfilcon A, pevafilcon A, phemfilcon A, lization agent is selected from the group consisting of US 2008/0085922 A1 Apr. 10, 2008

2.2.2".6,6'6"-Hexa-(1,1-dimethylethyl)4,4',4'-(2,4,6-trim said patient said an administration system comprising said ethyl-1,3,5-benzenetriyl)-trismethylene-triphenol (Irganox anti-allergic agent, wherein said administration system 1330), 1.3.5tris(3,5-di(1,1-dimethylethyl)4-hydroxyben releases to said patient a dosing effective amount of an Zyl-1H.3H,5H- 1,3,5-triazine-2,4,6-trione, pentaerythrityl anti-allergic agent. tetrakis3-3,5-di(1,1-dimethylethyl)-4-hydroxyphenyl 41. The method of claim 40 wherein the symptoms are propionate), octadecyl-3-3,5-di(1,1-dimethylethyl)-4-hy alleviated for about 5 minutes to about 24 hours. droxyphenyl-propionate, tris(2,4-di(1,1-dimethylethyl)- 42. The method of claim 40 wherein the symptoms are phenyl-phosphite, 2,2'-di(octadecyloxy)-5,5'-spirobi (1,3,2- alleviated for greater than about 12 hours. dioxaphosphorinane), dioctadecyl disulphide, didodecyl-3, 43. The method of claim 40 wherein the symptoms are 3'-thiodipropionate, dioctadecyl-3,3'-thiodipropionate, alleviated for about 12 hours to about 24 hours. butylhydroxytoluene, ethylene bis3.3-di3-(1,1-dimethyl 44. The method of claim 40 wherein the symptoms are ethyl)-4-hydroxyphenylbutyrate and mixtures thereof. alleviated for greater than about 24 hours. 34. The method of claim 31 wherein the oxidative stabi 45. The method of claim 40 wherein the dosage effective lization agent is selected from the group consisting of DTPA, amount is about 1 lug to about 20 Jug. CaNaDTPA, ZnNaDTPA, and CalDTPA. 35. The method of claim 31 wherein the ophthalmic 46. The method of claim 40 wherein the dosage effective device is etafilcon A the anti-allergic agent is ketotifen its amount is released from about 1 minute to about 300 pharmaceutically acceptable salts or mixtures thereof and minutes. the oxidative stabilization agent is selected from the group 47. The method of claim 40 wherein about 2 ug to about consisting of DTPA, CaNaDTPA, ZnNaDTPA, and 16 Jug is released in about 60 minutes. CalDTPA. 48. The method of claim 40 the administration system is 36. An ophthalmic device comprising about a localized a soft contact lens comprising a minimum effective amount amount of an anti-allergic agent. of an anti-allergic agent, wherein said the administration 37. The device of claim 36 wherein the localized amount system releases about 10% to about 75% of the anti-allergic is about 2 Lig to about 20g and said localized amount is in agent in about 60 minutes from administering said admin contact with the conjunctiva. istration system to the eye of a patient. 38. A method of alleviating the symptoms of allergic 49. The method of claim 48 wherein the administration conjunctivitis comprising administering to a patient an oph system comprises etafilcon A and ketotifen. thalmic device comprising about a localized amount of an 50. The method of claim 40 wherein the administration anti-allergic agent. system is a Soft contact lens comprising etafilcon A and a 39. The method of claim 38 wherein the localized amount minimum effective amount of ketotifen, wherein said the is about 2 Lig to about 20g and said localized amount is in administration system releases about 10% to about 75% of contact with the conjunctiva. ketotifen in about 60 minutes from administering said 40. A method alleviating the symptoms of allergic con administration system to the eye of a patient. junctivitis in a patient for an extended period of time, wherein said method comprises administering to the eye of k k k k k